bims-necame Biomed News
on Metabolism in small cell neuroendocrine cancers
Issue of 2026–04–05
six papers selected by
Grigor Varuzhanyan, UCLA
  1. [Clinical significance and key points for interpreting progastrin-releasing peptide and neuron-specific enolase in chemoradiotherapy for limited-stage small cell lung cancer].
  2. Regulation of neuronal invasion of small cell lung cancer by STMN2/β-alanine-controlled metabolic reprogramming.
  3. A single-cell and spatial atlas of prostate cancer reveals the combinatorial nature of gene modules underlying lineage plasticity and metastasis.
  4. Ferroptosis as a Translational Axis in Small Cell Lung Cancer: A Systematic Review of Redox Pathways and Precision Oncology Prospects.
  5. Single-cell spatial transcriptomics reveals tumor microenvironment heterogeneity in primary and lymph node-metastatic small cell lung cancer.
  6. Brief Report: Low Delta-like Ligand 3 expression and T Cell Exhaustion Drive Resistance to Tarlatamab combined with anti-PD-1 in Small-Cell Lung Cancer.
  1. Zhonghua Jie He He Hu Xi Za Zhi. 2026 Apr 12. 49(4): 482-490
    [Clinical significance and key points for interpreting progastrin-releasing peptide and neuron-specific enolase in chemoradiotherapy for limited-stage small cell lung cancer].
    Y Cui, G Xiang, L N Zhao.
      Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor. Although it accounts for only about 13% of all lung cancers, its rapid proliferation, early metastasis, and very poor prognosis result in an extremely low five-year survival rate. In recent years, immune checkpoint inhibitors have improved outcomes in a subset of patients; however, the proportion of patients who derive meaningful benefit remains limited. For patients with limited-stage SCLC (LS-SCLC) undergoing chemoradiotherapy (CRT), standardized serum biomarkers suitable for routine monitoring of treatment response and early detection of relapse have yet to be established. Progastrin-releasing peptide (ProGRP) is generally more specific than neuron-specific enolase (NSE) for SCLC, yet neither marker is diagnostic when used alone. This review summarizes the roles of ProGRP and NSE in LS-SCLC during chemoradiotherapy (CRT), with an emphasis on differential diagnosis (particularly when pleural effusion cytology suggests adenocarcinoma but ProGRP is markedly elevated-raising the possibility of SCLC, mixed histology, or transformation and underscoring the need for tissue confirmation), longitudinal monitoring, and prognostic implications. Notably, universally accepted cut-off values for survival prediction are lacking; therefore, clinical interpretation should focus on within-assay dynamic trends and incorporate potential interfering factors, including renal dysfunction and hemolysis.
    DOI:  https://doi.org/10.3760/cma.j.cn112147-20251204-00765
  2. Cell Rep. 2026 Mar 28. pii: S2211-1247(26)00286-X. [Epub ahead of print]45(4): 117208
    Regulation of neuronal invasion of small cell lung cancer by STMN2/β-alanine-controlled metabolic reprogramming.
    Yan Zhou, Runbo Zhong, Yanwei Zhang, Michael R Shurin, Galina V Shurin, Liwen Xiong, Tianqing Chu, Baohui Han, Haohua Teng, Yu Yang, Erpeng Wu, Chi Zhang, Lincheng Zhang, Wanting Liu, Yuqing Lou, Jun Lu, Yongjie Wang, Hua Zhong.
      Small cell lung cancer (SCLC) exhibits a high incidence of perineural invasion (PNI), a clinical feature associated with poor prognosis. Here, we establish PNI as an independent adverse prognostic factor in a surgical SCLC cohort. We further show that the neural microenvironment upregulates stathmin-2 (STMN2) in SCLC cells. STMN2, in a concentration-dependent manner, activates the β-alanine metabolic pathway, leading to intracellular β-alanine accumulation, which enhances tumor cell migration and invasion. In vivo, STMN2 knockdown suppresses neural invasion, an effect reversible upon β-alanine supplementation. This work defines a neural-STMN2-β-alanine-invasion axis that drives PNI in SCLC, providing mechanistic insights and highlighting a promising metabolic vulnerability for therapeutic intervention.
    Keywords:  CP: cancer; CP: neuroscience; SCLC; invasiveness; perineural invasion; stathmin-2
    DOI:  https://doi.org/10.1016/j.celrep.2026.117208
  3. bioRxiv. 2026 Mar 27. pii: 2026.03.25.711335. [Epub ahead of print]
    A single-cell and spatial atlas of prostate cancer reveals the combinatorial nature of gene modules underlying lineage plasticity and metastasis.
    Hanbing Song, Junxiang Xu, Keila Velazquez-Arcelay, Arda Demirci, Brendan L Raizenne, Sarah C Hsu, Joshua Choi, Julia H Pham, Yih-An Chen, Hannah N W Weinstein, Isaac Salzman, Margaret Tsui, Jon Akutagawa, Wisdom Adingo, Ezequiel Goldschmidt, Peter R Carroll, Julian C Hong, Christopher M Heaphy, Matthew R Cooperberg, Nancy Greenland, Joshua D Campbell, Franklin W Huang.
      Prostate cancer encompasses a spectrum of disease states driven by complex cellular heterogeneity. To delineate the transcriptional programs underlying lineage plasticity and metastasis, we constructed a comprehensive single-cell atlas of 128 patients, spanning localized, castration-resistant, and metastatic disease. Lineage plasticity was prevalent in localized disease, with subsets of tumor cells adopting distinct basal-like and club-like states. Luminal-like cancer cells also displayed extensive lineage infidelity, defined not by a binary loss of identity but by the combinatorial erosion of luminal gene modules associated with higher grade and stage. In the metastatic setting, gene program association analysis (GPAS) identified a broad induction of cell-cycle gene modules across organ sites as well as an induction of organ-specific gene modules, including osteomimetic signaling in bone, neuro-migratory genes in brain, and erythroid-like transitions in liver. Neuroendocrine prostate cancers (NEPCs) were not monolithic but defined by combinations of NE-associated gene modules including a novel HES6 program. Notably, these modules were detected at intermediate levels in localized samples, suggesting molecular plasticity precedes histological transformation. We also developed a refined NE signature that could distinguish NEPC tumors more accurately than previously published signatures. Within the tumor microenvironment (TME), we observed an elevation of pro-inflammatory Th17 T-cells in African American patients and identified a rare Schwann cell population. Finally, we present PCformer, a transformer-based foundation model trained on >500,000 cells to automate cell-state classification. Together, this comprehensive atlas demonstrates the complex nature of gene modules underlying lineage infidelity and plasticity in cancer cells and highlights distinct immune and stromal populations within the tumor ecosystem.
    DOI:  https://doi.org/10.64898/2026.03.25.711335
  4. Oncol Res. 2026 ;34(4): 5
    Ferroptosis as a Translational Axis in Small Cell Lung Cancer: A Systematic Review of Redox Pathways and Precision Oncology Prospects.
    Donatella Coradduzza, Anna La Salvia, Giuseppe Fanciulli, Maria Rosaria De Miglio.
       Background: An increasing number of studies have shown that ferroptosis is related to the initiation and development of small cell lung cancer (SCLC). The systematic review aimed to summarize the characteristics of ferroptosis from its pathogenetic role to translational therapeutic implications in SCLC.
    Methods: This systematic review, registered in PROSPERO (CRD420251090058), followed PRISMA 2020 guidelines. Comprehensive research of PubMed, Scopus, and Web of Science was performed for studies published between January 2010 and July 2025 investigating ferroptosis mechanisms, genetic or pharmacological modulation, or molecular profiling in SCLC. Two reviewers independently performed data extraction and quality assessment.
    Results: Nineteen preclinical studies met the inclusion criteria. Key regulators included solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), and acyl-CoA synthetase long chain family member 4 (ACSL4). The molecular subtypes of SCLC, achaete-scute homolog 1 (ASCL1), neuronal differentiation 1 (NEUROD1), POU class 2 homeobox 3 (POU2F3), and Yes1 associated transcriptional regulator (YAP1) exhibit differential ferroptosis gene expressions, influencing therapeutic responsiveness. Non-neuroendocrine subtypes are more ferroptosis-prone, whereas neuroendocrine variants display enhanced antioxidant defenses. Ferroptosis induction also promotes immune activation through stimulator of interferon genes (STING)-mediated CD8+ T-cell recruitment.
    Conclusions: Ferroptosis constitutes a promising therapeutic axis in SCLC. Integrating ferroptosis biomarkers into molecular stratification frameworks could refine patient selection and support precision oncology strategies, warranting further translational and clinical validation.
    Keywords:  Small cell lung cancer; ferroptosis; glutathione peroxidase 4; immunotherapy; lipid peroxidation; molecular subtypes; oxidative stress; regulated cell death; solute carrier family 7 member 11; systematic review; translational oncology
    DOI:  https://doi.org/10.32604/or.2025.073045
  5. Cell Rep Med. 2026 Mar 30. pii: S2666-3791(26)00130-8. [Epub ahead of print] 102713
    Single-cell spatial transcriptomics reveals tumor microenvironment heterogeneity in primary and lymph node-metastatic small cell lung cancer.
    Zicheng Zhang, Dongfang Wu, Ruanqi Chen, Modi Zhai, Fan Yang, Jiaqian Wang, Lei Guo, Li Liu, Jianming Ying, Lin Yang, Meng Zhou.
      Lymph node metastasis (LNM) is a critical prognostic and therapeutic determinant in small cell lung cancer (SCLC), yet its spatial cellular ecosystem remains poorly understood. Here, we perform single-cell spatial transcriptomics using the CosMx Spatial Molecular Imager on 105 primary and metastatic lymph node specimens from 75 SCLC patients, generating a comprehensive atlas of over 600,000 cells. We identify three LNM-enriched malignant subclusters with distinct metabolic and angiogenic programs that spatially correlate with immune exclusion features. Spatial analysis reveals vascular-immune crosstalk, wherein endothelial cells orchestrate immune activation through avoidance of malignant cells while forming functional perivascular niches with cytotoxic T cells during LNM. Cellular neighborhood analysis delineates distinct multicellular niches and identifies a pan-immune hotspot (PIHs-1) whose abundance is an independent predictor of survival. This study provides a high-resolution spatial map of the SCLC tumor microenvironment during LNM and establishes spatially defined architectures as both mechanistic insights and translatable biomarkers.
    Keywords:  lymph node metastasis; small cell lung cancer; spatial molecular imaging; spatial transcriptomics; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102713
  6. J Thorac Oncol. 2026 Mar 26. pii: S1556-0864(26)00146-2. [Epub ahead of print] 103693
    Brief Report: Low Delta-like Ligand 3 expression and T Cell Exhaustion Drive Resistance to Tarlatamab combined with anti-PD-1 in Small-Cell Lung Cancer.
    Akito Fukuda, Tomoyo Fukami, Kotaro Nomura, Jumpei Kashima, Shogo Kumagai, Yasushi Goto, Yasushi Yatabe, Tatsuya Yoshida.
       INTRODUCTION: Small cell lung cancer (SCLC) is an aggressive malignancy with poor prognosis. Tarlatamab, a bispecific T cell engager that targets CD3 and delta-like ligand 3 (DLL3), is the standard of care for patients with previously treated SCLC. However, the mechanisms underlying acquired tarlatamab resistance remain unclear.
    METHODS: We assessed two patients with extensive-stage SCLC treated with tarlatamab and an anti-programmed cell death protein 1 (PD-1) antibody in a phase 1b clinical trial (jRCT: 2051240045). We analyzed tumor biopsy samples obtained at baseline and at time of progressive disease using multiplexed immunohistochemistry (mIHC).
    RESULTS: Pathological analysis of post-resistance specimens revealed a phenotypic shift in both cases, characterized by tumor cells with abundant cytoplasm and reduced synaptophysin expression levels. mIHC revealed low DLL3 expression on tumor cells at time of progression. Additionally, exhausted CD8+ T cells expressing PD-1+, T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and/or lymphocyte-activation gene 3 (LAG3), and immunosuppressive cells, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) regulatory T cells and CD206+ M2 tumor-associated macrophages, were significantly more abundant in the tumor microenvironment (TME) than that in samples obtained before tarlatamab plus anti- PD1combination therapy.
    CONCLUSIONS: Acquired resistance to tarlatamab plus anti-PD-1 in SCLC was associated with low DLL3 antigen expression particularly in the setting of phenotypic switch to a non-small cell lung cancer morphology and an increasingly immunosuppressive TME. Therefore, combination strategies that incorporate immune checkpoint blockade or myeloid-targeted therapies may be warranted to enhance treatment outcomes.
    Keywords:  acquired resistance; immunotherapy; small cell lung cancer; tarlatamab
    DOI:  https://doi.org/10.1016/j.jtho.2026.103693
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