bims-necame 2026-03-08 papers

bims-necame

Biomed News

on Metabolism in small cell neuroendocrine cancers

Issue of 2026–03–08
ten papers selected by
Grigor Varuzhanyan, UCLA

Small Cell Lung Cancer Establishes a Metabolic Autocrine Mechanism Through Active Extracellular ATP Transport.
ALDH1L2 induces resistance to chemotherapy in small cell lung cancer by inhibiting ferroptosis.
Single-cell profiling of tumor lineage plasticity and the immune microenvironment in transformed small cell lung cancer.
Heterogeneous associations between molecular subtypes of small cell lung cancer and survival prognosis: a systematic review highlighting knowledge gaps.
A Hierarchy of Luminal Transcription Factors Defines AR Cistrome and Is Lost in Neuroendocrine Prostate Cancer.
Cytologic Features Across Molecular Subtypes of Small Cell Lung Carcinoma: Classical Uniformity With Exceptions in POU2F3-Positive Cases.
Clinical Utility of Transcriptomic Signatures to Identify Androgen Receptor and Neuroendocrine Signaling in Prostate Cancer.
Intercepting YAP Activation in Prostate Cancer Blocks Neuroendocrine Progression.
Integrative Molecular Analysis to Predict Clinical Benefit of Everolimus in Patients With Gastro-Entero-Pancreatic Neuroendocrine Tumors (GEP-NETs).
PRRT for well-differentiated Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs).

Cancer Sci. 2026 Mar 02.

Small Cell Lung Cancer Establishes a Metabolic Autocrine Mechanism Through Active Extracellular ATP Transport.

Takeshi Tsuruda, Manabu Kodama, Keiichi I Nakayama.

  Small cell lung cancer (SCLC) is an aggressive malignancy with a 5-year survival rate of less than 7%. SCLC is characterized by accelerated de novo purine nucleotide biosynthesis, which fuels its rapid proliferation. While ATP serves as an essential metabolic substrate for nucleotide polymer synthesis and as the universal energy currency that fuels essential biological processes, it can also act as a potent extracellular signaling molecule. Here, we identify an autocrine mechanism in which SCLC actively exports ATP to the extracellular space through pannexin 1 (PANX1) channels, thereby promoting its own proliferation via purinergic signaling. Marked elevation of extracellular ATP was observed in SCLC cells. Clinical meta-analysis revealed that high PANX1 expression is significantly associated with poor survival in SCLC patients. Pharmacological inhibition or genetic knockdown of PANX1 suppressed extracellular ATP levels and markedly reduced SCLC cell proliferation, whereas PANX1 overexpression increased extracellular ATP and accelerated growth. This ATP efflux is driven by calcium-dependent activation of PANX1, with the calcium/calmodulin-dependent protein kinase II (CaMKII)-TRPA1 axis identified as a key upstream regulator. Moreover, blockade of the P2RX7 receptor abrogated ATP-induced proliferation, indicating that SCLC establishes a metabolic autocrine loop through ATP release and P2RX7 activation. In mouse xenograft models, PANX1 knockdown suppressed, whereas PANX1 overexpression enhanced, tumor growth in vivo. These findings indicate that SCLC exploits a PANX1-dependent ATP release mechanism to engage P2RX7-mediated autocrine signaling and suggest that targeting this axis may represent a potential therapeutic opportunity for this lethal cancer.

Keywords:  adenosine triphosphate (ATP); ligand‐gated ion channel 7 (P2RX7); metabolic autocrine; pannexin 1 (PANX1); purinergic receptor P2X; small cell lung cancer (SCLC)

DOI:  https://doi.org/10.1111/cas.70350
Redox Biol. 2026 Feb 23. pii: S2213-2317(26)00096-0. [Epub ahead of print]91 104098

ALDH1L2 induces resistance to chemotherapy in small cell lung cancer by inhibiting ferroptosis.

Yueming Zhang, Ruibin Yi, Xinyi Zhou, Qiong Lyu, Huiying Liu, Yaru Zhu, Peng Luo, Weitao Shen, Jian Zhang.

  Small cell lung cancer (SCLC) is known for its rapid growth and early metastasis, and SCLC patients are highly susceptible to chemoresistance. Studies have shown that the combination of ferroptosis induction and TRX pathway inhibition can significantly inhibit SCLC tumor growth, but the molecular mechanisms underlying ferroptosis in SCLC are poorly understood. In this study, we explored the regulatory role of the ALDH1L2-related metabolic pathway in SCLC chemoresistance by machine learning. We found that ALDH1L2 expression is a poor prognostic factor for SCLC patients and that high ALDH1L2 expression can negatively regulate the level of cellular lipid peroxidation and inhibit ferroptosis, thereby promoting SCLC chemoresistance. Mechanistically, ALDH1L2 interacts with the TRX2-PRDX3 antioxidant network to reduce the levels of hyperoxidized PRDX3 and oxidized PRDX3 dimers in the plasma membrane under cisplatin-induced stress and decrease cellular susceptibility to ferroptosis, thus promoting SCLC chemoresistance. In addition, we found that thiostrepton, a PRDX3 inhibitor, can synergize with chemotherapy to suppress tumor growth in SCLC, suggesting that thiostrepton might be a promising new tool for overcoming SCLC chemoresistance.

Keywords:  ALDH1L2; Chemoresistance; Ferroptosis; PRDX3; Small cell lung cancer

DOI:  https://doi.org/10.1016/j.redox.2026.104098
J Transl Med. 2026 Mar 04.

Single-cell profiling of tumor lineage plasticity and the immune microenvironment in transformed small cell lung cancer.

Jie Huang, Zhenhua Zhang, Guodi Cai, Weiye Huang, Yu-Qing Chen, Jian Zhang, Lei Yang, Qing Zhou, Jin-Ji Yang, Junjian Wang.

   BACKGROUND: The transformation of non-small cell lung cancer (NSCLC) into small cell lung cancer (SCLC) is a recognized treatment resistance mechanism, most often arising from EGFR-mutant lung adenocarcinoma (LUAD). However, the underlying mechanisms of transformation remain poorly understood.
METHODS: Single-cell RNA sequencing was employed to analyze the tumor cell heterogeneity and to map the intratumoral immune cell landscape of 73,195 cells from five LUAD, three transformed small cell lung cancer (T-SCLC) and four SCLC patients. Multiplex immunofluorescence (mIF) staining and in vitro studies were further conducted to validate the stem-like feature of a malignant cell cluster and the enrichment and the function of interferon-stimulated gene-positive (ISG+) lymphocytes in transformation.
RESULTS: Although increased intratumoral heterogeneity was observed upon SCLC transformation, a stem-like malignant cell subpopulation was identified to recur across subtypes and groups as the pioneering force of lineage plasticity for SCLC transformation. Further mIF staining and transcription factor analysis validated the stem-like feature. Additionally, tumor immune microenvironment (TIME) analysis revealed that ISG+ T cells and B cells were enriched in T-SCLC. Further cell co-culture analyses disclosed that ISG+ lymphocytes promoted neuroendocrine differentiation in LUAD cells via type I interferons (IFN-Is). Deciphering cell-cell interactions revealed that the stem-like malignant cells might activate and attract ISG+ T cells. Finally, we developed an ISG-associated gene signature that significantly correlates with poor prognosis in LUAD.
CONCLUSION: Our findings provide a comprehensive understanding of the lineage plasticity and the immune landscape in T-SCLC, highlighting the crucial role of the stem-like cell cluster and ISG+ lymphocytes in LUAD-to-SCLC transformation.

Keywords:  IFN; Lineage plasticity; MX1; Stemness; Transformed SCLC

DOI:  https://doi.org/10.1186/s12967-026-07940-6
Eur J Med Res. 2026 Mar 06.

Heterogeneous associations between molecular subtypes of small cell lung cancer and survival prognosis: a systematic review highlighting knowledge gaps.

Shumeng Li, Hui Li, Jinghong Wu, Lin Cheng, Ganlin Zhang, Teng Ma, Guowang Yang.

   BACKGROUND: Small cell lung cancer (SCLC) is a heterogeneous disease with different pathogenic mechanisms. A range of molecular classification systems has been proposed based on the tumor's molecular characteristics. However, the relationship between these various molecular subtypes and survival prognosis remains unclear and has not been incorporated into clinical practice. Therefore, we conducted a systematic review of studies investigating the relationship between molecular subtypes of SCLC and patient survival prognosis.
METHOD: A comprehensive search was conducted in the PubMed, Embase, Cochrane, and Web of Science databases, utilizing combinations of terms related to SCLC, molecular subtypes, and survival prognosis. Two independent reviewers were tasked with data extraction and quality assessment.
RESULTS: Following a comprehensive review of the pertinent literature, eight studies were included. Some methodological heterogeneity across these studies contributed to frequently inconsistent conclusions. Our findings tend to suggest that the inflammatory subtype (SCLC-I), which belongs to the non-neuroendocrine (non-NE) subtype, exhibits a survival advantage in most cases, while the ASCL1-dominant subtype (SCLC-A), which belongs to the NE subtype, shows a poorer survival prognosis, except in some exceptional cases.
CONCLUSIONS: This is one of the first comprehensive systematic reviews to explore the relationship between molecular subtypes and survival prognosis in SCLC. Future high-quality studies employing standardized subtype definitions are warranted to validate these prognostic associations and enable definitive conclusions. Furthermore, emerging multi-omics and integrated spatial analyses have revealed novel subtypes and predictors, which are significantly associated with survival prognosis.

Keywords:  Small cell lung cancer; Subtypes; Survival prognosis; Systematic review

DOI:  https://doi.org/10.1186/s40001-026-04052-1
Cancer Heterog Plast. 2025 ;pii: 0008. [Epub ahead of print]2(2):

A Hierarchy of Luminal Transcription Factors Defines AR Cistrome and Is Lost in Neuroendocrine Prostate Cancer.

Viriya Keo, Xiaodong Lu, Lourdes Brea, Xianglin Shi, Jindan Yu, Jonathan C Zhao.

  Androgen receptor (AR) is a hormonal transcription factor (TF) that binds to cis-regulatory elements of prostate lineage-specific genes to govern androgen response and progression of prostate cancer (PCa). This AR cistrome has been reported to be controlled by multiple chromatin-pioneering factors such as FOXA1, HOXB13, and GATA2. However, how these pioneer factors cooperate to regulate the AR cistrome remains unclear. Here, through comparative ChIP-seq analyses, we found that FOXA1 alone was sufficient to recruit AR to its binding sites regardless of H3K4me1. FOXA1 further enlisted HOXB13 and/or GATA2 to augment AR binding and enhancer activation, while HOXB13 and/or GATA2 alone were unable to recruit each other, nor AR. Moreover, HOXB13 knockdown attenuated AR and GATA2 expression and chromatin binding but failed to reprogram their cistromes, suggesting a role as a cofactor rather than a pioneer factor. During the neuroendocrine transformation (NET) of PCa, AR, GATA2, and HOXB13 were lost due to promoter hypermethylation, whereas FOXA1 was down-regulated by transcriptional repression. Lastly, through analyses of tissue microarrays, we confirmed that FOXA1 protein levels were drastically reduced in neuroendocrine PCa, as compared to AR-positive PCa. Therefore, our findings report a hierarchical network of TFs, pioneered by FOXA1 and facilitated by HOXB13 and GATA2, that defines lineage-specific AR cistrome and was lost during NET of PCa.

Keywords:  ChIP-seq, pioneer factor, cistrome reprogramming; FOXA1, GATA2, DNA methylation; HOXB13; Neuroendocrine prostate cancer

DOI:  https://doi.org/10.47248/chp2502020008
Cytopathology. 2026 Mar 06.

Cytologic Features Across Molecular Subtypes of Small Cell Lung Carcinoma: Classical Uniformity With Exceptions in POU2F3-Positive Cases.

Kai Mizoguchi, Yuki Teramoto, Masahiro Hirata, Hironori Haga.

   OBJECTIVE: Small cell lung carcinoma (SCLC) comprises molecular subtypes defined by transcription factor expression, but cytologic correlates of these groups remain poorly characterised. We investigated whether cytomorphologic features differ across subtypes and identified variants that may confound diagnosis.
METHODS: We conducted a single-center, retrospective study of 30 SCLC cases diagnosed between 2021 and 2024. Molecular subtypes were assigned on histologic tissue using immunohistochemistry and classified as SCLC-A (ASCL1), SCLC-N (NEUROD1), SCLC-P (POU2F3) and SCLC-I (inflamed subtype). Paired cytology specimens, including conventional smears stained with Papanicolaou and Giemsa as well as liquid-based cytology, were reviewed. Classical morphology was defined by established SCLC criteria, and non-classical morphology by deviations such as enlarged nuclei with prominent nucleoli, increased cytoplasm and reduced nuclear moulding.
RESULTS: Twelve tumours were classified as SCLC-A, 6 as SCLC-N, 9 as SCLC-P and 3 as SCLC-I. Cytomorphology was uniformly classical in 28 cases, encompassing all SCLC-A, SCLC-N and SCLC-I tumours. Two SCLC-P cases demonstrated non-classical morphology with relatively abundant cytoplasm and conspicuous nucleoli, imparting an appearance more reminiscent of non-small cell carcinoma.
CONCLUSIONS: Cytomorphology is largely conserved across molecular subtypes of SCLC, but a minority of POU2F3-positive tumours may display non-classical features. Recognition of this variant is important to avoid misclassification, particularly when only limited cytology material is available. These findings suggest that lineage-defining programs may occasionally imprint the cytologic phenotype and highlight the value of considering subtype-oriented ancillary testing in challenging cases.

Keywords:  POU2F3; cytodiagnosis; immunohistochemistry; molecular subtype; small cell lung carcinoma; transcription factors

DOI:  https://doi.org/10.1111/cyt.70067
JCO Precis Oncol. 2026 Mar;10 e2500756

Clinical Utility of Transcriptomic Signatures to Identify Androgen Receptor and Neuroendocrine Signaling in Prostate Cancer.

Yu-Wei Chen, Joanne Xiu, Kelsey Anne Poorman, Charles J Ryan, Brady Gilg, Matthew James Oberley, Gloria Sura, George W Sledge, Shuang G Zhao, Alan Tan, Himisha Beltran, Rana R McKay.

PURPOSE: This study aimed to define molecular subtypes of prostate cancer by integrating androgen receptor (AR) signaling, neuroendocrine prostate cancer (NEPC) transcriptional signatures, and genomic alterations to inform biomarker-driven therapies in metastatic castration-resistant prostate cancer.
METHODS: We analyzed 8,019 prostate tumors using DNA/RNA sequencing (Caris Life Sciences), classifying them into four molecular subtypes (AR+/NE-, AR-/NE+, AR+/NE+, AR-/NE-). Genomic alterations, cell surface target expression, and overall survival (OS) were evaluated.
RESULTS: Of the 8,019 tumors, 87.2% were adenocarcinoma, 1.9% NEPC, and 0.4% had mixed histology; 63% were from primary sites and 36.5% from metastases. The median age was 68 years; 63% were White, 15% Black, and 2.6% Asian or Pacific Islander. Most tumors were classified as AR+/NE- (91%), and 4.6% were AR-/NE+. TP53 and PTEN alterations were enriched in AR-negative subtypes, whereas SPOP mutations were more frequent in AR+ tumors. FOLH1 (prostate-specific membrane antigen) expression was the highest in AR+ tumors, whereas DLL3 expression was elevated in NE+ tumors. Median OS was significantly longer in tumors with high AR signaling (55.0 v 14.0 months, P < .00001) and lower with the NEPC signature (54.3 v 16.1 months, P < .00001). Combined stratification showed the most favorable outcome in AR+/NE- tumors (55.3 months) and the poorest in AR-/NE+ tumors (12.0 months).
CONCLUSION: Prostate cancer exhibits distinct molecular subtypes defined by AR signaling activity, NEPC transcriptional profiles, and genomic alterations. These biologically and clinically relevant subgroups provide a framework for precision oncology approaches and inform patient selection for biomarker-driven trials such as the ongoing PREDICT study (ClinicalTrials.gov identifier: NCT06632977).

DOI: https://doi.org/10.1200/PO-25-00756
Cancer Res. 2026 Mar 05.

Intercepting YAP Activation in Prostate Cancer Blocks Neuroendocrine Progression.

Arianna Brevi, Marco Lorenzoni, Sara Caputo, Yasutaka Yamada, Matteo Grioni, Laura L Cogrossi, Laura Martinez-Vidal, Valeria Cassina, Deborah Cipria, Chiara Venegoni, Paola Zordan, Vittoria Matafora, Anna S Tascini, Nazario P Tenace, Riccardo Campanile, Vito Cucchiara, Valeria Pinna, Elena Jachetti, Rossella Galli, Angela Bachi, Maurizio Colecchia, Alberto Briganti, Massimo Freschi, Francesco Mantegazza, Angelo Lombardo, Francesca Demichelis, Himisha Beltran, Massimo Alfano, Matteo Bellone.

The emergence of the neuroendocrine phenotype in castration resistant prostate cancer (CRPC) is associated with poor patient prognosis. Castration-induced death of fully differentiated, androgen-sensitive PC cells might foster interactions among rare androgen-independent, poorly differentiated cancer cells and the extracellular matrix (ECM) that promotes the development of neuroendocrine PC (NEPC). Here, we investigated physical and molecular interactions between poorly differentiated PC cells with exocrine (PAC) or neuroendocrine features (PNE), which recapitulated pre-existing human CRPC-like cells, and decellularized prostate ECM. Without androgens, PAC cells and PC-derived ECM promoted in vitro invasiveness of PNE cells by inducing integrin α2 upregulation and YAP activation, indicating a cell-to-cell and cell-to-matrix contact-driven process. Inhibition of RANK/RANKL and NF-κB prevented integrin α2 upregulation in PNE cells, and integrin α2β1 and YAP inhibition also reduced PNE invasiveness. Microenvironment-conditioned PNE cells showed YAP-dependent metastatic behavior in vivo, and YAP inhibition suppressed the development of NEPC and metastasis in castration-naïve mice and of CRPC-NE in transgenic PC mice. Importantly, YAP inhibitors also restrained the growth of human CRPC organoids. These findings unveil mechanisms of NEPC development and implicate the integrin α2-YAP axis as a therapeutic target in PC patients receiving androgen-deprivation therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2704
Cancer Control. 2026 Jan-Dec;33:33 10732748261432278

Integrative Molecular Analysis to Predict Clinical Benefit of Everolimus in Patients With Gastro-Entero-Pancreatic Neuroendocrine Tumors (GEP-NETs).

Miran Han, Eunbyeol Lee, Ji Eun Shin, Min Suk Kwon, Sung Hee Lim, Jung Yong Hong, Seung Tae Kim.

  IntroductionNeuroendocrine tumors (NETs) are rare and heterogeneous. Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is widely used in gastrointestinal and pancreatic NETs (GEP-NETs). Owing to the lack of validated biomarkers, exploratory analyses of molecular pathways may help identify subgroups that derive clinical benefit from everolimus.MethodsWe conducted a retrospective observational cohort study of patients with GEP-NETs who received everolimus and underwent tumor next-generation sequencing (NGS). Genomic alterations were categorized into seven predefined signaling pathways (PI3K/AKT/mTOR, MAPK, DNA damage repair (DDR), developmental, epigenetic regulation, JAK-STAT, and cell-cycle regulation), and patients were classified as mutated (≥1 alteration) or wild-type. Clinical outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Associations between pathway alterations and outcomes were assessed.ResultsTwenty-eight patients were included. Median PFS was 26.4 months (95% CI, 17.3-37.1) and median OS was 41.0 months (95% CI, 36.6-not reached [NR]). Alterations in the PI3K/AKT/mTOR pathway were associated with more favorable treatment outcomes, including a higher ORR (47.6% vs. 14.3%; OR, 5.17; 95% CI, 0.49-275.05; p=0.191) and a significantly higher DCR (85.7% vs. 28.6%; OR, 13.0; 95% CI, 1.40-199.5; p=0.009). Survival outcomes also tended to be longer in this group compared with wild-type tumors, with median OS of 59.0 vs. 40.8 months (p=0.321) and median PFS of 26.4 vs. 18.6 months (p=0.858). In contrast, alterations in DDR-related genes were associated with lower ORR and DCR, while alterations in cell-cycle regulation pathways were associated with shorter OS and PFS and numerically lower response rates. No significant differences in survival or response outcomes were observed for MAPK, JAK-STAT, epigenetic, or developmental pathways.ConclusionsPathway-level genomic alterations were associated with differential clinical benefit from everolimus in GEP-NETs, with PI3K/AKT/mTOR alterations suggesting greater benefit, while DDR and cell-cycle alterations indicated reduced benefit. Despite the small cohort, these findings support the potential of pathway-based biomarkers and warrant prospective validation.

Keywords:  PI3K/AKT/mTOR pathway; everolimus; gastrointestinal and pancreatic neuroendocrine tumors (GEP-NETs); next-generation sequencing (NGS); predictive biomarker

DOI:  https://doi.org/10.1177/10732748261432278
Endocr Relat Cancer. 2026 Mar 02. pii: ERC-25-0495. [Epub ahead of print]

PRRT for well-differentiated Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs).

Virginia Corbett, Garima Gupta, Aman Chauhan.

Background: Neuroendocrine tumors (NETs) are rare, heterogeneous neoplasms with varying prognoses and management approaches. Peptide receptor radionuclide therapy (PRRT), targeting tumors expressing somatostatin receptors, delivers cytotoxic radiation to tumor cells. While PRRT has demonstrated efficacy in advanced, well-differentiated NETs, the optimal sequencing with other therapies remains an area of active research.
Objective: This review explores PRRT's role in NET management, focusing on its mechanisms, clinical efficacy, safety profile, and its integration into a multi-modal treatment strategy. We also examine evidence on the sequencing of PRRT with surgery, liver directed therapy, chemotherapy and targeted therapies to optimize treatment outcomes.
Methods: We conducted a comprehensive review of recent clinical trials, cohort studies, and expert consensus guidelines to assess PRRT's place in the treatment paradigm. Factors influencing treatment sequencing, such as tumor type, receptor expression, disease burden, and patient-specific characteristics, are also discussed.
Results: PRRT has proven effective for patients with advanced, somatostatin receptor-positive NETs, especially for inoperable tumors or those progressing after other therapies. While PRRT plays a vital role in management, its sequencing with other treatments remains complex, with evidence supporting its use both early and late in treatment based on individual patient factors.
Conclusion: Optimizing its sequencing with other treatments requires further research but offers potential for improved outcomes. A personalized, multidisciplinary approach is essential for maximizing PRRT's benefits in NET management. This review article summarizes current evidence and describes patient specific circumstances, enabling treating provider to make informed PRRT sequencing decisions.

DOI: https://doi.org/10.1530/ERC-25-0495