bims-necame 2026-05-24 papers

bims-necame

Biomed News

on Metabolism in small cell neuroendocrine cancers

Issue of 2026–05–24
ten papers selected by
Grigor Varuzhanyan, UCLA

Reframing small cell lung cancer: therapeutic lessons from hematologic malignancies.
MYC pathway reprogramming through a TIP60 coactivator switch in neuroendocrine lineage transition in prostate cancer.
Dependencies in heterogeneous, lineage plastic patient-derived prostate cancer organoids revealed through integrated single-cell multiomics and CRISPR screening.
Extracellular vesicles as mediators of prostatic diseases: connecting function to diagnostic and therapeutic applications.
Diachronous primary Neuroendocrine tumour of the mediastinum: Dual FDG and DOTA avidity on PET/CT.
Epigenomic profiling of neuroendocrine lung cancers identifies a classical-neuroendocrine ASCL1/NKX2-1 subtype and a SOX11-associated differentiation axis linked to reduced immunogenicity.
From biology to the clinic: research evidence and therapeutic advances of TROP2-targeted antibody-drug conjugates in small cell lung cancer.
Assessment of delta-like ligand 3 (DLL3) immunostaining in neuroendocrine tumors of the gynecological tract and comparing expression with other high-grade gynecological malignancies.
Multiomic analyses delineate human neuroendocrine tumor cell states in relation to normal enteroendocrine cell ontogeny.
Targeting the CHD3 chromatin remodeler exploits a synthetic lethal vulnerability in dual SMARCA4/SMARCA2-deficient cancers via derepression of PARD3B.

Front Oncol. 2026 ;16 1821271

Reframing small cell lung cancer: therapeutic lessons from hematologic malignancies.

Kanak Parmar, Ira Surolia, Anish Thomas.

  Small cell lung cancer (SCLC) remains one of the most aggressive malignancies, characterized by rapid proliferation, early metastatic dissemination, and poor long-term survival despite initial sensitivity to therapy. SCLC shares several biologic and therapeutic principles with hematologic malignancies, including lineage state dependence, adaptive resistance through non-genetic plasticity, and emerging susceptibility to antigen-directed immune therapies. Reframing SCLC through this lens provides a conceptual framework for understanding treatment failure and identifying new therapeutic strategies. A defining feature of SCLC is its dynamic transition between neuroendocrine (NE) and non-neuroendocrine (non-NE) states, driven by epigenetic and transcriptional reprogramming rather than new genetic alterations. These state transitions regulate antigen expression, immune visibility, and therapeutic vulnerability, enabling tumors to evade both cytotoxic and immune-based treatments. This plasticity parallels lineage switching and antigen escape observed in hematologic malignancies treated with targeted and immune therapies. Recent advances in antigen-directed therapy, particularly bispecific T cell engagers and antibody-drug conjugates targeting lineage-associated proteins such as DLL3, SEZ6, and TROP2, have demonstrated promising clinical activity. However, therapeutic efficacy is limited by antigen heterogeneity, evolving tumor states, and microenvironmental barriers including immune exclusion and T cell dysfunction. Epigenetic therapies targeting regulators such as EZH2 and LSD1 offer a strategy to reprogram tumor state, enhance antigen presentation, and sensitize tumors to immunotherapy. Beyond lineage biology, SCLC exhibits dependence on replication stress and DNA damage response pathways, though targeting these vulnerabilities alone has yielded modest clinical benefit. Emerging evidence highlights the role of metabolic and stress-response adaptations, including lactate-mediated immune suppression and integrated stress signaling, in sustaining tumor fitness and resistance. Circulating tumor DNA and epigenomic profiling provide noninvasive approaches to monitor tumor evolution, lineage state, and treatment response over time, offering potential for biomarker-guided therapeutic adaptation. Overall, durable clinical benefit in SCLC will likely require temporally sequenced, biomarker driven combination strategies that anticipate and constrain tumor plasticity. Integrating lineage-directed targeting, epigenetic modulation, immune engagement, and metabolic intervention may enable more effective and sustained disease control in this highly adaptive cancer.

Keywords:  DNA damage response; antibody drug conjugates; antigen-directed therapy; biomarkers; bispecific T cell engagers; circulating tumor DNA; epigenetic priming; lung cancer

DOI:  https://doi.org/10.3389/fonc.2026.1821271
bioRxiv. 2026 May 08. pii: 2026.05.05.723058. [Epub ahead of print]

MYC pathway reprogramming through a TIP60 coactivator switch in neuroendocrine lineage transition in prostate cancer.

Zhen Sun, Jimmy L Zhao, Zahra F Khan, Wazim M Ismail, Teng Han, Subhiksha Nandakumar, Serina Young, Matthew Lange, Pan Cheng, Richard Koche, Nikolaus Schultz, Alexandre Gaspar-Maia, Charles L Sawyers.

Prostate adenocarcinomas (PRAD) can acquire resistance to androgen receptor signaling inhibitors through lineage transition to a cell state known as neuroendocrine prostate cancer (NEPC). Using a panel of isogenic PRAD and NEPC mouse tumoroids, we show that NEPC cells acquire new transcription factor (TF) dependencies that function in a previously undefined network. Through selective perturbation of each TF, we identify ASCL1 as a key regulator of NE lineage fate whereas MYCL functions downstream to drive NEPC growth/survival by recruitment of the TIP60/KAT5 acetyltransferase. Interestingly, while dependencies on specific TF family paralogs can vary across NEPC models, all show markedly enhanced dependency on TIP60. Moreover, the H2A.Z-acetyltransferase activity of the TIP60 complex (TIP60-C) is required for NEPC as well as the acetyl-reader BRD8, which is newly incorporated as a TIP60-C subunit with the NEPC transition. Targeted degradation studies in isogenic tumoroids reveal increased dependence on MYCL in NEPC relative to its paralog MYC in PRAD. In addition to a paralog switch (MYC to MYCL), the MYC pathway-addicted NE state is accompanied by a chaperone switch (from TIP60-C to SRCAP) for H2A.Z histone exchange and a coactivator switch (to TIP60) for MYC target gene expression. The NE-specific coupling of MYCL with TIP60 reveals a previously unappreciated opportunity to target MYC-driven NE diseases through pharmacological inhibition of TIP60.

DOI: https://doi.org/10.64898/2026.05.05.723058
bioRxiv. 2026 May 08. pii: 2026.05.07.723570. [Epub ahead of print]

Dependencies in heterogeneous, lineage plastic patient-derived prostate cancer organoids revealed through integrated single-cell multiomics and CRISPR screening.

Samir Zaidi, Maren Büttner, Weiran Feng, Caitlin Baxter, D Henry Kates, Tiago Paiva Prudente, Diana Zakharova, Sanjoy Mehta, Subhiksha Nandakumar, Chen Khuan Wong, Hojin Lee, Pierre-Jacques Hamard, Wenfei Kang, Jungmin Choi, Ronan Chaligné, Robert Cohen, Yu Chen, Ari Firestone, Zhenghao Chen, Charles L Sawyers.

Lineage plasticity and tumor heterogeneity limit the effectiveness of targeted therapies, yet the functional dependencies used to nominate therapeutic targets are often derived from homogeneous systems that fail to capture this complexity. Here, we establish a framework to resolve state-specific genetic vulnerabilities by integrating single-cell multiomics (RNA and ATAC) with pooled CRISPR-Cas9 screening across a large panel of patient-derived organoids (PDOs) from castrate-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC). We generate a single-cell multiome atlas spanning >190,000 cells across 22 PDOs, defining seven lineage states-including intermediate and plastic populations not resolved by bulk profiling-and demonstrate that these lineage programs robustly classify independent transcriptomic datasets from prostate cancer patient tumors. By systematically coupling this atlas to subtype-resolved CRISPR screens, we construct a functional dependency map linking cell state in heterogeneous 3D human tumor models. We show that intratumoral heterogeneity fundamentally reshapes the interpretation of gene essentiality, whereby gene-level depletion reflects the composite behavior of co-existing subpopulations, and identify a general principle in which resistant "limiting" populations disproportionately determine aggregate fitness effects. This framework reveals both canonical and previously unrecognized lineage-restricted dependencies within highly plastic tumor and NEPC states, including a therapeutically targetable dependency on the aryl hydrocarbon receptor (AHR) in a novel hybrid stem-like/ASCL1 population. Together, these data establish an extensive multi-dimensional prostate cancer resource, identify novel lineage-resolved biology, and provide a generalizable strategy for interpreting functional genomics in heterogeneous human tumors.

DOI: https://doi.org/10.64898/2026.05.07.723570
Extracell Vesicles Circ Nucl Acids. 2026 ;7(2): 545-562

Extracellular vesicles as mediators of prostatic diseases: connecting function to diagnostic and therapeutic applications.

Julie Bishara, Morolake Morakinyo, Sharanjot Saini.

  Diseases of the prostate gland, including benign prostatic hyperplasia (BPH) and prostate cancer (PCa), affect a significant proportion of men worldwide. The incidence of these diseases increases with advancing age decreased quality of life and mortality in cases of aggressive PCa. Advanced PCa shows a spectrum of disease states, including castration-resistant prostate cancer (CRPC) and therapy-resistant neuroendocrine prostate cancer (NEPC). NEPC is a highly aggressive, AR-independent state that evolves from CRPC by "lineage switching". Although the underlying cellular mechanisms have been examined extensively, the role of extracellular-mediated intercellular communication is less well understood. Emerging evidence suggests an important role of extracellular vesicles (EVs) in the pathobiology of these diseases. EVs have been shown to be critical for imparting tumor aggressiveness via inducing epithelial to mesenchymal transition (EMT), stemness and immune evasion. Understanding EV-mediated signaling that governs the progression of prostatic diseases is crucial for developing effective targeted therapies and robust biomarkers for prognosis and risk stratification. Advances in EV engineering have enabled the development of targeted exosome-based therapeutics capable of delivering drugs, biologic payloads, or immune-stimulating signals. In this article, we review our current knowledge on the role of EVs in prostatic diseases, explore their diagnostic and therapeutic applications, and outline future directions aimed at translating EV-based technologies into tools for improved clinical management.

Keywords:  BPH; EVs; biomarkers; exosomes; prostate cancer; therapy

DOI:  https://doi.org/10.20517/evcna.2025.96
J Pak Med Assoc. 2026 Apr;76(4): 618-619

Diachronous primary Neuroendocrine tumour of the mediastinum: Dual FDG and DOTA avidity on PET/CT.

Nadia Nazir, Ayesha Zubair, Aamna Hassan, Kashif Saddique.

Primary neuroendocrine tumours (NETs) of the mediastinum are exceedingly rare, accounting for a small fraction of thoracic neoplasms. Their biological behaviour is heterogeneous, ranging from indolent to highly aggressive depending upon their histological grading. Dual-tracer PET/CT imaging with fluorodeoxyglucose (FDG) and gallium-68 DOTA-conjugated peptides provides complementary information, reflecting heterogeneity of tumour including both metabolic activity and somatostatin receptor expression. barovariability.

DOI: https://doi.org/10.47391/JPMA.26-32
Lung Cancer. 2026 May 18. pii: S0169-5002(26)00525-8. [Epub ahead of print]217 109464

Epigenomic profiling of neuroendocrine lung cancers identifies a classical-neuroendocrine ASCL1/NKX2-1 subtype and a SOX11-associated differentiation axis linked to reduced immunogenicity.

Takashi Sato, Junko Hamamoto, Katsura Emoto, Ryo Nagashio, Yuri Yagami, Hiroki Yamamoto, Ryosuke Inoue, Hiromi Matsuo, Masayuki Shirasawa, Yuki Kuchitsu, Shin Kawano, Yuichiro Hara, Seungyeul Yoo, Takahiro Fukushima, Kai Sugihara, Hideki Terai, Itaru Sanoyama, Yoshiki Murakumo, Hideharu Domoto, Mizuha Haraguchi-Hashiguchi, Kazu Shiomi, Masashi Mikubo, Hiroyuki Yasuda, Hideo Watanabe, Katsuhiko Naoki.

BACKGROUND: Heterogeneity of neuroendocrine (NE) differentiation in pulmonary high-grade NE carcinoma, mainly small-cell lung cancer (SCLC), has been recently explored based on the expression of lineage transcription factors such as ASCL1, NEUROD1 and POU2F3. However, molecular classification based on these factors remains incomplete, and NE differentiation in lung cancers is more heterogeneous than previously appreciated. Here, we investigated the heterogeneity of NE differentiation using epigenomic profiling across a range of lung cancers with NE components, predominantly large-cell neuroendocrine carcinoma (LCNEC).
METHODS: We analyzed super-enhancer profiles of 24 formalin-fixed paraffin-embedded tumor tissues from patients with primary lung cancers containing LCNEC components. Associations between epigenomic profiles and NE factors were examined. The functional role of SOX11 was assessed by transcriptomic analysis following CRISPR-Cas9-mediated deletion, as well as by analysis of human LCNEC/SCLC tumor and organoid datasets.
RESULTS: We identified a classical NE subtype characterized by high expression of ASCL1 and NKX2-1, along with high positivity for canonical NE markers. In addition, we identified a unique differentiation axis characterized by a neural transcription factor SOX11. Transcriptomic analyses revealed loss of neuronal gene signatures accompanied by induction of immune response-associated genes. Consistent with these findings, analysis of the human LCNEC/SCLC data showed enrichment of neuronal genes among those positively correlated with SOX11 expression and immune-associated genes among those negatively correlated. Furthermore, SOX11 was associated with reduced expression of immune-related genes, including MHC class I components.
CONCLUSIONS: Our epigenomic profiling identifies a classical ASCL1/NKX2-1 subtype and a SOX11-associated axis linked to tumor immunogenicity in NE lung cancers.

DOI: https://doi.org/10.1016/j.lungcan.2026.109464
Transl Lung Cancer Res. 2026 Apr 30. 15(4): 103

From biology to the clinic: research evidence and therapeutic advances of TROP2-targeted antibody-drug conjugates in small cell lung cancer.

Haoyu Lu, Meiying Zhu, Yaning Luo, Qiyu Fan, Lihan Shang, Na Wang, Fanming Kong.

  Trophoblast cell surface antigen 2 (TROP2) is a type I transmembrane glycoprotein that was initially identified in studies related to trophoblastic cells and has been implicated in epithelial cell proliferation and the maintenance of cellular stemness. While TROP2 is expressed at low levels in normal epithelial tissues, it is markedly overexpressed in a wide range of malignancies, including small cell lung cancer (SCLC), where it plays a critical role in promoting tumor cell proliferation, invasion, and metastasis. SCLC is characterized by aggressive biological behavior, early dissemination, and rapid development of therapeutic resistance. Despite improvements in first-line outcomes achieved with the combination of immunotherapy and chemotherapy, patients with relapsed or refractory disease continue to face low response rates, high recurrence, and substantial treatment-related toxicity. With antibody-drug conjugates (ADCs) targeting human epidermal growth factor receptor 2 (HER2) demonstrating clear clinical benefit in HER2-mutant non-small cell lung cancer (NSCLC), the tumor-selective overexpression of TROP2 relative to normal tissues has positioned it as an attractive target for ADC-based therapy. TROP2-targeted ADCs therefore represent an innovative therapeutic strategy and offer new promise for the treatment of SCLC. In this review, we systematically summarize the biological characteristics of TROP2 and the emerging clinical evidence supporting TROP2-directed ADCs in SCLC. We further propose an application framework integrating TROP2 expression levels, SCLC molecular subtypes, and DNA damage response (DDR) status, and discuss future research directions, including deeper characterization of TROP2 biology, optimization of combination strategies with immunotherapy and DDR-targeted agents, and the development of precision treatment approaches based on standardized TROP2 assessment and relevant biomarkers.

Keywords:  Antibody-drug conjugate (ADC); biomarkers; clinical trials; small cell lung cancer (SCLC); trophoblast cell surface antigen 2 (TROP2)

DOI:  https://doi.org/10.21037/tlcr-2025-1-1467
Ann Diagn Pathol. 2026 May 19. pii: S1092-9134(26)00060-2. [Epub ahead of print]84 152664

Assessment of delta-like ligand 3 (DLL3) immunostaining in neuroendocrine tumors of the gynecological tract and comparing expression with other high-grade gynecological malignancies.

Maggie Tsang, Ruoji Zhou, Yuna Kang, Sanaz Memarzadeh, Nora Ostrzega, Neda Moatamed.

  Neuroendocrine tumors (NETs) of the gynecologic tract are diagnostically challenging because of their heterogeneity. Delta-like ligand 3 (DLL3), an inhibitory Notch receptor ligand, is frequently overexpressed in NETs and has emerged as a potential diagnostic and therapeutic target. This study evaluated DLL3 expression in 76 paraffin-embedded tissue samples from 74 patients, including cervical and ovarian small cell carcinomas/NETs, cervical large cell carcinoma/NET, metastatic NETs, dedifferentiated/undifferentiated carcinomas, carcinosarcomas, and high-grade serous carcinomas. DLL3 positivity was defined by cytoplasmic staining and assessed by staining intensity (0-3+) and percentage of positive tumor cells. DLL3 expression was detected in 83% of cervical small cell carcinomas/NETs, 67% of ovarian small cell carcinomas/NETs, and 100% of cervical large-cell carcinoma/NETs, all showing strong (3+) staining and seen in 5% to 100% of the tumor cells. Metastatic NETs demonstrated lower expression (14%, 3+), which was seen in 90% of the tumor cells. Among dedifferentiated/undifferentiated carcinomas, 60% showed DLL3 positivity in scattered undifferentiated foci with staining intensities ranging from 1+ to 3+. DLL3 expression was also identified in 62% of carcinosarcomas within scattered foci of sarcomatous areas, with 2+ to 3+ intensity. In contrast, high-grade serous carcinomas lacked DLL3 expression. These findings demonstrate frequent DLL3 expression in gynecologic NETs and selected dedifferentiated malignancies, supporting DLL3 as a promising diagnostic marker and potential therapeutic target in gynecologic cancers.

Keywords:  Delta-like ligand 3 (DLL3); Gynecology; Neuroendocrine tumors

DOI:  https://doi.org/10.1016/j.anndiagpath.2026.152664
J Clin Invest. 2026 May 21. pii: e197772. [Epub ahead of print]

Multiomic analyses delineate human neuroendocrine tumor cell states in relation to normal enteroendocrine cell ontogeny.

Pratik Np Singh, Elsa Hadj Bachir, James R Howe, Andrew M Bellizzi, Paloma Cejas, Shariq Madha-Krause, Charles B Epstein, Jennifer Chan, Bradley E Bernstein, Matthew H Kulke, Qiao Zhou, Ramesh A Shivdasani.

  Cancers reflect aberrant growth and differentiation of normal cell populations. Biological understanding of small intestine neuroendocrine tumors (SI-NETs) is hampered because their closest normal counterparts, enteroendocrine cells (EECs), constitute tiny fractions of intestinal epithelium. Recent characterization of adult human EEC ontogeny from intestinal stem cells can help overcome that limitation. Transient expression of transcription factor gene ASCL1 normally ensures proper timing and fidelity of well-differentiated EECs, which express NEUROD1. Here we report that SI-NETs resembled mature enterochromaffin cells; however, individual tumor cells co-expressed stem/progenitor genes, harboring each differentiation state along the EEC trajectory except ASCL1+ precursors. We found that enhancers normally active, and others inactive, during EEC differentiation underlie aberrant SI-NET gene activity. SI-NETs uniformly expressed NEUROD1 but lacked ASCL1, owing to inaccessible chromatin and repressive H3K27me3 marking at the ASCL1 locus. Multiple cyclin-dependent kinase inhibitor (CDKi) genes were similarly silenced, other than CDKN1B, the only gene recurrently mutated in SI-NETs. Deletion of CDKN1B altered cell cycle kinetics during human EEC differentiation, and deletions of ASCL1 or CDKN1B activated certain genes that are expressed in SI-NETs but not in the normal EEC trajectory. We propose that a limited CDKi repertoire and absence of ASCL1-dependent constraints on EEC maturation together explain unique SI-NET characteristics.

Keywords:  Adult stem cells; Cancer; Development; Gastroenterology; Neuroendocrine regulation; Oncology

DOI:  https://doi.org/10.1172/JCI197772
NPJ Precis Oncol. 2026 May 22.

Targeting the CHD3 chromatin remodeler exploits a synthetic lethal vulnerability in dual SMARCA4/SMARCA2-deficient cancers via derepression of PARD3B.

Mariko Takeuchi, Yoshie Okimoto, Makoto Fukushima, Harumi Hirano, Hideaki Ogiwara.

SWI/SNF-deficient cancers characterized by dual SMARCA4/SMARCA2 loss, including subsets of lung adenocarcinoma and small cell carcinoma of the ovary, hypercalcemic type, represent a major therapeutic challenge. While SMARCA2 paralog-targeting strategies exist for single-subunit loss of SMARCA4, dual SMARCA4/SMARCA2-deficient tumors lack actionable targets. Here, we identify the CHD3/NuRD nucleosome remodeling complex as a critical synthetic lethal vulnerability in these malignancies. Through integrated genomic analyses, we demonstrate that in the absence of SWI/SNF, CHD3 acts as an essential "epigenetic brake" specifically at the enhancer of the cell polarity regulator PARD3B. Loss of CHD3 triggers aberrant chromatin hyper-accessibility and toxic derepression of PARD3B. We further elucidate that PARD3B accumulation is a critical mediator of cell death, which is strongly associated with the attenuation of MYC signaling signatures. This attenuation likely arises from the spatial perturbation of upstream signaling hubs or secondary cellular responses, reducing MYC transcriptional output without degrading the protein itself. Therapeutically, CHD3 depletion led to robust tumor regression in dual SMARCA4/SMARCA2-deficient xenografts, validating the in vivo mechanism of PARD3B upregulation. Collectively, our study defines a novel mode of synthetic lethality driven by "gain-of-toxicity" rather than the loss of survival signals, uncovering a fatal cross-complex dependency. We propose that targeting CHD3 to trigger toxic PARD3B derepression offers a promising therapeutic avenue for treatment-refractory dual SMARCA4/SMARCA2-deficient cancers.

DOI: https://doi.org/10.1038/s41698-026-01499-7