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Signaling Pathways Dysregulation in Cancer: Advances and New Therapeutics Hopes
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Signaling Pathways Dysregulation in Cancer: Advances and New Therapeutics Hopes

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 20 July 2025 | Viewed by 17306

Special Issue Editor

Dr. Daniela Miricescu

E-Mail Website
Guest Editor
Department of Biochemistry, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
Interests: PI3K/AKT/mTOR; oxidative stress; breast cancer; burns; colorectal cancer; PLGA nanoparticles; platelet rich plasma
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Malignant neoplasms, characterized by successive genetic and epigenetic alterations of healthy cells, are one of the leading causes of death within the adult population. Usually, most cancers emerge at the epithelial cells, leading to organ-specific carcinomas affecting skin, liver, lung, breast, or pancreas. Since oncogenic mutations induce gene overexpression and subsequently cause protein dysregulation, the PI3K/AKT/mTOR, TGF-β family, Ras/Raf/MEK/ERK, and the Wnt/β-catenin signaling pathway dysregulations are correlated with the proliferation, angiogenesis, invasion, and metastasis of cancer cells. Therefore, inhibitors targeting these pathways are considered as novel therapeutic candidates for the development of potential anticancer agents.

We cordially invite submissions of original research and comprehensive review articles for inclusion in this Special Issue.

This Special Issue is overseen by Dr. Daniela Miricescu with the assistance of Dr. Constantin Stefani ( Department of Family Medicine and Clinical Base, Dr. Carol Davila Central Military Emergency University Hospital).

Dr. Daniela Miricescu
Guest Editor

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Keywords

  • cancer
  • epithelial cells
  • oncogenic mutations
  • PI3K/AKT/mTOR
  • TGF-β
  • Ras/Raf/MEK/ERK
  • Wnt/β-catenin
  • angiogenesis
  • invasion
  • metastasis
  • inhibitors

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Published Papers (7 papers)

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Research

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11 pages, 1204 KiB  
Article
Cancer Cell’s Achilles Heels: Considerations for Design of Anti-Cancer Drug Combinations
by Valid Gahramanov, Frederick S. Vizeacoumar, Alain Morejon Morales, Keith Bonham, Meena K. Sakharkar, Santosh Kumar, Franco J. Vizeacoumar, Andrew Freywald and Michael Y. Sherman
Int. J. Mol. Sci. 2024, 25(24), 13495; https://doi.org/10.3390/ijms252413495 - 17 Dec 2024
Viewed by 760
Abstract
Loss of function screens using shRNA (short hairpin RNA) and CRISPR (clustered regularly interspaced short palindromic repeats) are routinely used to identify genes that modulate responses of tumor cells to anti-cancer drugs. Here, by integrating GSEA (Gene Set Enrichment Analysis) and CMAP (Connectivity [...] Read more.
Loss of function screens using shRNA (short hairpin RNA) and CRISPR (clustered regularly interspaced short palindromic repeats) are routinely used to identify genes that modulate responses of tumor cells to anti-cancer drugs. Here, by integrating GSEA (Gene Set Enrichment Analysis) and CMAP (Connectivity Map) analyses of multiple published shRNA screens, we identified a core set of pathways that affect responses to multiple drugs with diverse mechanisms of action. This suggests that these pathways represent “weak points” or “Achilles heels”, whose mild disturbance should make cancer cells vulnerable to a variety of treatments. These “weak points” include proteasome, protein synthesis, RNA splicing, RNA synthesis, cell cycle, Akt-mTOR, and tight junction-related pathways. Therefore, inhibitors of these pathways are expected to sensitize cancer cells to a variety of drugs. This hypothesis was tested by analyzing the diversity of drugs that synergize with FDA-approved inhibitors of the proteasome, RNA synthesis, and Akt-mTOR pathways. Indeed, the quantitative evaluation indicates that inhibitors of any of these signaling pathways can synergize with a more diverse set of pharmaceuticals, compared to compounds inhibiting targets distinct from the “weak points” pathways. Our findings described here imply that inhibitors of the “weak points” pathways should be considered as primary candidates in a search for synergistic drug combinations. Full article
(This article belongs to the Special Issue Signaling Pathways Dysregulation in Cancer: Advances and New Therapeutics Hopes)
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15 pages, 1292 KiB  
Article
Whole-Exome Sequencing, Mutational Signature Analysis, and Outcome in Multiple Myeloma—A Pilot Study
by Lorenz Oelschläger, Axel Künstner, Friederike Frey, Theo Leitner, Lisa Leypoldt, Niklas Reimer, Niklas Gebauer, Lorenz Bastian, Katja Weisel, Verena-Wilbeth Sailer, Christoph Röcken, Wolfram Klapper, Björn Konukiewitz, Eva Maria Murga Penas, Michael Forster, Natalie Schub, Helal M. M. Ahmed, Jutta Kirfel, Nikolas Christian Cornelius von Bubnoff, Hauke Busch and Cyrus Khandanpouradd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2024, 25(24), 13418; https://doi.org/10.3390/ijms252413418 - 14 Dec 2024
Cited by 1 | Viewed by 1397
Abstract
The complex and heterogeneous genomic landscape of multiple myeloma (MM) and many of its clinical and prognostic implications remains to be understood. In other cancers, such as breast cancer, using whole-exome sequencing (WES) and molecular signatures in clinical practice has revolutionized classification, prognostic [...] Read more.
The complex and heterogeneous genomic landscape of multiple myeloma (MM) and many of its clinical and prognostic implications remains to be understood. In other cancers, such as breast cancer, using whole-exome sequencing (WES) and molecular signatures in clinical practice has revolutionized classification, prognostic prediction, and patient management. However, such integration is still in its early stages in MM. In this study, we analyzed WES data from 35 MM patients to identify potential mutational signatures and driver mutations correlated with clinical and cytogenetic characteristics. Our findings confirm the complex mutational spectrum and its impact on previously described ontogenetic and epigenetic pathways. They show TYW1 as a possible new potential driver gene and find no significant associations of mutational signatures with clinical findings. Further studies are needed to strengthen the role of mutational signatures in the clinical context of patients with MM to improve patient management. Full article
(This article belongs to the Special Issue Signaling Pathways Dysregulation in Cancer: Advances and New Therapeutics Hopes)
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23 pages, 7303 KiB  
Article
Functional and Biological Characterization of the LGR5Δ5 Splice Variant in HEK293T Cells
by Matthias Kappler, Laura Thielemann, Markus Glaß, Laura Caggegi, Antje Güttler, Jonas Pyko, Sarah Blauschmidt, Tony Gutschner, Helge Taubert, Sven Otto, Alexander W. Eckert, Frank Tavassol, Matthias Bache, Dirk Vordermark, Tom Kaune and Swetlana Rot
Int. J. Mol. Sci. 2024, 25(24), 13417; https://doi.org/10.3390/ijms252413417 - 14 Dec 2024
Viewed by 1453
Abstract
The regulator of the canonical Wnt pathway, leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), is expressed in the stem cell compartment of several tissues and overexpressed in different human carcinomas. The isoform of the stem cell marker LGR5, named LGR5Δ5 and first described [...] Read more.
The regulator of the canonical Wnt pathway, leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), is expressed in the stem cell compartment of several tissues and overexpressed in different human carcinomas. The isoform of the stem cell marker LGR5, named LGR5Δ5 and first described by our group, is associated with prognosis and metastasis in oral squamous cell carcinoma (OSCC) and soft tissue sarcoma (STS). In a proof-of-principle analysis, the function of LGR5Δ5 was investigated in HEK293T cells, a model cell line of the Wnt pathway, compared to full-length LGR5 (FL) expression. The CRISPR/CAS knockout of LGR5 and LGR4 (thereby avoiding the side effects of LGR4) resulted in a loss of Wnt activity that cannot be restored by LGR5Δ5 but by LGR5FL rescue. The ability to migrate was not affected by LGR5Δ5, but was reduced by LGR5FL overexpression. The CRISPR/CAS of LGR4 and 5 induced radiosensitization, which was enhanced by the overexpression of LGR5FL or LGR5Δ5. RNA sequencing analysis revealed a significant increase in the ligand R-spondin 1 (RSPO1) level by LGR5Δ5. Furthermore, LGR5Δ5 appears to be involved in the regulation of genes related to the cytoskeleton, extracellular matrix stiffness, and angiogenesis, while LGR5FL is associated with the regulation of collagens and histone proteins. Full article
(This article belongs to the Special Issue Signaling Pathways Dysregulation in Cancer: Advances and New Therapeutics Hopes)
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15 pages, 3305 KiB  
Article
SPRED2 Is a Novel Regulator of Autophagy in Hepatocellular Carcinoma Cells and Normal Hepatocytes
by Tianyi Wang, Tong Gao, Masayoshi Fujisawa, Toshiaki Ohara, Masakiyo Sakaguchi, Teizo Yoshimura and Akihiro Matsukawa
Int. J. Mol. Sci. 2024, 25(11), 6269; https://doi.org/10.3390/ijms25116269 - 6 Jun 2024
Cited by 3 | Viewed by 2077
Abstract
Sprouty-related enabled/vasodilator-stimulated phosphoprotein homology 1 domain containing 2 (SPRED2) is an inhibitor of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway and has been shown to promote autophagy in several cancers. Here, we aimed to determine whether SPRED2 plays a role in [...] Read more.
Sprouty-related enabled/vasodilator-stimulated phosphoprotein homology 1 domain containing 2 (SPRED2) is an inhibitor of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway and has been shown to promote autophagy in several cancers. Here, we aimed to determine whether SPRED2 plays a role in autophagy in hepatocellular carcinoma (HCC) cells. The Cancer Genome Atlas (TCGA) Liver Cancer Database showed a negative association between the level of SPRED2 and p62, a ubiquitin-binding scaffold protein that accumulates when autophagy is inhibited. Immunohistochemically, accumulation of p62 was detected in human HCC tissues with low SPRED2 expression. Overexpression of SPRED2 in HCC cells increased the number of autophagosomes and autophagic vacuoles containing damaged mitochondria, decreased p62 levels, and increased levels of light-chain-3 (LC3)-II, an autophagy marker. In contrast, SPRED2 deficiency increased p62 levels and decreased LC3-II levels. SPRED2 expression levels were negatively correlated with translocase of outer mitochondrial membrane 20 (TOM20) expression levels, suggesting its role in mitophagy. Mechanistically, SPRED2 overexpression reduced ERK activation followed by the mechanistic or mammalian target of rapamycin complex 1 (mTORC1)-mediated signaling pathway, and SPRED2 deficiency showed the opposite pattern. Finally, hepatic autophagy was impaired in the liver of SPRED2-deficient mice with hepatic lipid droplet accumulation in response to starvation. These results indicate that SPRED2 is a critical regulator of autophagy not only in HCC cells, but also in hepatocytes, and thus the manipulation of this process may provide new insights into liver pathology. Full article
(This article belongs to the Special Issue Signaling Pathways Dysregulation in Cancer: Advances and New Therapeutics Hopes)
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Review

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22 pages, 2088 KiB  
Review
Immune Cell Interactions and Immune Checkpoints in the Tumor Microenvironment of Gastric Cancer
by Andreea-Raluca Cozac-Szőke, Dan Alexandru Cozac, Anca Negovan, Andreea Cătălina Tinca, Alexandra Vilaia, Iuliu-Gabriel Cocuz, Adrian Horațiu Sabău, Raluca Niculescu, Diana Maria Chiorean, Alexandru Nicușor Tomuț and Ovidiu Simion Cotoi
Int. J. Mol. Sci. 2025, 26(3), 1156; https://doi.org/10.3390/ijms26031156 - 29 Jan 2025
Cited by 1 | Viewed by 1368
Abstract
Gastric cancer (GC) ranks as the fifth most prevalent malignant neoplasm globally, with an increased death rate despite recent advancements in research and therapeutic options. Different molecular subtypes of GC have distinct interactions with the immune system, impacting the tumor microenvironment (TME), prognosis, [...] Read more.
Gastric cancer (GC) ranks as the fifth most prevalent malignant neoplasm globally, with an increased death rate despite recent advancements in research and therapeutic options. Different molecular subtypes of GC have distinct interactions with the immune system, impacting the tumor microenvironment (TME), prognosis, and reaction to immunotherapy. Tumor-infiltrating lymphocytes (TILs) in the TME are crucial for preventing tumor growth and metastasis, as evidenced by research showing that patients with GC who have a significant density of TILs have better survival rates. But cancer cells have evolved a variety of mechanisms to evade immune surveillance, both sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) and Programmed Death-Ligand 1 (PD-L1) playing a pivotal role in the development of an immunosuppressive TME. They prevent T cell activation and proliferation resulting in a decrease in the immune system’s capacity to recognize and eliminate malignant cells. These immune checkpoint molecules function via different but complementary mechanisms, the expression of Siglec-15 being mutually exclusive with PD-L1 and, therefore, providing a different therapeutic approach. The review explores how TILs affect tumor growth and patient outcomes in GC, with particular emphasis on their interactions within the TME and potential targeting of the PD-L1 and Siglec-15 pathways for immunotherapy. Full article
(This article belongs to the Special Issue Signaling Pathways Dysregulation in Cancer: Advances and New Therapeutics Hopes)
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15 pages, 1290 KiB  
Review
Dysregulated Signaling Pathways in Canine Mammary Tumor and Human Triple Negative Breast Cancer: Advances and Potential Therapeutic Targets
by Chen Mei, Ying Liu, Zhenyi Liu, Yan Zhi, Zhaoling Jiang, Xueze Lyu and Hongjun Wang
Int. J. Mol. Sci. 2025, 26(1), 145; https://doi.org/10.3390/ijms26010145 - 27 Dec 2024
Cited by 2 | Viewed by 1846
Abstract
In 2022, human breast cancer (HBC) and canine mammary tumors (CMTs) remained the most prevalent malignant tumors worldwide, with high recurrence and lethality rates, posing a significant threat to human and dog health. The development of breast cancer involves multiple signaling pathways, highlighting [...] Read more.
In 2022, human breast cancer (HBC) and canine mammary tumors (CMTs) remained the most prevalent malignant tumors worldwide, with high recurrence and lethality rates, posing a significant threat to human and dog health. The development of breast cancer involves multiple signaling pathways, highlighting the need for effective inhibitory drugs that target key proteins in these pathways. This article reviews the dysregulation of the EGFR, PI3K/AKT/mTOR, Hippo, pyroptosis, and PD-1/PD-L1 signaling pathways in HBC and CMT, as well as the corresponding drugs used to inhibit tumor growth, with the aim of providing theoretical support for the development of more efficient drugs. Full article
(This article belongs to the Special Issue Signaling Pathways Dysregulation in Cancer: Advances and New Therapeutics Hopes)
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26 pages, 1785 KiB  
Review
Targeting PI3K/AKT/mTOR and MAPK Signaling Pathways in Gastric Cancer
by Diana-Theodora Morgos, Constantin Stefani, Daniela Miricescu, Maria Greabu, Silviu Stanciu, Silvia Nica, Iulia-Ioana Stanescu-Spinu, Daniela Gabriela Balan, Andra-Elena Balcangiu-Stroescu, Elena-Claudia Coculescu, Dragos-Eugen Georgescu and Remus Iulian Nica
Int. J. Mol. Sci. 2024, 25(3), 1848; https://doi.org/10.3390/ijms25031848 - 3 Feb 2024
Cited by 49 | Viewed by 7377
Abstract
Gastric cancer (GC) is the fourth leading cause of death worldwide, with more than 1 million cases diagnosed every year. Helicobacter pylori represents the main risk factor, being responsible for 78% of the cases. Increased amounts of salt, pickled food, red meat, alcohol, [...] Read more.
Gastric cancer (GC) is the fourth leading cause of death worldwide, with more than 1 million cases diagnosed every year. Helicobacter pylori represents the main risk factor, being responsible for 78% of the cases. Increased amounts of salt, pickled food, red meat, alcohol, smoked food, and refined sugars negatively affect the stomach wall, contributing to GC development. Several gene mutations, including PIK3CA, TP53, ARID1A, CDH1, Ras, Raf, and ERBB3 are encountered in GC pathogenesis, leading to phosphatidylinositol 3-kinase (PI3K) protein kinase B (AKT)/mammalian target of rapamycin (mTOR)—PI3K/AKT/mTOR—and mitogen-activated protein kinase (MAPK) signaling pathway activation and promoting tumoral activity. Helicobacter pylori, growth factors, cytokines, hormones, and oxidative stress also activate both pathways, enhancing GC development. In clinical trials, promising results have come from monoclonal antibodies such as trastuzumab and ramucirumab. Dual inhibitors targeting the PI3K/AKT/mTOR and MAPK signaling pathways were used in vitro studies, also with promising results. The main aim of this review is to present GC incidence and risk factors and the dysregulations of the two protein kinase complexes together with their specific inhibitors. Full article
(This article belongs to the Special Issue Signaling Pathways Dysregulation in Cancer: Advances and New Therapeutics Hopes)
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