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Cells
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Signal Transduction and Targeted Therapy for Tumors
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Signal Transduction and Targeted Therapy for Tumors

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: 30 August 2026 | Viewed by 8191

Special Issue Editor

Dr. Rodolfo Daniel Cervantes-Villagrana

E-Mail Website
Guest Editor
Department of Pharmacology, Moores Cancer Center, School of Medicine, University of California San Diego, La Jolla, San Diego, CA 92093, USA
Interests: molecular cell biology; cell signaling; cancer biology; cell migration; tumor biology; metastasis; pharmacology; cancer cell biology; cancer immunology; cell culture

Special Issue Information

Dear Colleagues,

Cancer represents a global health concern, with its contribution to worldwide mortality increasing each year. Due to its variety and multifactorial nature, cancer represents a complex challenge in biomedical research. Cancer therapeutics involve not only targeting tumor cells but also disrupting the communication between cancer cells and non-transformed cells that are hijacked during tumor progression, such as leukocytes (immunotherapy) or endothelial cells (anti-angiogenic therapy), thereby altering the tumor microenvironment, increasing the anti-tumor response, and reducing the dissemination of tumor cells. Analyzing the signal transduction pathways involved in angiogenic, immunosuppressive, and neurogenic switches triggered by the interaction between tumor cells and adjacent tissue cells may reveal novel therapeutic opportunities to halt and reverse tumor progression.

This Special Issue will investigate the wide range of signal transduction processes linked to cancer and explore the effectiveness of emerging therapeutic targets, drugs, and treatment combinations against cancer-associated processes, such as metastasis, migration and invasion, resistance or persistence, tumor angiogenesis, immunosuppression, tumor neurogenesis/axonogenesis, perineural invasion, and neuropathic pain. By investigating signal transduction processes linked to cancer, we may be able to develop creative targeted therapies to counteract cancer progression.

This Special Issue will showcase reviews and original research articles using cells and animal models.

Dr. Rodolfo Daniel Cervantes-Villagrana
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cancer progression
  • metastasis
  • invasion
  • cancer signaling
  • cell communication
  • cancer neuroscience
  • tumor angiogenesis
  • target therapy
  • immunotherapy
  • drug resistance
  • anti-tumor therapy

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Published Papers (5 papers)

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Research

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21 pages, 8347 KB  
Article
Estrogen Receptor-α36 Mediates EGFR-SGK1 Signaling-Related Erk Activation in Gastric Cancer
by Yibo Zhang, Hongyan Zhou, Yifan Xiao, Shubing Yang, Qingqing Xu, Xin Liu, Wenli Huang, Mingshan Pi, Qi Xiong, Xiaochuan Wang, Xiji Shu and Yiyuan Xia
Cells 2026, 15(9), 787; https://doi.org/10.3390/cells15090787 - 26 Apr 2026
Viewed by 508
Abstract
Introduction: Gastric cancer is a prevalent and aggressive malignancy driven by complex signaling networks. Estrogen receptor-α36 (ER-α36), a membrane-localized receptor, mediates non-genomic signaling and promotes tumor progression. ER-α36 can interact with epidermal growth factor receptor (EGFR) to activate downstream mitogen-activated protein kinase (MAPK) [...] Read more.
Introduction: Gastric cancer is a prevalent and aggressive malignancy driven by complex signaling networks. Estrogen receptor-α36 (ER-α36), a membrane-localized receptor, mediates non-genomic signaling and promotes tumor progression. ER-α36 can interact with epidermal growth factor receptor (EGFR) to activate downstream mitogen-activated protein kinase (MAPK) signaling, but the detailed mechanism in gastric cancer remains unclear. This study aimed to explore whether ER-α36 promotes gastric cancer progression by regulating serum and glucocorticoid-regulated kinase 1 (SGK1)-mediated Erk1/2 activation.Methods:We collected 53 human gastric adenocarcinoma specimens and detected ER-α36 expression by immunohistochemistry. Bioinformatics analysis was used to identify ER-α36-related kinases. Gastric cancer cell lines (SGC7901, HGC27, NCI-N87, and MFC) were used for in vitro studies. Western blotting, qRT-PCR, immunofluorescence, co-immunoprecipitation (Co-IP), wound healing, MTT, and Transwell invasion analyses, and nude mouse orthotopic tumor models were applied to investigate the function and mechanism of the ER-α36/SGK1/Erk1/2 axis. Results: ER-α36 was positively expressed in 62.3% of gastric adenocarcinoma tissues and was associated with poor differentiation and prognosis. SGK1 was identified as a key kinase downstream of ER-α36. ER-α36, SGK1, and p-Erk1/2 were co-upregulated in gastric cancer tissues and cells. ER-α36 regulated Raf/MEK1/2/Erk1/2 phosphorylation in an SGK1-dependent manner. EGF-induced Erk1/2 activation required both ER-α36 and SGK1. Overexpression of ER-α36 promoted the proliferation, migration, and invasion of gastric cancer cells, while SGK1 knockdown abolished these oncogenic effects. In vivo experiments confirmed that ER-α36 promoted gastric tumor growth and EGFR/Erk signaling, which was attenuated by SGK1 knockdown. Conclusions: ER-α36 contributes to the malignant progression of gastric adenocarcinoma by activating the Erk1/2 pathway through SGK1. The ER-α36–SGK1–Erk1/2 axis may serve as a novel therapeutic target for gastric cancer. Full article
(This article belongs to the Special Issue Signal Transduction and Targeted Therapy for Tumors)
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21 pages, 5183 KB  
Article
4-Methoxydalbergione Induces Dual Activation of Apoptosis and Autophagy-Dependent Cell Death via ROS–MAPK Signaling in Human Neuroblastoma Cells
by Tonking Bastola, Ren-Bo An, Chi-Su Yoon, Hyuncheol Oh and Jungwon Seo
Cells 2026, 15(5), 431; https://doi.org/10.3390/cells15050431 - 28 Feb 2026
Viewed by 916
Abstract
Neuroblastoma, the predominant extracranial solid malignancy in the pediatric population, remains a major clinical challenge due to pronounced intratumoral heterogeneity and intrinsic therapeutic resistance. 4-Methoxydalbergione (4-MD), a benzoquinone derivative isolated from Dalbergia odorifera, has demonstrated anticancer activity in several tumor models; however, [...] Read more.
Neuroblastoma, the predominant extracranial solid malignancy in the pediatric population, remains a major clinical challenge due to pronounced intratumoral heterogeneity and intrinsic therapeutic resistance. 4-Methoxydalbergione (4-MD), a benzoquinone derivative isolated from Dalbergia odorifera, has demonstrated anticancer activity in several tumor models; however, its effects and underlying cell death mechanisms in neuroblastoma remain unclear. Here, we investigated the cytotoxic effects of 4-MD in human neuroblastoma cells using cell viability assays, flow cytometry, immunoblotting, and fluorescence microscopy. 4-MD reduced cell viability in a dose- and time-dependent manner and induced caspase-3 cleavage accompanied by MAPK activation, indicating apoptotic cell death. Concurrently, 4-MD promoted autophagosome accumulation, as evidenced by LC3-II accumulation, acidic vesicular organelle formation, ATG5 upregulation, and p62 degradation, in association with activation of the AMPK/mTOR/ULK1 signaling axis. Pharmacological inhibition of autophagy significantly attenuated 4-MD-induced cytotoxicity without affecting caspase-3 activation, demonstrating a caspase-independent, pro-death role of autophagy. Reactive oxygen species (ROS) acted as a critical upstream mediator, as antioxidant treatment suppressed both apoptotic and autophagic signaling. Moreover, inhibition of Na+,K+-ATPase with ouabain selectively reduced autophagy-dependent cell death, implicating autosis as an additional mechanism. Notably, 4-MD exhibited minimal toxicity toward primary cortical neurons. Collectively, these findings demonstrate that 4-MD engages multiple, non-redundant cell death pathways through coordinated ROS–MAPK–AMPK/mTOR/ULK1 signaling, highlighting its potential to overcome therapeutic resistance in heterogeneous neuroblastoma cells. Full article
(This article belongs to the Special Issue Signal Transduction and Targeted Therapy for Tumors)
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25 pages, 7655 KB  
Article
Pancreatic Cancer Stem Cells Co-Expressing SOX2, OCT4, and TERThigh Represent an Aggressive Subpopulation
by Erika Curiel-Gomez, Damaris P. Romero-Rodriguez, Mauricio Rodriguez-Dorantes, Vilma Maldonado and Jorge Melendez-Zajgla
Cells 2026, 15(2), 129; https://doi.org/10.3390/cells15020129 - 11 Jan 2026
Cited by 1 | Viewed by 1167
Abstract
The aggressiveness of pancreatic ductal adenocarcinoma (PDAC) has been linked to cancer stem cells (CSCs) and telomerase activity; however, the mechanism underlying this association remains unclear. In this study, we engineered dual transcriptional reporters (SORE6-GFP and TERT-BFP) to isolate SOX2+OCT4+ [...] Read more.
The aggressiveness of pancreatic ductal adenocarcinoma (PDAC) has been linked to cancer stem cells (CSCs) and telomerase activity; however, the mechanism underlying this association remains unclear. In this study, we engineered dual transcriptional reporters (SORE6-GFP and TERT-BFP) to isolate SOX2+OCT4+TERThigh subpopulations from AsPC-1 and BxPC-3 cells. We combined Fluorescence-Activated Cell Sorting with functional assays, RNA-seq, and network analysis. Clinically, tumors co-expressing high SOX2/OCT4/TERT levels were associated with reduced overall survival, whereas single-gene elevations were not prognostic. We identified a minority SOX2+OCT4+TERThigh fraction (~9%) enriched for pluripotency transcripts (SOX2, OCT4, NANOG, and ALDH1A1), which exhibited the highest proliferative, migratory, and invasive capacities. Transcriptomic profiling of SOX2+OCT4+TERThigh cells showed enrichment of KRAS, telomere maintenance, epithelial–mesenchymal transition, and developmental pathways (WNT and Hedgehog). Connectivity profiling highlighted actionable vulnerabilities, including NF-κB, WNT, and telomerase inhibition pathways. Together, these data define an aggressive telomerase-engaged, pluripotency-driven CSC-like state in PDAC and suggest testable therapeutic strategies that target TERThigh dependencies. Full article
(This article belongs to the Special Issue Signal Transduction and Targeted Therapy for Tumors)
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16 pages, 9877 KB  
Article
The Crosstalk Mechanism of EGFR and ER in EGFR-Mutant Lung Adenocarcinoma
by Ying-Yi Chen, Wei-Ting Huang, Yu-Fu Su, Yi-Jen Hung, Hao-Ai Shui, Yi-Shing Shieh and Tsai-Wang Huang
Cells 2026, 15(2), 98; https://doi.org/10.3390/cells15020098 - 6 Jan 2026
Viewed by 1119
Abstract
Breast cancer and lung adenocarcinoma share common features, including female predominance and the expression of estrogen receptor (ER) and epidermal growth factor receptor (EGFR) during carcinogenesis. Patients with breast cancer have a significantly higher risk of developing second primary lung cancer than those [...] Read more.
Breast cancer and lung adenocarcinoma share common features, including female predominance and the expression of estrogen receptor (ER) and epidermal growth factor receptor (EGFR) during carcinogenesis. Patients with breast cancer have a significantly higher risk of developing second primary lung cancer than those without breast cancer. ER beta expression is associated with resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant lung adenocarcinoma, indicating a potentially important interaction between ER and EGFR. However, the mechanisms underlying this crosstalk remain poorly understood. Our clinical data showed a significant correlation between antiestrogen treatment for breast cancer and mutant EGFR expression (p = 0.021) in lung adenocarcinoma patients. In vitro, tamoxifen upregulated phosphorylated EGFR (p-EGFR) in EGFR-mutant lung adenocarcinoma cell lines. Heparin-binding EGF-like growth factor was identified as a key mediator from the ER pathway that stimulates p-EGFR. Tamoxifen counteracts estrogen’s effect and restores p-EGFR upregulation. Furthermore, coadministration of tamoxifen and the EGFR TKI gefitinib potentially inhibited p-EGFR expression in EGFR-mutant lung adenocarcinoma. Regular follow-up with chest computed tomography is recommended for patients with breast cancer. For those diagnosed with both ER-positive breast cancer and EGFR-mutant lung adenocarcinoma, combined tamoxifen and EGFR TKI therapy may offer an effective targeted treatment strategy. Full article
(This article belongs to the Special Issue Signal Transduction and Targeted Therapy for Tumors)
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Review

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43 pages, 8626 KB  
Review
Advances in Targeting Growth Factor Signalling in Neuroblastoma and Overcoming Drug Resistance
by Karina Ivanenko, Ruslan Shaymardanov, Vladimir Prassolov and Timofey Lebedev
Cells 2026, 15(1), 4; https://doi.org/10.3390/cells15010004 - 19 Dec 2025
Cited by 1 | Viewed by 2056
Abstract
Neuroblastoma is an embryonal tumour that arises from the malignant transformation of neural crest cells and remains one of the deadliest malignancies in children under five. Neural crest development is regulated by dynamic switches in transcriptional programmes, guided by a variety of growth [...] Read more.
Neuroblastoma is an embryonal tumour that arises from the malignant transformation of neural crest cells and remains one of the deadliest malignancies in children under five. Neural crest development is regulated by dynamic switches in transcriptional programmes, guided by a variety of growth factors. Due to its developmental origin, neuroblastoma is unique in that these tumours often retain overactivation of growth factor signalling, which can be targeted by receptor tyrosine kinase (RTK) inhibitors. However, mutations in kinases, except for ALK, are extremely rare in neuroblastoma. Furthermore, the high degree of intratumoural heterogeneity often renders RTK inhibition ineffective as a monotherapy. For high-risk tumours, which lack effective treatment options, there remains an unmet need for targeted therapies. This review summarises the roles of growth factor receptors in neural crest and neuroblastoma development in light of recent single-cell studies. We provide a systematic overview of RTK inhibitors that can target growth factor signalling in neuroblastoma and detail their current status in clinical development. We also explore the role of intratumoural heterogeneity in resistance to RTK inhibitors, focusing on the adrenergic-to-mesenchymal transition, which drives a switch in growth factor receptor expression. Finally, we discuss strategies to overcome RTK inhibitor resistance by targeting neuroblastoma cell plasticity, disrupting downstream signalling pathways, or inhibiting escape mechanisms from cell death. This review provides a theoretical basis for developing novel combination therapies incorporating RTK inhibitors. Full article
(This article belongs to the Special Issue Signal Transduction and Targeted Therapy for Tumors)
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