bims-necame 2025-09-07 papers

bims-necame

Biomed News

on Metabolism in small cell neuroendocrine cancers

Issue of 2025–09–07
ten papers selected by
Grigor Varuzhanyan, UCLA

Seizure-Related Homolog Protein 6 (SEZ6): Biology and Therapeutic Target in Neuroendocrine Carcinomas.
Molecular Characteristics, Heterogeneity, Plasticity, and Cell of Origin of Neuroendocrine Bladder Cancer.
LHX2 Rewires the Metabolic and Epigenetic Landscape to Drive Tumor Progression in Prostate Cancer.
CRISPR Screen Identifies HDAC3 as a Novel Radiosensitizing Target in Small Cell Lung Cancer.
EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer.
Lineage-specific transcription factor landscape of thymic neuroendocrine tumors.
Unbiased CRISPR Synthetic Lethal Screening for Genetic Vulnerabilities in Succinate Dehydrogenase (SDH)-loss Model of Paraganglioma.
MYC and p53 Alterations Cooperate through VEGF Signaling to Repress Cytotoxic T Cell and Immunotherapy Responses in Prostate Cancer.
Pancreatic hepatoid adenocarcinoma with neuroendocrine differentiation and elevated AFP: a case report.
Patient-derived organoids reveal hypoxia-driven plasticity and therapeutic vulnerabilities in pheochromocytomas and paragangliomas.

Clin Cancer Res. 2025 Sep 05.

Seizure-Related Homolog Protein 6 (SEZ6): Biology and Therapeutic Target in Neuroendocrine Carcinomas.

Emelie Gezelius, Natasha Rekhtman, Marina K Baine, Charles M Rudin, Alexander Drilon, Alissa J Cooper.

Seizure-related homolog protein 6 (SEZ6) is a cell surface type 1 transmembrane protein involved in neuronal development, expression of which in adult tissues is almost exclusively limited to the central nervous system. Aberrant expression of SEZ6 has been associated with neurodevelopmental and psychiatric disorders including epilepsy, schizophrenia, and Alzheimer's disease. More recently, SEZ6 overexpression has been detected in small cell lung cancer (SCLC) and other high-grade neuroendocrine malignancies, although our understanding of the function of SEZ6 as a driver of cancer is limited. A lineage-defining transcription factor of SCLC, ASCL1, has been implicated as a regulator of SEZ6 expression. SEZ6 has emerged as a novel target for antibody-drug conjugate (ADC) therapy, and early studies have shown promising antitumor activity, demonstrating the potential for SEZ6 to be targeted by drugs with alternate mechanisms of action. Here, we review the current knowledge of the biology of SEZ6 and its implications in malignancy, summarize the preclinical and clinical findings of SEZ6 targeted ADCs, and discuss future directions to further elucidate the role of SEZ6 in SCLC and other neuroendocrine neoplasms.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-2090
Cancer Heterog Plast. 2025 ;2(1):

Molecular Characteristics, Heterogeneity, Plasticity, and Cell of Origin of Neuroendocrine Bladder Cancer.

Dongbo Xu, Qiang Li.

  Neuroendocrine bladder cancer (NEBC) is a rare but highly aggressive cancer, representing approximately 1% of urinary bladder cancer. The most common NEBC is small cell bladder cancer (SCBC), characterized by high rates of recurrence, chemotherapy resistance, and early mortality. SCBC is histologically identical to small cell lung cancer (SCLC) but remains significantly understudied. Advances in next-generation sequencing techniques have partially elucidated the molecular characteristics of NEBC and identified druggable targets. This review compiles recent studies on human NEBC samples, summarizing key findings on their genomic alterations and molecular subtyping. Notably, it highlights specific mutations in the TERT promoter and epigenetic modifiers in NEBC, as well as molecular subtyping based on lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. Furthermore, this review explores the significant tumor heterogeneity and cellular plasticity observed in NEBC and discusses its cell of origin and potential therapeutic targets (MET inhibitor or DLL3) identified by preclinical NEBC models. Emerging evidence suggests that NEBC may share a common origin with urothelial carcinoma (UC), arising from a UC precursor. Advancing our understanding of NEBC tumorigenesis and identifying druggable targets will enhance treatment outcomes for patients with NEBC.

Keywords:  cell of origin; heterogeneity; molecular characteristics; neuroendocrine bladder cancer; plasticity; small cell bladder cancer

DOI:  https://doi.org/10.47248/chp2502010005
Cancer Res. 2025 Sep 03.

LHX2 Rewires the Metabolic and Epigenetic Landscape to Drive Tumor Progression in Prostate Cancer.

Jun Jiang, Shaojie Liu, Chao Xu, Limin He, Hongji Li, Yike Zhou, Zhengxuan Li, Yu Li, Fa Yang, Yuchen Wei, Tong Lu, Keying Zhang, Jingliang Zhang, Pang Wang, Li Guo, Changhong Shi, Weihong Wen, Rui Zhang, Donghui Han, Weijun Qin.

Neuroendocrine prostate cancer (NEPC) evolves as an aggressive phenotype during prolonged androgen deprivation therapy, lacking effective clinical management. Here, we elucidated a reciprocal metabolic-epigenetic mechanism involving a positive feedback loop between glycolysis and the transcription factor LHX2 that promotes PCa progression. Mechanistically, enzalutamide-mediated inhibition of the androgen receptor (AR) led to upregulation of key glycolytic enzymes. Elevated glycolysis resulted in lactate accumulation and subsequent histone lactylation, which in turn enhanced LHX2 expression. Reciprocally, LHX2 transcriptionally activated the lactate dehydrogenase LDHA, which further amplified lactate production. Furthermore, LHX2 augmented the expression of the lineage-determining enzyme DNMT1, potentiating neuroendocrine gene expression and tumor growth. Significantly, the antiviral agent paritaprevir could directly bind to LHX2, effectively suppressing neuroendocrine marker expression and tumor progression. These findings uncover a potential role for LHX2 in orchestrating NEPC development, offering putative therapeutic targets for treating this aggressive cancer phenotype and overcoming drug resistance.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0587
Mol Cancer Ther. 2025 Sep 03.

CRISPR Screen Identifies HDAC3 as a Novel Radiosensitizing Target in Small Cell Lung Cancer.

Ujas A Patel, Mary Y Shi, Jalal M Kazan, Kevin C J Nixon, Xiaozhuo Ran, Sree N Nair, Olivia Huang, Lifang Song, Mansi K Aparnathi, Michael Y He, Mehran Bakthiari, Rehna Krishnan, Razan K Hessenow, Vivek Philip, Troy Ketela, Verena Jendrossek, Razqallah Hakem, Housheng H He, Robert Kridel, Benjamin H Lok.

Small cell lung cancer (SCLC) is an aggressive malignancy, with most patients presenting with prognostically poor extensive-stage disease. Limited progress in standard care stresses the urgent need for novel therapies. Radiotherapy offers some survival benefit for selected SCLC patients but could be enhanced with radiosensitizers. Here, we identify HDAC3 as a novel radiosensitizing target in SCLC using a CRISPR knockout screen and demonstrate its efficacy and mechanism. SBC5 cells were transduced with a custom EpiDrug sgRNA library and treated with ionizing radiation (IR) to identify radiosensitizing genes. HDAC3 emerged as a candidate and was validated through genetic knockdown (KD) and pharmacologic inhibition (RGFP966) in multiple SCLC cell lines. Both approaches enhanced radiosensitivity, as shown by cell viability (dose-modification factor [DMF]10 = 1.14-1.69) and clonogenic assays (DMF10 = 1.16-1.41). We assessed changes in chromatin accessibility by ATAC-seq, and IR-induced DNA damage and repair using γH2AX foci detection, DSB repair assays and immunoblotting of repair proteins. HDAC3-deficient cells exhibited increased chromatin accessibility, greater IR-induced DSBs, and impaired repair capacity, resulting in persistent DNA damage. This repair defect sensitized cells to PARP inhibitors, where combining RGFP966 with Olaparib or Talazoparib produced additive to synergistic effects. In SCLC xenograft models, HDAC3 KD or RGFP966, combined with IR, achieved significant tumor growth inhibition. Collectively, we identified HDAC3 as a novel radiosensitizing target in SCLC. Its functional loss increased the generation and persistence of IR-induced DNA DSBs, effectively sensitizing SCLC cell lines and xenografts to IR, providing a potential radiosensitization strategy to treat SCLC.

DOI: https://doi.org/10.1158/1535-7163.MCT-24-0861
Res Sq. 2025 Aug 21. pii: rs.3.rs-7360528. [Epub ahead of print]

EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer.

Leigh Ellis, Beatriz German, Katherine Morel, Teia Noel, Nadia Boufaied, Deborah Burkhart, Sujun Chen, Felipe Dezem, Xintao Qiu, Henry Long, Stefan DiFazio, Sylvan Baca, Ayesha Shafi, Matthew Freedman, Himisha Beltran, Christopher Sweeney, Housheng He, Myles Brown, Jasmine Plummer, Simon Knott, David Labbé.

Phenotypic plasticity is a recognized mechanism of therapeutic resistance in prostate cancer (PCa), however current knowledge of driver mechanisms and therapeutic interventions are limited. Using genetically engineered mouse models (GEMMs) devoid of Pten and Rb1, we previously demonstrated the chromatin reprogramming factor enhancer of zeste homolog 2 (EZH2) as an important regulator of alternative transcription programs promoting phenotypic plasticity. Here, using a multi-omics approach we demonstrate that EZH2 regulates multilineage cell states dependent on the RNA binding protein Tristetraprolin (TTP) that mediates RNA stability and activation of translation. Combined chemical inhibition of EZH2 and PI3K/mTORC1 resulted in superior anti-tumor activity in murine and human phenotypic plastic models and was most significant when this combination was used with castration or enzalutamide. Together, these data indicate phenotypic plasticity dependence on coordination between EZH2, TTP and mTORC1 signaling that represent novel therapeutic dependencies for this lethal PCa phenotype.

DOI: https://doi.org/10.21203/rs.3.rs-7360528/v1
Lung Cancer. 2025 Aug 27. pii: S0169-5002(25)00623-3. [Epub ahead of print]208 108731

Lineage-specific transcription factor landscape of thymic neuroendocrine tumors.

Seiji Omura, Yutaka Kurebayashi, Junko Hamamoto, Hideki Terai, Tomohiro Imoto, Mikito Suzuki, Kazuo Nakagawa, Takahiro Suzuki, Takao Shigenobu, Akira Yoshizu, Chihaya Maeda, Masahiro Kaji, Yu Okubo, Shigeki Suzuki, Kyohei Masai, Kaoru Kaseda, Koichi Fukunaga, Hiroyuki Yasuda, Keisuke Asakura.

   INTRODUCTION: Thymic neuroendocrine tumors (TNETs) are rare malignancies characterized by aggressive clinical behavior and limited therapeutic options. In small cell lung cancer (SCLC), molecular subtypes based on the expression of lineage-defining transcription factors (TFs)-ASCL1, NEUROD1, POU2F3, and YAP1-have been proposed. However, the TF landscape of TNETs remains poorly defined. Given the pathological similarities among neuroendocrine tumors across organs, we aimed to investigate whether the TF-based classification system used in SCLC is applicable to TNETs.
METHODS: Sixteen pathologically confirmed TNETs-including large cell neuroendocrine carcinoma (LCNEC), thymic small cell carcinoma (TSCC), atypical carcinoid (AC), and typical carcinoid (TC)-were retrospectively analyzed. Immunohistochemistry was performed to evaluate classical neuroendocrine (NE) markers (synaptophysin, chromogranin A, CD56) and TFs (ASCL1, NEUROD1, POU2F3, YAP1). H-scores were calculated, and tumors were categorized according to TFs expression profiles.
RESULTS: Synaptophysin was strongly expressed in all cases, while chromogranin A and CD56 showed variable expression, with reduced levels in LCNEC and TSCC. The combined NE score was significantly higher in carcinoid tumors compared to LCNEC and TSCC. For TFs, ASCL1 expression was observed in 93.8 % of cases, whereas NEUROD1 and POU2F3 were rarely or not expressed. YAP1 expression was confined to LCNEC cases, all of which co-expressed ASCL1 and YAP1. Based on H-scores, TNETs were classified into three subgroups: (1) ASCL1-positive/YAP1-negative (n = 12, 75 %), (2) ASCL1/YAP1 double-positive (n = 3, 19 %), and (3) double-negative (n = 1, 6 %).
CONCLUSION: This study reveals molecular heterogeneity among TNETs. Notably, ASCL1 and YAP1 co-expression characterizes all LCNEC cases, making a distinct TF landscape in high-grade TNETs.

Keywords:  ASCL1; Immunohistochemistry; Molecular classification; Thymic neuroendocrine tumors; YAP1

DOI:  https://doi.org/10.1016/j.lungcan.2025.108731
bioRxiv. 2025 Aug 28. pii: 2025.08.26.672429. [Epub ahead of print]

Unbiased CRISPR Synthetic Lethal Screening for Genetic Vulnerabilities in Succinate Dehydrogenase (SDH)-loss Model of Paraganglioma.

Fatimah J Al Khazal, Michael J Emch, Cristina M de Araujo Correia, Judith Favier, John R Hawse, L James Maher.

Succinate dehydrogenase (SDH)-deficient paraganglioma and pheochromocytoma (PPGL) are rare neuroendocrine tumors for which no effective targeted therapies currently exist. To uncover new potential therapeutic targets, we performed an unbiased CRISPR-Cas9 genetic screen in immortalized mouse chromaffin cells (imCCs) with and without Sdhb loss. Our screen identified genes that differentially affect cell proliferation in Sdhb -deficient versus normal imCCs. Notably, several subunits of the transcriptional Mediator complex emerged as potential tumor suppressors, as their loss selectively promoted growth of Sdhb -deficient cells. Most strikingly , we found that the neddylation pathway-required for ubiquitin-mediated selective protein degradation-plays a critical role in controlling cell growth and survival in Sdhb -deficient imCCs. Specifically, loss of the neddylation regulator Ube2m led to increased proliferation, while loss of Ube2f suppressed growth of Sdhb -deficient imCCs. Consequently, global neddylation inhibitor MLN4924 (Pevonedistat) and UBE2F-CRL5 axis inhibitor HA-9104 were shown to downregulate neddylation, suppressing UBE2F activity and selectively inhibiting growth of Sdhb -deficient imCCs. This unexpected result highlights the neddylation pathway as a promising druggable vulnerability in this cell culture model of SDH-deficient PPGL.

DOI: https://doi.org/10.1101/2025.08.26.672429
Cancer Res. 2025 Sep 03.

MYC and p53 Alterations Cooperate through VEGF Signaling to Repress Cytotoxic T Cell and Immunotherapy Responses in Prostate Cancer.

Katherine C Murphy, Kelly D DeMarco, Lin Zhou, Jessica Peura, Hadiya K Giwa, Yvette Lopez-Diaz, Yu-Jui Ho, Junhui Li, Shi Bai, Karl Simin, Lihua J Zhu, Jason R Pitarresi, Arthur M Mercurio, Marcus Ruscetti.

Patients with castration-resistant prostate cancer (CRPC) are generally unresponsive to tumor targeted treatments and immunotherapies. Genetic alterations acquired during the evolution of CRPC may impact anti-tumor immunity and immunotherapy responses, which could inform personalized therapeutic strategies. Using our innovative electroporation-based mouse models, we generated distinct genetic subtypes of CRPC found in patients and uncovered unique immune microenvironments. Specifically, mouse and human prostate tumors with MYC amplification and p53 disruption had weak cytotoxic lymphocyte infiltration and an overall dismal prognosis. MYC and p53 cooperated to induce tumor intrinsic secretion of VEGF, which signaled through VEGFR2 expressed on CD8+ T cells to directly inhibit T cell migration and effector functions. Targeting VEGF-VEGFR2 signaling in vivo remodeled the immune suppressive prostate tumor microenvironment, leading to CD8+ T cell-mediated primary tumor and metastasis growth suppression and significantly increased overall survival in MYC and p53 altered CPRC. VEGFR2 blockade also led to induction of PD-L1 in tumors and produced anti-tumor efficacy in combination with PD-L1 immune checkpoint blockade in multiple preclinical CRPC mouse models. Thus, these results identify a genetic mechanism of immune suppression through VEGF signaling in prostate cancer that can be targeted to reactivate immune and immunotherapy responses in an aggressive subtype of CRPC.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2532
Front Oncol. 2025 ;15 1652925

Pancreatic hepatoid adenocarcinoma with neuroendocrine differentiation and elevated AFP: a case report.

Zhouliang Yang, Ting Li, Xiaowei Zhang.

   Background: Hepatoid adenocarcinoma (HAC) of the pancreas is a rare malignant tumor characterized by morphologic and immunophenotypic features resembling hepatocellular carcinoma. The tumor cells exhibit polygonal morphology with eosinophilic or clear cytoplasm and large, irregular nuclei. Immunophenotypically, the tumor cells are positive for alpha-fetoprotein (AFP) and glypican-3. Pancreatic HAC is rare, and neuroendocrine differentiation often complicates both diagnosis and treatment.
Case description: We report a case of pancreatic HAC with neuroendocrine differentiation and elevated AFP levels. A 46-year-old man was hospitalized due to progressive jaundice and dark urine that persisted for a week. Physical examination revealed bile duct dilation, a pancreatic head mass, and markedly increased AFP levels. The patient, with a history of schizophrenia and lung cancer surgery 2 years prior, was on regular medication. Following a pancreaticoduodenectomy, postoperative monitoring indicated normalization of AFP levels.
Conclusion: Elevated serum AFP levels may be a crucial indicator for preoperative pancreatic HAC diagnosis. Additionally, pancreatic HAC has unique histological and immunophenotypic characteristics. However, neuroendocrine differentiation complicates diagnosis and treatment. Therefore, complete surgical resection is the optimal treatment option for this condition.

Keywords:  alpha-fetoprotein; hepatocellular adenocarcinoma; neuroendocrine differentiation; pancreatic cancer; rare tumors; surgical resection

DOI:  https://doi.org/10.3389/fonc.2025.1652925
bioRxiv. 2025 Aug 23. pii: 2025.08.22.671868. [Epub ahead of print]

Patient-derived organoids reveal hypoxia-driven plasticity and therapeutic vulnerabilities in pheochromocytomas and paragangliomas.

Xiaojing Wang, Maite Calucho, Cynthia M Estrada-Zuniga, Mehwish Noureen, Hector Gonzalez-Cantu, Samantha Mossuto, Jonathan N Levi, Bethany Landry, Qianjin Guo, Kailee A Rutherford, Zi-Ming Cheng, Andreanne Sannajust, Sapna Raghunathan, Sanskriti Balaji, Viviane Nascimento da Conceicao, Summer Norris, S Yusra Munawar, Huyen Thi-Lam Nguyen, Jacob De Rosa, Gail Tomlinson, James X Wu, Michael W Yeh, Masha J Livhits, Anand Vaidya, James Powers, Ron Lechan, Art Tischler, Miao Zhang, Paul Graham, Camilo Jimenez, Mirko Peitzsch, Nicole Bechmann, Graeme Eisenhofer, Yanli Ding, Mio Kitano, Alice Soragni, Patricia L M Dahia.

Pheochromocytomas and paragangliomas (PPGLs) are rare chromaffin cell-derived neuroendocrine tumors of sympathetic (catecholamine-producing) or parasympathetic (nonsecretory) origin, frequently driven by dysregulation of hypoxia-inducible factor (HIF) signaling, particularly HIF-2α. Although often benign, PPGLs can metastasize unpredictably, with limited therapeutic options once disseminated. Progress has been hindered by the lack of robust preclinical models, especially those that capture their molecular complexity and microenvironmental influences. To address this gap, we established patient-derived tumor organoids (PDOs) from 35 PPGLs, encompassing a broad spectrum of clinical and molecular phenotypes. The organoids retained key immunohistochemical, genomic, transcriptomic, and catecholamine-secretory features of their parental tumors. PPGL organoids cultured under hypoxic conditions generally exhibited enhanced viability, supporting hypoxia as a driver of cell survival. Hypoxia activated HIF-1α and expanded ASCL1 + cell populations, suggesting a lineage shift toward an immature chromaffin state. In contrast, long-term normoxic cultures activated hypoxia inducible factor 2α (HIF-2α) and acquired a hybrid sympathoblast-mesenchymal identity in subpopulations with upregulation of extracellular matrix and cell cycle markers, independent of genotype. These features resemble high-risk neuroblastoma subtypes and establish a molecular parallel suggestive of shared lineage plasticity and pathogenic programs, detectable in primary PPGLs. Drug screening across a library of up to 51 drugs and combinations revealed both shared and unique vulnerabilities, with response rates to approved therapies matching clinical observations. The CDK4/6 inhibitor abemaciclib, previously unexplored in PPGLs, elicited the strongest activity. Abemaciclib-responsive PDOs and their matched tumors, including a metastatic sample, exhibited epithelial mesenchyme transition enrichment, nominating potential biomarkers for patient stratification. Our results establish PDOs as a novel platform for modeling neuroendocrine tumor biology, reveal microenvironment-driven plasticity in PPGLs, with potential translational relevance, and identify actionable vulnerabilities in a disease with few effective systemic therapies.
Main findings: PDOs can be successfully generated from PPGLs of various genetic backgrounds and reflect parental tumor propertiesPDO cultures grown in hypoxia retain main molecular features of parental tumors, have increased viability and a more immature developmental/biosynthetic profileLong term PDOs grown for 4 weeks in normoxia activate HIF2α, drift toward a hybrid sympathoblast-mesenchymal-like identity resembling relapsed/therapy resistant neuroblastomas, features that can be detected in primary tumorsA subset of PDOs respond to Abemaciclib, a drug class not previously used therapeutically in PPGLs.

DOI: https://doi.org/10.1101/2025.08.22.671868