bims-necame Biomed News
on Metabolism in small cell neuroendocrine cancers
Issue of 2026–04–26
nine papers selected by
Grigor Varuzhanyan, UCLA
  1. UHRF1 drives subtype-independent aggressiveness and immune evasion in small cell lung cancer through PRC2 interactions.
  2. YAP1 defines an emergent, plastic population of relapsed small cell lung cancer.
  3. A MYC family switch: L-MYC drives and maintains neuroendocrine lineage programs in prostate cancer.
  4. Organoid-based modeling unveils Dnmt3a-driven epigenetic regulation of phenotypic plasticity in small cell lung cancer.
  5. NFIB Regulates Chemoresistance in Small Cell Lung Cancer by Suppressing Notch Signaling Activity.
  6. Genome-wide Mapping of Histone Modifications and Transcription Factor Binding Sites in Neuroendocrine Small Cell Lung Cancer Cell Lines Using CUT&RUN.
  7. Tumour lysis syndrome following deliberately dose-reduced chemotherapy in extensive-stage small cell lung cancer with critical airway obstruction.
  8. The Quartet of Core Oncogenic Drivers in Neuroendocrine Prostate Cancer: Multi-Omics Dataset Integration to Forge a Translational Link Between Biology and Precision Therapy.
  9. B7-H3 Gene Expression Shapes Prognosis and Therapeutic Opportunities Across Prostate Cancer Patient Groups.
  1. iScience. 2026 Apr 17. 29(4): 115475
    UHRF1 drives subtype-independent aggressiveness and immune evasion in small cell lung cancer through PRC2 interactions.
    Yijun Gu, Jamie-Jean De La Torre, Yasamin Fazeli, J Mateo Valenzuela, Frederick Guzman, Roberto Tinoco, Claudia A Benavente.
      Small cell lung cancer (SCLC) is an aggressive neuroendocrine (NE) carcinoma characterized by early metastasis and an immune-cold microenvironment. We show that UHRF1, a chromatin-associated effector of RB1/E2F signaling, promotes SCLC growth and metastasis across major molecular subtypes. Using human SCLC cell lines, orthotopic and intracardiac xenografts, and genetically engineered mouse models, we found that loss of UHRF1 reduces proliferation, invasion, tumor burden, and metastasis while reprogramming tumors away from NE states toward an inflamed transcriptional program. UHRF1-deficient tumors upregulate chemokines and exhibit increased infiltration of CD8+ T cells and myeloid populations. Mechanistically, UHRF1 interacts with PRC2 to reinforce NE lineage programs and suppress inflammatory gene expression. UHRF1 loss derepresses DNA-methylation-silenced tumor antigens, including MAGE-A4, highlighting a potential vulnerability that could be leveraged therapeutically. Together, these findings connect RB1 loss with chromatin repression, lineage control, and immune exclusion, highlighting UHRF1-dependent repression as a therapeutic vulnerability in SCLC.
    Keywords:  biological sciences; cancer; epigenetics; immunology
    DOI:  https://doi.org/10.1016/j.isci.2026.115475
  2. J Thorac Oncol. 2026 Apr 20. pii: S1556-0864(26)00183-8. [Epub ahead of print] 103730
    YAP1 defines an emergent, plastic population of relapsed small cell lung cancer.
    C Allison Stewart, Kavya Ramkumar, Runsheng Wang, Yuanxin Xi, Alexa Halliday, Lixia Diao, Qi Wang, Alejandra Serrano, Sarah Groves, Simon Heeke, Azusa Tanimoto, Laura Kaiser, Whitney Lewis, Mukulika Bose, Pedro Da Rocha, Loukia Karacosta, Vito Quaranta, Jing Wang, Julie George, Luisa Maren Solis Soto, Bingnan Zhang, John V Heymach, Lauren A Byers, Carl M Gay.
      Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy characterized by rapid onset of chemoresistance and poor clinical outcomes. Transcriptional heterogeneity among treatment-naïve SCLC tumors underlies four transcriptional subtypes, each with distinct clinical vulnerabilities. Though previously hypothesized to delineate a distinct subtype, expression of YAP1 is largely absent from treatment-naïve, pure SCLC. To characterize relapsed SCLC, circulating tumor DNA, circulating tumor cells, and core needle biopsies from SCLC patients and preclinical models following resistance to standard-of-care therapies were analyzed. In contrast to treatment-naïve SCLC, these analyses reveal an emergent YAP1-positive cell population that coincides with treatment resistance. These YAP1-positive cells exhibit characteristics of drug tolerant persister cells, including senescence, stemness, and plasticity, as YAP1 positive cells largely abandon features characteristic of SCLC to adopt those of large-cell neuroendocrine carcinoma (LCNEC). As a result of this SCLC-like to LCNEC-like evolution, YAP1-positive cells lack several clinically relevant SCLC surface targets (i.e., DLL3, SEZ6), but are enriched for others (i.e., B7-H3, TROP2). We propose a model where YAP1 expressing cells emerge with SCLC treatment resistance and characterize a tenacious subpopulation capable of diverging from the treatment naïve lineage and adopting features to evade therapeutic response.
    Keywords:  SCLC; YAP1; intratumoral heterogeneity; plasticity
    DOI:  https://doi.org/10.1016/j.jtho.2026.103730
  3. Neoplasia. 2026 Apr 17. pii: S1476-5586(26)00036-9. [Epub ahead of print]77 101307
    A MYC family switch: L-MYC drives and maintains neuroendocrine lineage programs in prostate cancer.
    Jeyaluxmy Sivalingam, Kaleigh Ballagh, Kyung Hyun Cho, Yingli Shi, Lin Li, Preston Barron, Michael S Lan, Omar E Franco, Xiuping Yu.
      Neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant subtype that emerges through lineage plasticity following androgen receptor pathway inhibition. Although MYC family oncogenes are central to prostate cancer progression, the role of MYCL (L-MYC) in NEPC has remained poorly defined. Here, we show that MYCL is selectively and robustly upregulated in NEPC patient samples and experimental models, whereas MYC is concurrently suppressed and MYCN remains low, revealing a lineage-associated MYC family switch. MYCL expression strongly correlates with the neuroendocrine lineage regulators ASCL1 and INSM1 and inversely with adenocarcinoma-associated genes. Functionally, MYCL overexpression suppresses androgen receptor signaling, induces neuroendocrine-like transcriptional reprogramming, and remodels cytoskeletal and adhesion pathways associated with cellular plasticity, whereas MYCL knockdown disrupts neuroendocrine lineage identity and restores adenocarcinoma-associated gene expression, including MYC. Mechanistically, MYC suppression is associated with transcriptional regulation by ASCL1, while MYCL upregulation appears to occur within a permissive epigenetic landscape rather than through genomic amplification. Together, these findings identify MYCL as a lineage-specific regulator that drives and maintains neuroendocrine identity and define a MYC family regulatory switch in which MYCL replaces MYC to stabilize neuroendocrine lineage programs in advanced prostate cancer.
    Keywords:  MYCL; Neuroendocrine; Prostate cancer
    DOI:  https://doi.org/10.1016/j.neo.2026.101307
  4. Cancer Lett. 2026 Apr 16. pii: S0304-3835(26)00279-X. [Epub ahead of print]650 218516
    Organoid-based modeling unveils Dnmt3a-driven epigenetic regulation of phenotypic plasticity in small cell lung cancer.
    Liansheng Liu, Qingzhe Wu, Shuxian Fang, Zengyong Hu, Shicheng Yu, Hailong Wang, Hai Song, Qian Liu.
      Small cell lung cancer (SCLC) harbors pronounced intratumoral heterogeneity, yet epigenetic drivers of subtype plasticity remain poorly understood. Herein, we established paired neuroendocrine (NE)-high and NE-low SCLC organoids from pulmonary neuroendocrine cells (PNECs)-specific Trp53/Rb1/Pten-triple knockout mice. NE-high organoids developed prominent axon-like protrusions, while NE-low counterparts exhibited cystic structures. Both subtypes maintained primary tumor genetics and tumorigenicity. Transcriptomics revealed NE-high enrichment of neuronal programs versus innate immune pathway upregulation in NE-low organoids. Mechanistically, Polycomb repressive complex 2 (PRC2)-mediated H3K27me3 enrichment in NE-low organoids suppressed Dnmt3a, causing global DNA hypomethylation that reactivated endogenous retroviruses (ERVs), triggering cytosolic double-stranded RNA (dsRNA) accumulation and consequent antiviral interferon response. Notably, Carm1 stabilized Dnmt3a via transient methylation. Targeting Dnmt3a or Carm1 in NE-high organoids drove their transition to a NE-low state with ERV de-repression. Collectively, these findings establish a PRC2/CARM1/DNMT3A axis orchestrating SCLC plasticity, identifying DNA methyltransferase inhibition as a potential therapeutic strategy targeting SCLC heterogeneity and immunosuppression.
    Keywords:  Dnmt3a; Endogenous retroviruses (ERVs); Heterogeneity; Plasticity; Small cell lung cancer (SCLC)
    DOI:  https://doi.org/10.1016/j.canlet.2026.218516
  5. Cancer Rep (Hoboken). 2026 Apr;9(4): e70526
    NFIB Regulates Chemoresistance in Small Cell Lung Cancer by Suppressing Notch Signaling Activity.
    Weixin Qin, Ziyan Wang, Shuzhe Deng, Huilei Qiu, Hongxue Meng, Jingshu Geng.
       BACKGROUND: Small cell lung cancer (SCLC) is an aggressive malignancy characterized by the rapid development of therapy resistance, the underlying mechanisms of which remain incompletely understood. The transcription factor NFIB is a recognized oncogene in SCLC, promoting tumor progression by regulating metastasis and proliferation. However, its potential role in mediating chemotherapy resistance is poorly defined.
    AIMS: This study aimed to elucidate the mechanism by which NFIB regulates chemoresistance in SCLC and to assess the therapeutic potential of co-targeting NFIB and the Notch signaling pathway.
    METHODS AND RESULTS: Expression of NFIB and associated genes was analyzed in SCLC cell lines and clinical samples using Western blotting, quantitative real-time PCR (qRT-PCR), immunofluorescence (IF), and immunohistochemistry (IHC). Transcriptional regulation was examined by chromatin immunoprecipitation (ChIP), and drug sensitivity was measured via CCK-8 assays. We found that NFIB acts as a dual-function regulator, driving oncogenesis and controlling chemoresistance. NFIB knockdown activated the endogenous Notch pathway, which in turn promoted drug resistance. NFIB expression positively correlated with neuroendocrine (NE) markers and contributed to tumor heterogeneity, a process modulated by Notch1. Mechanistically, loss of NFIB relieved its repression of Notch1, leading to suppressed NE gene expression and yielding slow-cycling, chemoresistant cells with activated Notch signaling. Critically, combining Notch pathway inhibition with chemotherapy attenuated intratumoral heterogeneity and reversed this resistance phenotype.
    CONCLUSIONS: NFIB plays a paradoxical role in SCLC, serving as both an oncogenic driver and a key regulator of chemoresistance via Notch pathway activation. These findings revealed a novel resistance mechanism and propose a promising therapeutic strategy of combined Notch inhibition and chemotherapy for SCLC treatment.
    Keywords:  NFIB; SCLC; chemoresistance; heterogeneity; notch
    DOI:  https://doi.org/10.1002/cnr2.70526
  6. J Vis Exp. 2026 Apr 03.
    Genome-wide Mapping of Histone Modifications and Transcription Factor Binding Sites in Neuroendocrine Small Cell Lung Cancer Cell Lines Using CUT&RUN.
    Meijun Du, Jaime Wendt Andrae, Michael Tschannen, Angela Mathison, Victor Jin, Hui-Zi Chen.
      Chromatin remodeling proteins and transcription factors (TFs) play critical roles in the tumor biology of small cell lung cancer (SCLC). Genome-wide characterization of histone post-translational modifications (PTMs) and TF binding sites is essential for identifying regulatory DNA elements and gene pathways that will lead to a deeper mechanistic understanding of SCLC and nominate targets for therapeutic intervention. Cleavage Under Targets and Release Using Nuclease followed by next generation sequencing (CUT&RUN-seq) is a powerful method for mapping specific histone modifications and determining the DNA-binding profiles of a wide range of proteins in situ in the cellular genome. In CUT&RUN, the micrococcal nuclease (MNase) fused to Protein A/G is recruited via antibodies to the genomic locations of chromatin-associated proteins, where the underlying DNA fragments are released from bulk chromatin upon MNase activation and cleavage. This localized digestion generates small, locus-specific DNA fragments suitable for sequencing. Here, we present a detailed protocol for profiling histone modifications H3K4me3 (associated with active or open promoters) and H3K4me1 (associated with active enhancers), as well as the transcription factor E2F7, in SCLC. This protocol has been optimized for neuroendocrine (NE) SCLC cell line models, which are typically characterized by large nuclei, scant cytoplasm, and growth as non-adherent aggregates in suspension.
    DOI:  https://doi.org/10.3791/69656
  7. BMJ Case Rep. 2026 Apr 20. pii: e272527. [Epub ahead of print]19(4):
    Tumour lysis syndrome following deliberately dose-reduced chemotherapy in extensive-stage small cell lung cancer with critical airway obstruction.
    Sze Kye Teoh, Yen Shen Wong, Suhashini Ganapathy, Audi Adawiah Sulaiman Shah.
      A man in his late 60s presented with rapidly progressive dyspnoea and inspiratory stridor requiring emergency intubation. Bronchoscopy demonstrated critical bilateral main bronchial compression, and biopsy confirmed small cell lung cancer (SCLC) with bulky mediastinal disease. Deliberately dose-reduced carboplatin and etoposide were initiated. Despite prophylactic hydration and allopurinol, he developed fulminant tumour lysis syndrome (TLS) approximately 72 hours after chemotherapy initiation, meeting Cairo-Bishop criteria and died despite rasburicase and maximal supportive care.TLS is rare in solid tumours, and in SCLC, it is typically reported following spontaneous lysis or full-dose chemotherapy. This case demonstrates that even dose-reduced chemotherapy, when used emergently in bulky, chemosensitive disease, can precipitate catastrophic TLS. It highlights critical airway compromise in SCLC as a high-risk phenotype and highlights the need for heightened vigilance and anticipatory management when balancing urgent airway stabilisation against systemic therapy.
    Keywords:  Oncology; Respiratory medicine
    DOI:  https://doi.org/10.1136/bcr-2026-272527
  8. Int J Biol Sci. 2026 ;22(7): 3564-3579
    The Quartet of Core Oncogenic Drivers in Neuroendocrine Prostate Cancer: Multi-Omics Dataset Integration to Forge a Translational Link Between Biology and Precision Therapy.
    Youzhi Wang, Ning Wu, Junbo Li, Qian Cao, Jianfei Ye, Shudong Zhang.
      Prostate cancer (PC) is the most common cancer among American men and the second leading cause of cancer-related deaths. For advanced or metastatic PC, anti-androgen therapies, including androgen deprivation therapy (ADT), are considered standard treatment options. However, these therapies often result in the development of castration-resistant prostate cancer (CRPC) or neuroendocrine prostate cancer (NEPC), both of which present significant treatment challenge. The molecular mechanisms driving the progression from androgen - sensitive PC to castration-resistant and neuroendocrine phenotypes are still being actively investigated. This review aims to comprehensively evaluate the cellular and molecular mechanisms underlying the development of NEPC. Specifically, it will focus on the roles of cancer stem cells (CSCs), epithelial - mesenchymal transition (EMT), and autophagy in the pathogenesis and progression of NEPC. Furthermore, the review will explore the potential of targeting these processes for therapeutic intervention in advanced P. This review will integrate current findings from clinical trials, pre-clinical models, and molecular research to clarify the promising approaches for improving treatment outcomes for patients with advanced PC.
    Keywords:  CSCs; EMT; NEPC; PC; autophagy; lineage plasticity
    DOI:  https://doi.org/10.7150/ijbs.129521
  9. Clin Cancer Res. 2026 Apr 21.
    B7-H3 Gene Expression Shapes Prognosis and Therapeutic Opportunities Across Prostate Cancer Patient Groups.
    Allison Makovec, Ava P Gustafson, Nishant Gandhi, Swati Rampalli, Ali T Arafa, Andrew Elliott, Norm Smith, Martin Felices, Philippa R Kennedy, Eugene Shenderov, Akash Patnaik, Vivek Narayan, Elisabeth I Heath, Nicholas A Zorko, Xiaolei Shi, Emmanuel S Antonarakis, Rana R McKay, Justin Hwang.
       PURPOSE: B7-H3 (CD276) represents a promising therapeutic target tested in high-risk localized and treatment-refractory metastatic prostate cancer (PC). To guide therapeutic development and treatment strategies, we examined prostate tumors and evaluated expression, molecular features, and overall survival (OS), accounting for tissue site, hormone-sensitivity status, and race.
    EXPERIMENTAL DESIGN: 8,157 PC samples with paired DNA/RNA were analyzed based on annotations by tissue site, self-reported race, and disease state: hormone-sensitive (HSPC), castration-resistant (CRPC), or neuroendocrine PC (NEPC). Expression quartiles were B7-H3-high (>75th percentile) or B7-H3-low (<25th percentile). OS was evaluated using Kaplan-Meier and Cox proportional hazards models.
    RESULTS: B7-H3 expression was broadly maintained but varied by tumor site, hormone-sensitivity status, and race. High expression aligned with AR-associated transcription factors (HOXB13, FOXA1), AR-associated pathogenic dysregulations (AR-V7, SPOP, FOXA1, TMPRSS2:ERG fusions), and actionable surface antigens (TROP2, NECTIN-4). Weak correlations were found for lineage-plastic program regulators (EZH2, SOX2, ASCL1) and NEPC-associated surface antigens (DLL3, CEACAM5). High B7-H3 expression in primary tumors and HSPCs portended adverse OS (HR: 1.342, 1.30, CI: 1.19-1.512, 1.15-1.46, q < 0.0001), although favorable in metastatic tumors (HR: 0.823, CI: 0.719-0.942, q = 0.0048). No significant differences in OS were observed among CRPCs and NEPCs, although OS varied by race, with poorest survival in Asian/Pacific Islander metastatic PC patients (HR = 3.72, CI: 1.49-9.29, q = 0.012).
    CONCLUSIONS: Maintained B7-H3 expression in various PC settings supports its viability as a target. Associations with AR-related molecular factors, surface antigens, and investigative targets for cell therapy or antibody-drug conjugates (ADC) suggest potential dual-targeting strategies.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-26-0322
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