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Review

Targeting the Cellular Prion Protein as a Biomarker for Stem Cells, Cancer, and Regeneration

by
Niccolò Candelise
1,
Nicola Salvatore Orefice
2,3,
Elisabetta Mantuano
4 and
Stefano Martellucci
4,*
1
Independent Researcher, National Center for Drug Research and Evaluation, Italian National Institute of Health (ISS), 00161 Rome, Italy
2
Department of Anatomy and Neurosciences, Amsterdam University Medical Centers, Location VU Medical Center, Amsterdam Neuroscience, 1081 HZ Amsterdam, The Netherlands
3
MS Centrum Amsterdam, Amsterdam University Medical Centers, Location VU Medical Center, 1081 HZ Amsterdam, The Netherlands
4
Department of Life Sciences, Health, and Health Professions, Link Campus University, 00165 Rome, Italy
*
Author to whom correspondence should be addressed.
Biologics 2026, 6(1), 1; https://doi.org/10.3390/biologics6010001
Submission received: 22 October 2025 / Revised: 11 December 2025 / Accepted: 18 December 2025 / Published: 24 December 2025
(This article belongs to the Section Protein Therapeutics)
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Abstract

The cellular prion protein (PrPC) displays a functional repertoire that extends well beyond its classical link to transmissible spongiform encephalopathies. Abundant in the nervous system and localized within lipid raft microdomains, PrPC has emerged as a multifunctional signaling platform that regulates cell differentiation, neurogenesis, neuroprotection, and synaptic plasticity. Recent evidence highlights its dynamic expression in stem cell populations, where it participates in multimolecular complexes that control lineage commitment, particularly during neuronal differentiation. PrPC expression tightly correlates with stem cell status, making it a promising biomarker of stemness and developmental progression. Through interactions with growth factors, extracellular matrix components, and synaptic proteins, PrPC functions as a molecular integrator of signals essential for tissue repair and regeneration. Preclinical studies demonstrate that recombinant PrPC can stimulate neurogenesis and tissue repair, while monoclonal antibodies modulate its physiological and pathological functions. Likewise, cell-based therapies leveraging PrPC-enriched stem cells or PrPC-dependent signaling profiles have shown promise in models of neurodegeneration and ischemia. Conversely, dysregulated PrPC expression has also been observed in solid tumors, where it contributes to cancer cell survival, proliferation, metastasis, and therapy resistance, reinforcing its role as a regulator of cell fate and an oncological target. This review integrates stem cell biology, tissue regeneration, and oncology into a unified framework, offering a novel perspective in which PrPC emerges as a shared molecular hub governing both physiological repair and pathological tumor behavior, opening previously unrecognized conceptual and translational opportunities.

1. Introduction

The study of prion proteins emerged from neuropathology. Between the 1950s and the 1970s, neurodegenerative disorders such as Scrapie in sheep, Kuru in Papua New Guinea, and Creutzfeldt–Jakob disease (CJD) in humans were classified as “slow transmissible diseases of the central nervous system (CNS)”, yet the infectious agent remained elusive. The pioneering discovery occurred in 1982, when Prusiner introduced the term “prion” (proteinaceous infectious particle) to describe the abnormal isoform of the protein (scrapie prion protein: PrPSc) responsible for the disease [1,2]. This reframed an entire field, shifting focus to protein misfolding, templated conversion, and seeded aggregation.
For years, efforts centered on the biophysics and cell biology of misfolding and propagation, while the cellular prion protein (PrPC) was studied primarily as a precursor to PrPSc [3,4,5]. Postmortem analyses consistently revealed PrPSc aggregates in the CNS and peripheral tissues [6,7]. PrPC is abundant in several endocrine and exocrine tissues, and protease-resistant PrP (PrPres) accumulates in the pituitary in prion disease [8,9]. In parallel, studies in transgenic models showed that other proteopathic aggregates (e.g., the amyloid β peptide, Aβ) can spread in a manner analogous to prions, emphasizing generalizable principles of seeded aggregation across neurodegenerative disorders [10,11,12].
The cloning of the PRNP gene revealed that this protein is an endogenous component of mammalian biology, conserved across species and implicated in diverse physiological processes [13,14]. Studies have demonstrated that there are two further members of the prion gene family: Prnd, which encodes for the testis-specific protein Doppel, involved in the male reproductive system; and Sprn, which encodes for the newest PrP-like protein Shadoo, expressed in the CNS [15].
The emergence of PrP knockout models [16,17] prompted the exploration of PrP physiological roles. Martins et al. predicted a specific cell-surface receptor to mediate the endocytosis of PrPC and prions; antibodies against this receptor stained the surface of mouse neurons and recognized a 66-kDa membrane protein that binds PrPC both in vitro and in vivo [18]. Although its precise biological function remained uncertain [19], interest in PrPC grew rapidly [20,21].
The first PRNP knockout mouse was developed in 1992 by Büeler and co-workers [16] using a mixed C57BL/6 J × 129/Sv(ev) background, called Zurich I. This model showed that PrPC was dispensable for the development and displayed normal behavior with subtle alterations. This evidence prompted researchers to generate different PRNP null murine models by expanding the extent of PRNP locus deletion. In sharp contrast, these models (e.g., Zurich II) revealed progressive cerebellar neurodegeneration, later associated with the depletion of flanking genes such as Doppler [22,23]. The advent of gene editing in modern times led to the development of the Zurich III PRNP0/0 mouse, a co-isogenic line on a C57BL/6J background. By avoiding the removal of flanking regions and having a pure background, this model is nowadays considered the most informative for the understanding of the biological function of PrPC, revealing functions encompassing synaptic physiology, neuroprotection, neuronal survival, and stress responses [24,25,26].
Knockout models ranging from zebrafish to mice further demonstrated their involvement in diverse nervous system functions, including peripheral nerve myelination and protection against neurotoxic insults [27]. Contemporary studies have expanded this view, linking PrPC in stem cell biology, cell fate regulation, and regenerative processes [28,29].
Today, PrPC is increasingly recognized as a signaling hub that integrates extracellular cues from growth factors, adhesion molecules, and the extracellular matrix to regulate neurogenesis, differentiation, and tissue repair [26,30,31]. Significantly, its dynamic expression in stem cell compartments and its involvement in cancer biology position PrPC both as a biomarker of stemness and as a therapeutic target.
This review moves beyond pathology to highlight PrPC as a regulator of regeneration, focusing on its dual role in stemness and cancer, with translational implications for regenerative medicine and oncology.

2. Structure, Localization, and Signaling of the Cellular Prion Protein

PrPC is widely expressed, with the highest levels in the central and peripheral nervous systems from development through adulthood [31,32].
In humans, PrPC consists of approximately 250 amino acid residues. After synthesis, it undergoes several post-translational modifications, including at least three proteolytic cleavages and shedding events, resulting in fragments from both the N- and C-terminal regions [33,34]. Multiple enzymes have been implicated in these cleavages, particularly members of the ADAM (a-disintegrin and metalloproteinase) family [35].

2.1. Cleavage and Shedding of Prion Protein

α-cleavage takes place at residues 111/112, generating a soluble N-terminal fragment (N1) and a GPI-anchored C-terminal fragment (C1). This cleavage occurs constitutively in 10–50% of PrPC molecules but can be enhanced by various stimuli [36]. The precise cellular site and proteases responsible remain debated, with evidence pointing to endosomal/lysosomal compartments, late secretory pathway, and the plasma membrane [37,38]. The N-terminal domain includes an octapeptide repeat region that binds Cu2+ ions and contributes to oxidative stress resistance [39]. The central region harbors a lysine-rich cluster and a hydrophobic segment, while the C-terminal globular domain is organized into three α-helices, two short β-sheets, and connecting loops, stabilized by a disulfide bond between residues 179 and 214 [40]. N-linked glycans can be added at residues 181 and 197 [41].
β-cleavage occurs between residues 89/90, generating fragments N2 (soluble) and C2 (GPI-anchored). It occurs at low basal levels, possibly catalyzed by reactive oxygen species (ROS) acting on surface PrPC, but is enhanced during PrPSc formation [42,43,44].
γ-cleavage occurs near the GPI anchor attachment site (residue 230), releasing most of the protein into the extracellular medium [45,46,47].
In addition to the well-characterized α-, β-, and γ-cleavages, low-abundance proteolytic events of PrPC have been reported, suggesting further layers of post-translational regulation. These minor cleavage products, although occurring at low frequency, appear to modulate PrPC’s conformational stability and membrane dynamics. Early-stage unfolding of the GPI-anchored human prion protein exposes typically buried regions, rendering PrPC susceptible to additional cleavage near the C-terminus. Such events may contribute to the generation of truncated forms with altered structural flexibility or distinct subcellular localization [48]. Other authors further proposed that these low-level cleavages could have physiological relevance by influencing PrPC turnover, trafficking, and its capacity to engage in signaling complexes, while dysregulation of these proteolytic pathways may predispose PrPC to pathogenic misfolding under stress conditions [27].

2.2. GPI Anchor and Lipid Raft Localization

PrPC is a GPI-anchored glycoprotein that localizes to plasma membrane lipid rafts, dynamic microdomains enriched in cholesterol, and glycosphingolipids [49,50,51], where it engages with a variety of partners, including extracellular matrix components and soluble ligands [52,53].
Lipid rafts are enriched in signaling molecules and serve as regulatory platforms for protein-protein and protein-lipid interactions [54]. Perturbing raft composition with methyl-β-cyclodextrin (MβCD) alters signaling pathways, such as Akt activation, during differentiation [55]. In hematopoietic stem cells (HSCs), raft clustering or disruption modulates differentiation, mobilization, and quiescence [56].
Rafts can contain incomplete signaling pathways that become activated upon receptor recruitment or suppressed by modulation of intrinsic activity [57]. Their dynamic assembly and disassembly into functional clusters make them versatile hubs for PrPC-mediated signaling.

2.3. PrP Signaling Interactions in Physiological Processes

The preferential localization of PrPC in lipid rafts suggests a role in signal transduction, similar to other raft-associated GPI-anchored proteins. Unlike typical receptors, however, PrPC lacks an intracellular domain to transmit signals directly [58,59]. This has led to extensive efforts to identify physiological PrPC ligands and receptors [60].
PrPC-dependent signaling was first demonstrated by antibody-mediated cross-linking in the murine 1C11 neuronal differentiation model, which revealed a caveolin-1-dependent coupling of PrPC to the tyrosine kinase Fyn, a process closely related to cellular maturation. In addition, both neurotransmitter-associated functions and morphological changes appear to be involved. Clathrin may also contribute to the PrPC-dependent signaling mechanism leading to Fyn activation. Notably, PrPC-dependent Fyn activation was observed only in differentiated serotonergic or noradrenergic 1C11 progeny [19].
Subsequent studies identified additional PrPC interactors. The extracellular matrix protein laminin, along with the laminin receptor precursor and laminin receptor, binds to PrPC and mediates cell adhesion [61,62]. The co-chaperone stress-inducible protein 1 (STi-1) was identified as a PrPC ligand through antigen screening, and its binding was confirmed by pull-down and co-immunoprecipitation. In hippocampal neurons, STi-1 treatment activated ERK1/2 and promoted neuritogenesis and survival [63,64].
PrPC also interacts with NCAM in hippocampal neurons, recruiting transmembrane NCAM isoforms into lipid rafts and activating Fyn through receptor protein tyrosine phosphatase [65]. The NCAM-PrPC interactions promote Fyn-dependent axon elongation both in cis and via recombinant PrP applied in trans. These findings established PrPC as a signaling molecule involved in nervous system development [66].
PrPC exhibits complex signaling biology, engaging in receptor/ligand interactions with several partners that assemble within lipid rafts. Among these, the low-density lipoprotein receptor-related protein-1 (LRP1) has emerged as a central co-receptor in PrPC-dependent signaling. LRP1 is a multifunctional receptor [67] belonging to the LRP family [68,69], widely recognized for its roles in cell signaling and mitochondrial homeostasis [70,71]. It also contributes to neuroinflammation and the regulation of neuropathic pain [72], making it one of the most intriguing PrPC partners.
A growing body of work demonstrates that LRP1 orchestrates PrPC signaling across multiple cell types. Soluble PrPC (S-PrP) and PrPC-derived peptides activate ERK1/2, promote neurite outgrowth, and attenuate inflammatory gene expression through LRP1–N-methyl-d-aspartate receptor (NMDA) receptor assemblies in lipid rafts. [73,74]. Co-receptor requirements vary with different ligands, such as S-PrP, α2-macroglobulin, or tissue-type plasminogen activator (t-PA), reflecting the modular nature of the LRP1 signaling platform [75].
Furthermore, a minimal LRP1-binding motif within PrPC (residues 98–111) is sufficient to replicate full-length PrPC activities, triggering ERK1/2 signaling in macrophages, microglia, and PC12 cells, and even rescuing LPS hypersensitivity in PRNP−/− mice [76]. These studies provide a concrete molecular foundation for PrPC’s pleiotropic effects in neuronal survival, immune regulation, and neurorepair.
Complementary evidence from human SK-N-BE2 neuroblastoma cells showed that PrPC and LRP1 form a lipid raft–dependent multimolecular signaling complex that is essential for tPA-driven neuritogenic signaling [77].
Together, these findings define a PrPC/LRP1 axis that integrates extracellular cues within lipid rafts, linking prion protein biology to neuronal plasticity, inflammation control, and regenerative processes.
Besides the core biological functions described above and illustrated in Figure 1, PrPC is increasingly recognized as a hub for misfolded proteins, suggesting a potential role in either buffering toxic proteins or enhancing their transmission by acting as a generalized receptor.
Indeed, expression cloning identified PrPC as a high-affinity receptor for Aβ oligomers in neurons. Anti-PrP antibodies block Aβ binding and restore synaptic plasticity in hippocampal slices, suggesting that PrPC mediates Aβ-induced synaptic dysfunction [78]. Recently, a study in transgenic mice has linked PrPC to α-synuclein internalization via a clathrin-mediated mechanism, suggesting a role in the spreading of other misfolded proteins [79]. Additional studies reported time- and region-dependent increases in PrPC expression and oligomerization during opiate abstinence, indicative of a role in hippocampal plasticity and stress resilience [80].
Overall, the cellular prion protein appears to be at the crossroads of many biological functions. On the one hand, PrPC serves as a neuroprotective hub, connecting different cellular pathways; on the other hand, it may promote the spreading of pathogenic proteins and trigger neuroinflammation should their function be compromised.

3. Prion Potency in Stem Cell Biology

PrPC is an essential protein that interacts with numerous partners to regulate critical biological functions, including stem cell self-renewal, differentiation, pluripotency gene expression, and proliferation [81,82,83,84]. These processes vary between embryonic and adult stem cells, indicating tissue-specific regulation of PrPC expression [85].

3.1. Embryonic Stem Cells and Early Development

The spatial and temporal expression of PrPC during embryogenesis provides important insights into its physiological functions [86,87].
In the developing mammalian neuroepithelium, PrPC was shown to colocalize with neural markers such as nestin and MAP-2, supporting a role in early neurogenesis. Studies using embryonic stem cells (ESCs) confirmed that PrPC appears to be upregulated during neural differentiation, with its expression positively correlated with nestin expression [88].
In human embryonic stem cells (hESCs), PrPC plays a role in controlling cell cycle dynamics, self-renewal, and differentiation. Silencing PrPC resulted in altered cell-cycle progression and suppressed ectodermal differentiation, whereas overexpression inhibited lineage commitment across all three germ layers while maintaining proliferation. Moreover, in hESCs undergoing spontaneous differentiation, PrPC overexpression prevented the differentiation into all three germ-layer lineages and sustained a high proliferation rate [89].
In mouse embryos, PrPC is more expressed in ESCs than in somatic cells, with its presence detected in both neural and non-neural tissues, such as the kidney, amniotic membranes, and intestine [90,91]. Functional redundancy with related proteins has been suggested: loss of both PrP and Shadoo is lethal in early embryogenesis, particularly in trophoblastic lineages [92].
Recombinant PrP (recPrP) was reported to stimulate neuritogenesis, synapse formation, and axon elongation in embryonic hippocampal neurons via protein kinase C (PKC)- and Src-dependent pathways, while inhibitors of PKC and of Src kinases abolished axon elongation in response to recPrP stimuli [66].
In cattle, PRNP transcript abundance mirrors the pattern of PrP protein immunolabeling throughout gestation, with predominant expression in the brain, ganglia, spinal cord, and peripheral nerves. Similar to observations in mice, PrPC is abundant in differentiated neural cells located in the marginal zones of the CNS, whereas mitotically active progenitors in periventricular regions show little to no expression [93]. This pattern appears to continue into adulthood, with PrPC largely localized within the gray matter [94].
In zebrafish, PrP transcripts remain detectable as maternal RNA up to the gastrulation stage [95]. Furthermore, gene-deletion studies have shown that these PrP homologs are required for embryo viability in zebrafish, a finding that contrasts with observations made in mouse models [96]. Indeed, loss of PrP in zebrafish embryos causes developmental arrest during gastrulation, accompanied by impaired tissue integrity and reduced cell–cell adhesion, ultimately leading to abnormal brain formation in the absence of PrP [97].
Together, these findings suggest that PrPC plays a conserved role in early embryonic development, acting as a regulator of self-renewal and differentiation across multiple species. During embryogenesis, its expression parallels neurogenesis and lineage commitment, maintaining pluripotency and tissue integrity across species.

3.2. Adult Stem Cell Types and Lineages

In the adult brain, PrPC expression correlates with the differentiation of neural precursors into neurons. During constitutive adult neurogenesis in the hippocampal dentate gyrus (DG) and the olfactory bulb, PrPC is expressed adjacent to proliferative zones but not in dividing cells. Its levels were shown to increase during neuronal differentiation and enhanced precursor proliferation in vivo [28].
Mechanistic studies have linked PrPC to Notch and EGF-R signaling pathways, which are critical for maintaining neural stem cell architecture [98,99]. The modulation of Notch/EGF-R pathway activity in neural progenitors indicates the involvement of PrPC in progenitor/stem cell signaling cascade networks. In mesenchymal stem cells (MSCs), PrPC interacted with EGF-R to activate ERK1/2 and Akt, while PrPC silencing reduced the expression of neuronal markers such as βIII-tubulin, NFH, and GAP-43. Conversely, treatment with recombinant PrP enhanced neuronal differentiation [100]. This multimolecular complex is formed within lipid rafts, which have been shown to contribute to the neuronal differentiation of MSCs [55,101]. In contrast, treating the cells with recombinant PrP was proposed to enhance this expression [102].
Results have shown that PrP is capable of modulating self-renewal and proliferation in neural stem cells. PrP genes play a non-redundant role in regulating early differentiation and the complexity of the interactions that PrPC engages in during those processes [103]. In light of the established roles of these various actors in the self-renewal of neuroprogenitors, this global cascade ultimately supports PrPC’s role in maintaining neural stem cells.
In the hematopoietic system, PrPC is expressed in bone marrow and lymphoid cells at varying levels depending on maturation stage [104]. It is most abundant in primitive HSCs, where it supports long-term repopulating capacity [105]. Its preferential expression in early progenitors in bone marrow and thymus suggests a stage-specific regulation during hematopoiesis [106]. In humans, PrPC is detected in CD34+ stem progenitor cell populations in human bone marrow [107], and in immature CD43+B220−IL-7R− cell-enriched progenitors in mice [106].
PrPC is a conserved regulator of stem cell fate that integrates signals that control self-renewal, proliferation, and differentiation. Collectively, PrPC links developmental and regenerative processes, acting as a molecular integrator of stem cell maintenance and differentiation.

3.3. From Pluripotency to Differentiation: PrPC as a Biomarker in Stem Cells

The expression of PrPC is dynamically regulated during stem cell differentiation, positioning it as a candidate biomarker of stemness.
Among the proteins involved in neuronal differentiation, several studies have reported a correlation between PrP expression and maturation status. For instance, PrPC expression is modulated during neuronal differentiation of mesenchymal stem cells, making PrPC a marker of stemness in neuronal maturation [108].
PrPC has also been used in combination with PDGFRα to isolate cardiac progenitor cells from pluripotent stem cells [109]. This approach provides a strategy to enrich lineage-restricted populations while excluding undifferentiated cells, thereby improving the safety of transplantation approaches [110].
Studies examining PrPC in primary cultures and different skeletal muscle tissues have shown that the muscle isoform of the protein is functionally associated with myogenic processes. Supporting evidence includes observations from in vitro myocyte differentiation models, which recapitulate the early phases of muscle development and were the first to reveal this connection [111]. PrPC could be a good candidate as a biomarker for immature myocytes at the first stages of differentiation.

4. Prion Protein: From Stem Cells to Cancer

The contribution of PrPC to cell proliferation extends beyond stem and progenitor cells. Overexpression of PrPC has been documented in multiple tumor types, where it promotes tumor progression by enhancing proliferation, invasion, and metastasis. PrPC also regulates the properties of cancer stem cells (CSCs) through interactions with established stemness-associated proteins [112].
Consistent with its role in stemness, PrPC is enriched in subpopulations of tumor-initiating cells [113]. Recent findings implicated PrPC in the biology of glioblastoma, breast, prostate, gastric, and colorectal cancers [114] (Table 1).

4.1. Implications in Cancer Cell Survival, Proliferation, Invasion, and Metastasis

4.1.1. Gastric Cancer (GC)

PrPC expression was found to be elevated in gastric adenocarcinoma compared with normal tissue and correlated with tumor grade and progression. Functional studies in gastric cancer cell lines revealed that PrPC suppressed ROS accumulation, reduced apoptosis, and upregulated Bcl-2, hence acting as an anti-apoptotic factor [115]. Overexpression of PrPC promoted the proliferation and G1/S transition via PI3K/Akt activation and Cyclin D1 induction, with the octapeptide repeat region required for this effect [116]. PrPC also enhanced adhesion, invasion, and metastasis through the MEK/ERK-MMP11 axis, mediated by its N-terminal domain [117].

4.1.2. Glioblastoma (GBM)

PrPC expression is directly correlated with spherogenesis, in vivo tumorigenicity, and the proliferation rate of GBM cancer stem cells, the subpopulation responsible for the development, progression, and recurrence of most malignancies [118,119]. Moreover, reducing PrPC expression led to diminished levels of stemness and self-renewal markers and simultaneously triggered the activation of differentiation programs. These findings indicate that PrPC helps maintain the stem-like characteristics of human GBM CSCs, and that its suppression shifts the cells toward a more differentiated, less tumorigenic state [120]. In GBM cells, PrPC has been shown to modulate the expression of genes involved in migration, proliferation, and stemness-related pathways. Its depletion reduces GBM cell growth, compromises glioblastoma stem cells (GSCs) self-renewal, and diminishes migratory and invasive capacities, underscoring its key functional role in glioblastoma biology [121]. Additionally, engagement of cellular PrPC with its ligand, heat shock protein (HSP) 70/90, induced proliferation in glioblastoma cells [122].

4.1.3. Colorectal Cancer (CRC)

PrPC has been identified as a modulator of colorectal tumor growth and survival. Its interaction with heat shock organizing protein (HOP) was shown to induce ERK1/2 phosphorylation, thereby enhancing migration and invasion, whereas the disruption of the PrPC-HOP complex resulted in the inhibition of these processes [123]. Additionally, it has been demonstrated that a HOP peptide, which can bind PrPC and disrupt the PrPC-HOP interaction, inhibits the migration and invasion of CRC cells [124]. Also, PrPC accelerated the colorectal cancer metastasis via the Fyn-SP1-SATB1 axis [125]. It has been documented that a PrPC nuclear pool is present in SW480 and Caco-2/TC7 adenocarcinoma cell lines, as well as in HIEC-6, normal crypt-like cells. PrPC is targeted toward desmosomes or the nucleus in intestinal epithelial cells. Nuclear PrPC acted as a coregulator, able to finely tune the final steps of Wnt signaling and potentially other related pathways involved in the regulation of intestinal epithelial homeostasis [126].

4.1.4. Other Cancers

PrP is also involved in the development of Merlin-deficient tumors since it is overexpressed in human Merlin-deficient mesothelioma and in human Merlin-deficient meningiomas. Furthermore, PrPC appears to contribute to increased proliferation, cell-matrix adhesion, and survival in schwannoma cells [127]. PrPC is expressed in human pancreatic cancer (PC) cell lines. However, in these cell lines, the PrP is incompletely processed and exists as pro-PrP, which binds to filamin A (FLNa), a cytolinker for cell surface receptors to actin filaments. The binding of pro-PrP to FLNa was reported to disrupt FLNa’s normal functions, altering the cytoskeleton and signaling machinery, and resulting in more aggressive tumor cell growth [128].
Table 1. PrPC Key Interacting Partners in Physiological Regeneration and Cancer.
Table 1. PrPC Key Interacting Partners in Physiological Regeneration and Cancer.
Functional ContextCell/TissuePrP Interacting PartnerFunctional OutcomeRef.
Physiological regenerationEmbryonic Stem CellsPKC, SrcPromotion of neuritogenesis, Synapse formation, Axon elongation[66]
Nestin, MAP-2Promotion of early neurogenesis[88]
Adult Stem CellsNotch/EGF-RModulation of neural stem cell self-renewal and proliferation[98,99]
EGF-RPromotion of neuronal differentiation[100]
CancerGastric CancerBcl-2Anti-apoptotic activity[114,115]
PI3K/Akt, Cyclin D1Increased proliferation[116]
MEK/ERK-MMP11Promotion of adhesion, invasion, and metastasis[117]
GlioblastomaHSP70/90Induction of proliferation[122]
Colorectal CancerHOPEnancing migration and invasion[124]
Fyn-SP1-SATB1Acceleration of cancer metastasis[125]
Pancreatic CancerFLNaIncreased tumor cell aggression[128]

4.2. PrPC in Therapy Resistance and Poor Prognosis

PrPC plays multifaceted roles in cancer, acting as a promoter of survival and therapy resistance. It supports CSC phenotypes, regulates key signaling pathways (PI3K/Akt, MEK/ERK, JNK, Wnt/β-catenin), and mediates resistance to apoptosis and chemotherapy. Its overexpression correlates with poor prognosis in multiple cancers, including gastric, colorectal, breast, glioblastoma, lung, and pancreatic tumors [129].

4.2.1. Breast Cancer

Analysis of multiple human breast carcinoma cell lines showed that PrPC expression strongly correlates with resistance to TNF-induced cytotoxicity. Moreover, forced expression of human PrPC in previously TNF-sensitive MCF7 cells rendered them resistant to TNF-mediated cell death, an effect linked to altered mitochondrial cytochrome c release and changes in nuclear morphology. PrPC shields breast cancer cells from TNF-mediated cell death by altering mitochondrial apoptotic signaling. Collectively, the results support a role for PrPC in promoting tumor resistance [130,131]. Clinically, PrPC expression is associated with estrogen receptor (ER)-negative disease. Ten-year survival comparisons and multivariate analyses showed that ER-negative patients with PrPC-positive tumors did not seem to benefit from adjuvant chemotherapy [132], showing that PrPC could be a predictive factor for the benefit of adjuvant chemotherapy in ER-negative disease. In adriamycin-resistant breast cancer models, PrPC engages CD44 at the cell surface, an interaction that drives increased proliferation and migration [133]. Additionally, multidrug-resistant breast cancer cells were reported to evade cytotoxic attacks from P-glycoprotein substrates, suggesting a role for the interaction between P-glycoprotein and PrPC in this process [134].

4.2.2. Lung Adenocarcinoma

Expression-profiling studies have identified PRNP among genes differentially expressed between in situ and invasive lung adenocarcinoma, with PrPC levels markedly higher in highly invasive cell lines than in their less invasive counterparts. Silencing PrPC in lung adenocarcinoma cells reduced lamellipodium formation, impaired migration and invasion in vitro, and diminished metastatic colonization in vivo. PrPC expression correlated with JNK phosphorylation, and pharmacologic inhibition of JNK attenuated these PrPC-dependent effects. In addition, the transcription factor NFIL3 was shown to activate the PRNP promoter, thereby promoting migration and invasion in a PrPC-dependent manner. Elevated NFIL3 expression in patient tumor samples was likewise associated with invasive disease. Collectively, these findings indicate that the NFIL3-PrPC axis, acting through JNK-dependent control of lamellipodium dynamics and cell motility, is a key driver of lung adenocarcinoma invasiveness and metastatic potential [135].

4.2.3. Gastric Cancer

Du et al. demonstrated, using the adriamycin-sensitive gastric carcinoma line SGC7901 and its resistant derivative SGC7901/ADR, that PrPC contributes to the multidrug-resistant phenotype. Forced expression of PrPC rendered SGC7901 cells resistant to both P-gp-dependent and P-gp-independent chemotherapeutic agents, whereas PrPC silencing partially restored drug sensitivity in SGC7901/ADR cells. PrPC markedly increased P-gp expression, without affecting MRP or glutathione S-transferase π levels. It was further proposed that PrPC helps attenuate adriamycin-induced apoptosis, accompanied by modulation of Bcl-2 and Bax expression [136]. Also, studies have highlighted a significant association between PrPC and MGr1-Ag/37LRP in gastric cancer, suggesting that both proteins hold prognostic value. Their combined expression may help identify patients at increased risk of poor clinical outcomes and could assist in determining which individuals are more likely to benefit from adjuvant therapeutic strategies [137].

4.2.4. Colorectal Cancer

A PrPC-positive subset of CD44+ colorectal cancer stem cells has been identified, characterized by a heightened ability to regenerate tumors. PrPC has further been shown to drive epithelial-to-mesenchymal transition through the ERK2 (MAPK1) pathway, thereby enhancing metastatic potential [138]. Consistent with this function, PrPC is preferentially upregulated in the mesenchymal, poor-prognosis subtype of CRC, providing mechanistic support for its role in promoting mesenchymal features within colorectal tumors [139,140]. Building on these findings, proof-of-concept studies have demonstrated that antibody-based neutralization of PrPC can effectively target the mesenchymal subtype of colorectal cancer, highlighting its potential as a therapeutic approach [141]. PRNP expression appears to be modulated by upstream inputs from both the Wnt–β-catenin and glucocorticoid pathways [142]. Moreover, 5-fluorouracil-resistant colorectal cancer cells were shown to express high levels of PrPC, which facilitates anti-cancer drug resistance by regulating signaling pathways that govern survival, proliferation, and apoptosis [143]. In human colon cancer cell line (SNU-C5) and in oxaliplatin-resistant cell line (SNU-C5/Oxal-R), authors showed that melatonin induced oxaliplatin-mediated apoptosis through inhibition of cellular prion protein [144]. Also, PrPC appears to facilitate carcinogenic behavior in colon cancer cells by augmenting their invasive capacity and diminishing their susceptibility to doxorubicin-triggered apoptosis [145].

4.2.5. Other Contexts

In human pancreatic cancer, PrPC is expressed in ductal adenocarcinoma and contributes to the aggressiveness of the cancer [146]. Evidence suggests that PrPC can reduce integrin αvβ3 expression and activation, a shift that is linked to increased cellular aggressiveness and may contribute to metastatic progression. [147]. Elevated PrPC levels correlate with the emergence of tumor cell traits that confer resistance to TNF-α– and TRAIL-mediated cell death, as well as reduced sensitivity to chemotherapeutic drugs, including paclitaxel and anthracyclines [148].
Broadly, PrPC contributes to tumor progression and therapy resistance across multiple cancers. Overexpressed in gastric, colorectal, glioblastoma, breast, lung, and pancreatic tumors, PrPC appears to promote oncogenic signaling through PI3K/Akt, MEK/ERK, Wnt/β-catenin, and JNK pathways. It seems to sustain cancer stem cell properties, supporting self-renewal and epithelial-to-mesenchymal transition. Functionally, PrPC could act as an anti-apoptotic factor by modulating Bcl-2, Bax, and ROS levels, and could interact with partners such as HSPs, HOP, and FLNa to remodel the cytoskeleton and enhance migration. Its overexpression seems to correlate with poor prognosis and multidrug resistance, highlighting its dual role as both a marker of tumor aggressiveness and a potential therapeutic target for neutralization strategies.

5. PrPC as a Therapeutic Target in Cancer Treatment and Regenerative Medicine

PrPC is increasingly recognized as a multifunctional molecule with significant therapeutic potential, and strategies to target it are now being explored in both oncology and regenerative medicine.

5.1. Cancer Treatment

Given the large number of interactors, PrPC has been proposed as central to several signaling pathways that can promote or halt tumor progression, depending on the partner and cell type.
In glioblastoma, the disruption of the PrPC-HOP interaction was shown to impair tumor growth, to attenuate cognitive decline, and to improve the overall survival, highlighting this pathway as a therapeutic target to suppress CSCs and improve patient outcomes [149]. However, targeting PrPC with anti-prion antibodies led to rapid neurotoxicity in mice and in organotypic cerebellar slices, further exacerbated by PrPC overexpression [150], suggesting that disrupting PrPC interactions may be harmful rather than neuroprotective.
In colon cancer, antibodies against PrPC exhibit variable anti-proliferative activity against human colon cancer cells. Treatment increased apoptosis, as evidenced by reduced Bcl-2 expression, and inhibited tumor growth in vivo [151]. In colon cancer cell lines and human colorectal tissue exposed to hypoxia, PrPC was found to accumulate and increase tumorigenicity [152]. This event was shown to be downstream of the increased expression of the HSP family A (HSP70) member 1-like, HSPA1L, which in turn increased the stability of the hypoxia inducible factor 1 α. HSPA1L was further found to bind and inhibit the E3 ligase activity of the glycoprotein GP78, reducing PrPC ubiquitination and degradation [112].
Organoid studies further underscore the relevance of PrPC. Intestinal crypts from PRNP-knockout mice formed fewer and smaller organoids compared to wild-type controls. These organoids displayed normal architecture and E-cadherin/β-catenin staining but contained more apoptotic cells and underdeveloped crypt domains [126].
Together, these results highlight the potential of targeting PrPC or its regulatory partners as a potent anti-tumor strategy. Nevertheless, as aforementioned, the disruption of PrPC signaling pathways might be noxious, hence requiring the selective targeting of cancer cells to avoid potential unwanted effects in other tissues. To this end, both nanoparticles and antibody drug conjugates are emerging as promising approaches for direct targeting of cancer niches and avoidance of off-target effects [153,154,155].

5.2. Excitability, Tissue Repair, and Regeneration

Besides its roles in cancer modulation and progression, PrPC has also been linked to neuronal and tissue regeneration. In PC12 cells, PrPC activation through the Fyn pathway was shown to stimulate neurite outgrowth and cell differentiation [156]. Primary neurons cultured from PRNP0/0 mice displayed higher excitability due to a greater membrane impedance in PrPC null neurons [157]. In CRISPR-engineered mice to express G92N-mutated PrPC, hippocampal pyramidal neurons appeared necrotic. The mice developed seizures consistent with altered neuronal excitability, rescued by NMDA-R antagonists [158]. Moreover, PrPC was shown to contribute to peripheral myelin maintenance [159], neuronal iron uptake, and Ca2+ homeostasis in cerebellar granule neurons, as well as to the regulation of synaptic balance by binding copper ions [160]. Collectively, these functions position PrPC as a key player in the process of nerve regeneration and the regulation of overall neuronal excitability.
Beyond the nervous system, evidence has been collected on the role of PrPC in tissue regeneration. Studies in skeletal muscle demonstrated that PrPC deficiency slows regeneration of the tibialis anterior, an effect linked to the reduced activation of the p38 stress pathway and premature withdrawal of myogenic precursor cells from the cell cycle. Restoration of PrPC expression reversed these defects, supporting its role in muscle repair. [161].
Indirect evidence of PrPC on tissue regeneration has been gathered from its anti-oxidative activity. For instance, rats exposed to exogenous mitochondria and PrPC-overexpressing adipose-derived MSCs showed that MSCs reduced inflammation, oxidative stress, and mitochondrial damage following intracranial hemorrhage [162]. On a similar note, induced pluripotent stem cell clones derived from patients carrying the GPI-anchorless mutation of PrPC showed increased sensitivity to oxidative stress, suggesting a role in stress resilience [163]. Further evidence linking PrPC to oxidative stress comes from MScs, where PrPC-dependent activation of JAK2/STAT3 during hypoxia preconditioning enhances proliferation, stress resistance, and therapeutic efficacy in a murine hindlimb ischemia model [164]. Lastly, PrPC expression on hematopoietic stem cells supports engraftment and long-term self-renewal in serial transplantation assays [165] and protects hematopoietic progenitors against genotoxic stress [166].
Together, these context-dependent interactions highlight PrPC as a versatile modulator of cellular behavior across physiology, cancer biology, and therapy resistance (Figure 2).

6. Concluding Remarks

Across embryonic, adult, and lineage-specific stem cells, PrPC emerges as a highly conserved regulator of stem cell identity. During embryogenesis, its spatial and temporal expression patterns align with neurogenesis and germ layer specification, while loss-of-function studies in mice, cattle, and zebrafish reveal its essential contribution to tissue integrity, cell–cell adhesion, and early developmental viability. In adult systems, PrPC maintains neurogenic competence, modulates Notch and EGF-R signaling in neural progenitors, and sustains the long-term repopulating potential of hematopoietic stem cells, highlighting its evolutionarily conserved role in maintaining stem cell reservoirs and coordinating lineage progression. [28,98,105].
Functionally, PrPC integrates extracellular cues within lipid rafts, orchestrating downstream activation of ERK1/2, Akt, and JAK/STAT3 cascades to balance self-renewal and differentiation. This integrative capacity is mediated in part by LRP1, a multifunctional co-receptor that forms part of a PrPC-LRP1-NMDA receptor signaling triad. Recent work demonstrates that PrPC-derived peptides engage LRP1 to activate protective ERK signaling, promote neurite outgrowth, and suppress inflammatory responses in microglia and macrophages, effects that are abolished in PRNP−/− models [73,74,76]. These findings establish a molecular framework linking prion protein signaling to neurorepair and immunomodulation.
In the pathological context, the same molecular network can be co-opted by tumor cells, where PrPC expression confers selective advantages. Elevated PrPC sustains cancer stem cell (CSC) phenotypes, drives proliferation, epithelial–mesenchymal transition (EMT), and invasion, and activates PI3K/Akt, MEK/ERK, Wnt/β-catenin, and JNK pathways to promote multidrug resistance and survival under stress. High PrPC expression correlates with poor prognosis in gastric, colorectal, breast, glioblastoma, lung, and pancreatic cancers, identifying it as both a functional driver and a biomarker of aggressive phenotypes [118,129].
From a translational perspective, this duality of function places PrPC at the crossroads of oncology and regenerative medicine. In cancer, the inhibition of PrPC or the disruption of its complexes with LRP1 or Hop/STi-1 impairs tumor growth, reduces stemness, and restores chemosensitivity [141,149]. Conversely, in regenerative contexts, the upregulation or exogenous delivery of PrPC enhances tissue repair, mitigates oxidative stress, and improves the efficacy of stem-cell therapies in neural, muscular, and hematopoietic systems [161,162,164]. This context-dependent behavior underscores PrPC’s potential as a bidirectional therapeutic target, a molecule whose modulation must be finely tuned to either restrain oncogenic signaling or amplify regenerative outcomes.
Despite its translational potential, several limitations temper the use of PrPC as a biomarker or therapeutic target. Its expression is highly context-dependent, differing across tissues, developmental stages, and disease states, and its post-translational processing generates heterogeneous molecular species that further complicate its specificity. Moreover, PrPC activates distinct downstream pathways in regenerative [108,109,110,111] vs. oncogenic [118,129] contexts, underscoring the need for mechanistic discrimination before clinical application. Future studies should systematically map PrPC expression and processing across standardized platforms, including organoids, patient-derived xenografts, and single-cell profiling, and define the molecular determinants that shift its signaling between protective and pathological roles. Such validation will be critical to establishing PrPC as a reliable biomarker and a safe, actionable therapeutic target.
Taken together, PrPC can be redefined as a master regulator of cell fate, bridging pluripotency and lineage commitment in health while driving malignancy in disease. By integrating extracellular cues within lipid raft-associated signaling complexes and coordinating downstream molecular pathways, PrPC enables stem and progenitor cells to maintain a dynamic balance among self-renewal, differentiation, and survival. Its dual nature, protective and regenerative in physiological contexts, but pro-survival and tumorigenic under pathological conditions, highlights its context-dependent influence on cellular behavior. This functional versatility positions PrPC as a central node in cellular homeostasis and a promising therapeutic target at the crossroads of regenerative medicine and oncology, where precise modulation of its signaling may either enhance tissue repair or suppress tumor progression.
This review differs from previous syntheses by unifying stem cell biology, tissue regeneration, and oncology into a single, integrated framework centered on PrPC as a regulator of cell fate. While earlier reviews have examined PrPC in neurobiology or prion disorders, to our knowledge, none of them have systematically connected its roles in stemness, lineage commitment, regenerative signaling, and cancer progression. By comparing these traditionally separate fields, our article provides a novel perspective in which PrPC emerges as a shared molecular hub that governs both physio-logical repair mechanisms and pathological tumor behavior, offering new conceptual links and translational opportunities that have not been previously articulated.

Author Contributions

N.C. contributed to the bibliographic research, followed the review development, reviewed, and edited the manuscript. N.S.O. and E.M. contributed to the bibliographic research, reviewed, and edited the manuscript. S.M. conceptualized, drafted, wrote, reviewed, and edited the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Acknowledgments

While preparing this work, the authors used Grammarly (Version 14.1267.0) to improve language and readability without altering the core content. After using this tool, the authors reviewed and edited the content as needed and took full responsibility for the publication’s content.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

AktProtein Kinase B
ASCsAdult Stem Cells
Bcl-2B-cell lymphoma 2
CRCColorectal Cancer
CSCsCancer Stem Cells
CJDCreutzfeldt–Jakob Disease
CNSCentral Nervous System
DGHippocampal Dentate Gyrus
EGF-REpidermal Growth Factor Receptor
EREstrogen Receptor
ERKExtracellular signal-regulated kinase
ESCsEmbryonic Stem Cells
FynTyrosine-protein kinase Fyn
FLNaFilamin A
GBMGlioblastoma
GCGastric Cancer
GSCsGlioblastoma Stem Cells
HOPHeat shock Organizing Protein
HSPHeat Shock Protein
HSCsHematopoietic Stem Cells
LRP1Low-density lipoprotein Receptor-related Protein-1
MEKMitogen-activated protein kinase
MMP11Matrix metalloproteinase-11
NMDA-RN-methyl-d-aspartate receptor
MAP2Microtubule-Associated Protein 2
MβCDMethyl-β-cyclodextrin
MSCsMesenchymal Stem Cells
PI3KPhosphoinositide 3-kinase
PCPancreatic Cancer
PKCProtein Kinase C
PrPCCellular prion protein
recPrPRecombinant prion protein
PrPResProtease-resistant prion protein
PrPScScrapie prion protein
S-PrPSoluble prion protein
SATB1Special AT-rich sequence-binding protein 1
SP1Specificity Protein 1
STi-1Stress-inducible protein 1
t-PATissue-type plasminogen activator

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Figure 1. Representation of the molecular interactions that enable PrPC to function as a signaling hub at the cell surface. PrPC resides within lipid rafts, where it engages key partners, including NCAM (green), Caveolin-1 (orange), LRP1 (purple), and the co-chaperone STi-1 (pink), to initiate intracellular signaling cascades that promote, respectively, axon elongation, cellular maturation, neuronal survival and immune regulation, and neuritogenesis. Together, these signaling complexes illustrate how PrPC integrates extracellular cues to regulate neurodevelopment, synaptic function, and regenerative processes. Created in BioRender. Martellucci, S. (2025) https://BioRender.com/wanejla (accessed on 17 December 2025).
Figure 1. Representation of the molecular interactions that enable PrPC to function as a signaling hub at the cell surface. PrPC resides within lipid rafts, where it engages key partners, including NCAM (green), Caveolin-1 (orange), LRP1 (purple), and the co-chaperone STi-1 (pink), to initiate intracellular signaling cascades that promote, respectively, axon elongation, cellular maturation, neuronal survival and immune regulation, and neuritogenesis. Together, these signaling complexes illustrate how PrPC integrates extracellular cues to regulate neurodevelopment, synaptic function, and regenerative processes. Created in BioRender. Martellucci, S. (2025) https://BioRender.com/wanejla (accessed on 17 December 2025).
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Figure 2. Schematic representation of major PrPC interactors (violet), functions (yellow), and cell responses (green). PrPC integrates distinct molecular interactions across stem cells, cancer cells, and drug-resistant phenotypes. In stem cells, PrPC engagement with laminin/integrins and Notch activates Fyn-, ERK1/2-, and EGF-R–dependent signaling, promoting differentiation, survival, and stem cell self-renewal. In cancer and cancer stem cells, interactions with CD44, Notch, and Wnt activate ECM-associated pathways, MAPK/PI3K, EGF-R, and β-catenin signaling, driving migration, invasion, proliferation, and tumor progression. In drug-resistant cells, PrPC cooperates with P-glycoprotein, PI3K/Akt, and CD44 to enhance anti-apoptotic activity, epithelial–mesenchymal transition, and chemotherapeutic resistance. Partially overlapping sets of interacting proteins between stem cells and cancer stem cells have been reported, although these interactions can determine different cellular responses. Created in BioRender. Martellucci, S. (2025) https://BioRender.com/wanejla (accessed on 17 December 2025).
Figure 2. Schematic representation of major PrPC interactors (violet), functions (yellow), and cell responses (green). PrPC integrates distinct molecular interactions across stem cells, cancer cells, and drug-resistant phenotypes. In stem cells, PrPC engagement with laminin/integrins and Notch activates Fyn-, ERK1/2-, and EGF-R–dependent signaling, promoting differentiation, survival, and stem cell self-renewal. In cancer and cancer stem cells, interactions with CD44, Notch, and Wnt activate ECM-associated pathways, MAPK/PI3K, EGF-R, and β-catenin signaling, driving migration, invasion, proliferation, and tumor progression. In drug-resistant cells, PrPC cooperates with P-glycoprotein, PI3K/Akt, and CD44 to enhance anti-apoptotic activity, epithelial–mesenchymal transition, and chemotherapeutic resistance. Partially overlapping sets of interacting proteins between stem cells and cancer stem cells have been reported, although these interactions can determine different cellular responses. Created in BioRender. Martellucci, S. (2025) https://BioRender.com/wanejla (accessed on 17 December 2025).
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MDPI and ACS Style

Candelise, N.; Orefice, N.S.; Mantuano, E.; Martellucci, S. Targeting the Cellular Prion Protein as a Biomarker for Stem Cells, Cancer, and Regeneration. Biologics 2026, 6, 1. https://doi.org/10.3390/biologics6010001

AMA Style

Candelise N, Orefice NS, Mantuano E, Martellucci S. Targeting the Cellular Prion Protein as a Biomarker for Stem Cells, Cancer, and Regeneration. Biologics. 2026; 6(1):1. https://doi.org/10.3390/biologics6010001

Chicago/Turabian Style

Candelise, Niccolò, Nicola Salvatore Orefice, Elisabetta Mantuano, and Stefano Martellucci. 2026. "Targeting the Cellular Prion Protein as a Biomarker for Stem Cells, Cancer, and Regeneration" Biologics 6, no. 1: 1. https://doi.org/10.3390/biologics6010001

APA Style

Candelise, N., Orefice, N. S., Mantuano, E., & Martellucci, S. (2026). Targeting the Cellular Prion Protein as a Biomarker for Stem Cells, Cancer, and Regeneration. Biologics, 6(1), 1. https://doi.org/10.3390/biologics6010001

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