bims-necame 2026-05-10 papers

Issue of 2026–05–10
five papers selected by
Grigor Varuzhanyan, UCLA

Mol Biol Rep. 2026 May 05. pii: 710. [Epub ahead of print]53(1):

Oncogenic MAGEA4 directs neuroendocrine differentiation and survival in prostate cancer cells through the SIRT1/Acetyl-p53/BCL-2 axis.

Maresha Ramakrishna, Teja Nallavolu, Ramesh Ummanni.

BACKGROUND: Neuroendocrine prostate cancer (NEPC) is a highly aggressive and therapy-resistant subtype of prostate cancer (PCa) that emerges following the androgen receptor (AR) targeted therapies. Identification of potential molecular drivers governing neuroendocrine differentiation (NED) and survival is critical for developing therapeutic strategies. Cancer-testis antigens of the Melanoma-associated antigen family (MAGE) are the emerging players of oncogenic regulators. However, their role in NEPC remains unexplored.
METHODS: Proteomic and transcriptomic analyses were performed to identify differential expression of target proteins in NEPC. Functional characterization of MAGEA4 was performed using stable overexpression, siRNA-mediated knockdown in androgen-dependent/independent, and NEPC cell lines. For target validation, neuroendocrine markers, morphological characteristics, apoptotic signaling, oxidative pathways, and cell survival were evaluated using molecular, biochemical, and pharmacological approaches targeting SIRT1, p53 acetylation, BCL-2/BCL-XL and NRF2.
RESULTS: MAGEA4 was upregulated in NEPC cells and in advanced prostate cancer tissues. Overexpression of MAGEA4 induced neuroendocrine differentiation, promoted androgen-independent survival, and conferred resistance to apoptosis. Furthermore, MAGEA4 upregulated SIRT1 activity, which deacetylated p53, thereby suppressing pro-apoptotic signaling. Additionally, MAGEA4 enhanced the oxidative stress resistance through activation of the SIRT1/PGC-1α/NRF2 axis, suggesting a role in retaining the NED phenotype. In MAGEA4-positive cells, inhibition of BCL-2 and/or NRF2 attenuated the neuroendocrine characteristics, suggesting therapeutic vulnerability.
CONCLUSION: These findings highlight that MAGEA4 may contribute to neuroendocrine differentiation and survival in prostate cancer cells, and may represent a potential therapeutic vulnerability in aggressive prostate cancers.

Keywords: Acetyl p53; BCL-2; MAGEA4; NE-LNCaP and NCI-H660; NRF2; SIRT1

DOI: https://doi.org/10.1007/s11033-026-11878-9

bioRxiv. 2026 Apr 30. pii: 2026.04.27.721078. [Epub ahead of print]

Direct interaction between cancer cells and fibroblasts promotes early chemoresistance to standard-of-care drug therapy in small cell lung cancer (SCLC).

Nilu Dhungel, Brian Latimer, David Custis, Ana-Maria Dragoi.

Cancer-associated fibroblasts (CAFs) are now recognized as key regulators of tumor progression and therapeutic resistance, yet the cancer cells-fibroblasts crosstalk that ultimately promotes chemoresistance remain incompletely understood. Here, we show that direct physical contact between small cell lung cancer (SCLC) cells and lung fibroblasts induces early resistance to standard-of-care chemotherapeutic agents, etoposide and cisplatin. Using both 2D and 3D co-culture models, we demonstrate that early acquired therapy resistance entails cell-cell contact and cannot be recapitulated by conditioned media alone. Mechanistically, direct interaction promotes transcriptional reprogramming in cancer cells, including upregulation of YAP1 and epithelial-to-mesenchymal transcription factors (EMT-TFs), which partially mediate the resistant phenotype. A high-throughput drug screening identified idarubicin as a compound that retains efficacy despite fibroblast-mediated protection, suggesting it could bypass microenvironment-induced resistance early on. Together, our findings identify direct tumor-fibroblasts contact as an early driver of chemoresistance and highlight a potential therapeutic strategy targeting cell-cell interactions within the tumor microenvironment.

DOI: https://doi.org/10.64898/2026.04.27.721078

Front Oncol. 2026 ;16 1806742

Mechanistic insights and molecular therapy for neuroendocrine prostate cancer.

Yichen Niu, Senyu Zhang, Shouyi Zhang, Jun Tao, Yuyan Zhu.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer with a poor prognosis, strongly associated with androgen deprivation therapy. Recent studies have revealed that neuroendocrine transdifferentiation in NEPC is influenced by both transcription factor activity and epigenetic regulation. This review systematically discusses the origin hypotheses, molecular subtypes, driving mechanisms, and therapeutic strategies of NEPC, focusing on the critical roles of transcription factors and epigenetic modifications in lineage plasticity. Furthermore, we summarize the latest advancements in targeted therapies. By integrating multiomics data and preclinical models, this review provides a theoretical foundation for precision treatment of NEPC.

Keywords: epigenetic alteration; neuroendocrine differentiation; prostate cancer; targeted therapy; transcriptional regulation

DOI: https://doi.org/10.3389/fonc.2026.1806742

NPJ Precis Oncol. 2026 May 06.

Prognostic biomarkers and Hedgehog pathway activation in early prostate cancer neuroendocrine differentiation via spatial profiling.

Wenhao Zhu, Xiaomei Gao, Yinzhao Wang, Guyu Tang, Minfeng Chen, Lin Qi, Yi Cai.

Prostate cancer (PCa) progression to treatment-related neuroendocrine PCa (t-NEPC) often involves an early neuroendocrine differentiation (NED) phase lacking identified biomarkers. We utilized GeoMx Digital Spatial Profiling and single-cell RNA sequencing on human PCa tissues ranging from hormone-naïve (HNPC) to t-NEPC, with extensive multi-omics validation. Our results established early NED as a distinct, prognostically adverse subtype. We identified and validated 6 NED markers (FMN2, APLP1, SCG2, SCG3, CHGB, and RIMBP2), demonstrating specificity for NE cells and consistent upregulation throughout NEPC progression. Notably, the Hedgehog (Hh) pathway was specifically activated in early NED, manifested by high SHH ligand in neuroendocrine cells, GLI1 upregulation, and intercellular communication mediated via the SHH-Hh axis. Conversely, in late-stage t-NEPC, Hh pathway activity was significantly downregulated, while MYC-driven proliferation pathways predominated. A risk score derived from the 6-gene NED markers effectively stratified patients, correlating with pronounced NE features and shorter progression-free survival in 86 endocrine-treated patients and externally in The Cancer Genome Atlas (TCGA). In conclusion, this study delineates the dynamic molecular landscape of early NED, establishing a clinically promising biomarker panel and highlighting the Hh pathway as a stage-specific therapeutic target.

DOI: https://doi.org/10.1038/s41698-026-01398-x

Nat Commun. 2026 May 07.

GLUT6-facilitated noncanonical glucose metabolic rewiring enables resistance to targeted cancer therapy.

Huimin Lei, Ruixue Xia, Yabin Tang, Jun Lu, Chan Xiang, Yujing Li, Hongyu Liu, Peichen Zou, Ayinazhaer Aihemaiti, Wei Zhang, Ying Shen, Baohui Han, Yuchen Han, Hua Zhong, Hongzhuan Chen, Liang Zhu.

Targeting glucose metabolism has long been pursued as an anticancer strategy, yet its clinical translation remains challenging. Achieving therapeutic selectivity requires identifying actionable metabolic distinctions between different malignant traits. Here, we uncover a noncanonical, lactate-independent glucose metabolic pathway facilitated by the glucose transporter 6 (GLUT6), which confers targeted therapy resistance in lung cancer. Downstream, GLUT6 promotes glucose influx and diversion toward methylglyoxal production, leading to kelch-like ECH-associated protein 1 (KEAP1) dimerization and nuclear factor erythroid 2-related factor 2 (NRF2) pathway activation, driving resistance. Upstream, GLUT6 expression is transcriptionally upregulated by therapy-induced MYC associated zinc finger protein (MAZ) activation. Targeting GLUT6 prevents and overcomes EGFR and KRAS inhibitors resistance. Moreover, the MAZ-GLUT6-NRF2 axis correlates with clinical treatment response and relapse. The preferential reliance on GLUT6-a noncanonical transporter with minimal systemic homeostasis perturbation-highlights its promise as a target for overcoming resistance and revitalizing glucose metabolism-based anticancer strategies.

DOI: https://doi.org/10.1038/s41467-026-72922-7