bims-necame 2025-08-31 papers

bims-necame

Biomed News

on Metabolism in small cell neuroendocrine cancers

Issue of 2025–08–31
eight papers selected by
Grigor Varuzhanyan, UCLA

Epigenetic De-repression of PROX1 Promotes Neuroendocrine Prostate Cancer Progression.
Neuropeptide Precursor VGF Promotes Neuroendocrine Differentiation and Cancer-Associated Fibroblast Activation in Small Cell Lung Cancer.
Molecular Iodine Induces Anti- and Pro-Neoplastic Effects in Prostate Cancer Models.
Characteristic miRNA profiles represent clinicopathological diversity of small cell lung cancer.
Urinary exosomal RAB11A serves as a novel non-invasive biomarker for diagnosis, treatment response monitoring, and prognosis in small cell lung cancer.
Loss of NOTCH2 creates a TRIM28-dependent vulnerability in small cell lung cancer.
Proneural gene Mash1 (Ascl1) is expressed in multiple lineages and regulates their differentiation and specification.
Anti-tumor potential of combinatory GSK3 inhibition in human 3D models of pancreatic neuroendocrine tumors and patient-derived GEP-NET primary cultures.

Cancer Res. 2025 Aug 21.

Epigenetic De-repression of PROX1 Promotes Neuroendocrine Prostate Cancer Progression.

Varadha Balaji Venkadakrishnan, Adam Presser, Nathaniel C E Voss, James Neiswender, Lisa Brenan, Keira Prenza Sosa, Kenny Weng, Andres M Acosta, Francisca Vazquez, Himisha Beltran.

Histologic transformation of prostate cancer from adenocarcinoma to neuroendocrine prostate cancer (NEPC) is associated with aggressive disease and poor prognosis. This lineage transition is accompanied by Polycomb complex 2 (PRC2)-mediated epigenetic de-repression of cell-fate determining transcription factors, including prospero-homeobox 1 (PROX1). Here, we sought to functionally characterize the role of PROX1 in NEPC. An unbiased CRISPR screen in two NEPC patient-derived organoid models demonstrated high cellular dependency for PROX1. Knockout of PROX1 impeded tumor growth in NEPC models and overexpression of PROX1 promoted tumor growth and spontaneous metastasis in prostate adenocarcinoma. Transcriptomic and cistromic analyses across castration resistant adenocarcinoma and neuroendocrine models pointed to PROX1-mediated regulation of neuroendocrine-lineage transcriptional programs. Immunoprecipitation followed by mass spectrometry identified three phosphorylated sites in the DNA-binding domain of PROX1 that are critical for its stability and function. CHEK1 and CDK2 were predicted to be upstream kinases that phosphorylate PROX1, and treatment with a CHEK1 or CDK2 inhibitor reduced NEPC viability. Together, these results substantiate the role of PROX1 in NEPC and identify PROX1 phosphorylation in the DNA binding domain, which might represent a therapeutic target in NEPC.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0636
Cancer Res. 2025 Aug 26.

Neuropeptide Precursor VGF Promotes Neuroendocrine Differentiation and Cancer-Associated Fibroblast Activation in Small Cell Lung Cancer.

Wen Ding, Jianzheng Zhu, Jianshan Mo, Shumin Ouyang, Guopin Liu, Yingxue Su, Danyuan Sun, Jiangling Ye, Yanle Wu, Jiayu Yan, Menghan Xue, Peibin Yue, Jin-Jian Lu, Libin Wang, Yandong Wang, Xiaolei Zhang.

Small cell lung cancer (SCLC) is a highly aggressive malignancy with limited therapeutic options. Neuroendocrine differentiation is a prominent feature of SCLC. This study identified VGF, a secreted neuropeptide precursor, as a critical regulator of neuroendocrine differentiation in SCLC, particularly the ASCL1+ subtype. VGF orchestrated upregulation of the transcription factor ASCL1 through a CREB-dependent mechanism, thereby promoting neuroendocrine differentiation. Furthermore, VGF mediated the transformation of fibroblasts into cancer-associated fibroblasts (CAFs), establishing metabolic coupling between SCLC cells and CAFs via lactate exchange. A therapeutic strategy targeting VGF and monocarboxylate transporter 1 (MCT-1) disrupted neuroendocrine differentiation and SCLC-CAF metabolic coupling, demonstrating significant efficacy in both in vitro and in vivo models. Together, this study provides insights into the mechanisms underlying SCLC neuroendocrine differentiation and reveals targets and therapeutic strategies for advanced SCLC.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0405
Int J Mol Sci. 2025 Aug 13. pii: 7800. [Epub ahead of print]26(16):

Molecular Iodine Induces Anti- and Pro-Neoplastic Effects in Prostate Cancer Models.

Carlos Montes de Oca, Lourdes Álvarez, Carmen Aceves, Brenda Anguiano.

  Advanced prostate cancer frequently develops resistance to antiandrogen therapy and acquires an aggressive neuroendocrine phenotype. Antiandrogens stimulate peroxisome proliferator-activated receptor gamma (PPARG) signaling and cancer progression. Molecular iodine (I2) induces cytotoxic effects in prostate cancer cell lines and antineoplastic effects in neuroblastoma and breast cancer through the indirect activation of PPARG. We investigated the adjuvant effects of I2 and androgen deprivation in prostate cancer, as well as the role of PPARG in these projections. We used androgen-dependent and androgen-independent cell lines and TRAMP mice (transgenic adenocarcinoma of the mouse prostate) as biological models, as well as bicalutamide (Bic), enzalutamide (Enz), and charcoal-stripped fetal bovine serum (CS-FBS) as androgen deprivation models. I2 promoted cytotoxic effects, whereas in surviving cells, it stimulated the outgrowth of neurite-like projections, regulated lipid content, and reduced invasive capacity. Androgen deprivation plus I2 magnified these effects, while GW9662 (PPARG antagonist) did not block them. In vivo, I2 increased the degree of prostatic desmoplasia in the sham mice but did not amplify the stromal response or reduce the epithelial lesion score induced by castration in TRAMP. In conclusion, I2 showed anti-cancer (cytotoxic, anti-invasive) and pro-cancer (pro-neurite, lipid accumulation, desmoplasia) effects through a PPARG-independent mechanism.

Keywords:  PPARG; TRAMP; androgen deprivation; iodine; lipids; prostate

DOI:  https://doi.org/10.3390/ijms26167800
J Pathol. 2025 Aug 22.

Characteristic miRNA profiles represent clinicopathological diversity of small cell lung cancer.

Masafumi Horie, Hiroshi Takumida, Hayato Koba, Tsukasa Ueda, Hidenori Tanaka, Masami Suzuki, Yukinobu Ito, Ayumi Ito, Mao Kondo, Hiroshi I Suzuki, Isao Matsumoto, Seiji Yano, Akira Saito, Daichi Maeda.

  Small cell lung cancer (SCLC) is classified into distinct molecular subtypes based on the expression patterns of four transcription regulators: achaete-scute homolog 1 (ASCL1), neuronal differentiation 1 (NEUROD1), POU class 2 homeobox 3 (POU2F3), and yes-associated protein 1 (YAP1). MicroRNAs (miRNAs) play critical roles in cancer cellular processes but their subtype-specific implications in SCLC remain underexplored. Out of 46 surgically resected SCLC samples, miRNA visualization through in situ hybridization identified high expression of miR-375 in the ASCL1, NEUROD1, and ASCL1/NEUROD1 subtypes, and miR-9-5p in the POU2F3 subtype. Comprehensive enhancer profiling using SCLC cell lines indicated that miR-375 and miR-9-5p were regulated by super-enhancers in a subtype-specific manner. Multiplex immunohistochemistry by imaging mass cytometry found that the miR-9-5p-high SCLC was characterized by a higher stromal area ratio, increased numbers of CD8+ T cells and CD163- macrophages in the intra-tumoral area, and an increased number of plasma cells in the stromal area, as compared with the miR-9-5p-low SCLC. Finally, clinicopathological analysis revealed that the miR-375-high SCLC was associated with YAP1 downregulation, increased serum pro-gastrin-releasing peptide levels, and poor prognosis. These findings highlight the critical role of super-enhancer-related miRNAs in the diversity of SCLC, and underscore the potential for novel diagnostic and prognostic biomarkers based on these subtype-specific miRNAs. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords:  SCLC; imaging mass cytometry; miRNA; miR‐375; miR‐9‐5p; super‐enhancer; tumor microenvironment

DOI:  https://doi.org/10.1002/path.6458
Clin Proteomics. 2025 Aug 25. 22(1): 30

Urinary exosomal RAB11A serves as a novel non-invasive biomarker for diagnosis, treatment response monitoring, and prognosis in small cell lung cancer.

Weiwei Wang, Na Liu, Shanshan Wang, Chunkai Yu, Lei Pan, Man Zhang.

   BACKGROUND: Small cell lung cancer (SCLC) is an aggressive malignancy with a poor prognosis. This study aimed to analyze the urinary exosomal proteome of SCLC patients to identify and validate potential non-invasive biomarkers for improving diagnosis, treatment response monitoring, and prognosis prediction.
METHODS: We analyzed 90 urine samples from SCLC patients, divided into training (n = 38) and validation (n = 52) sets, including untreated, partial/complete remission, and relapsed groups. Ten healthy controls were included. Urinary exosomes were isolated by ultracentrifugation. The proteomic analysis employed data-independent acquisition mass spectrometry (DIA-MS) and parallel reaction monitoring (PRM). Immunohistochemistry was performed on 30 pairs of SCLC and adjacent normal tissues.
RESULTS: Proteomic analysis revealed distinct exosomal protein expression patterns across SCLC stages. RAB11A emerged as a key differentially expressed protein. PRM validation confirmed significant changes in RAB11A levels across disease stages. ROC curve analysis demonstrated excellent diagnostic performance of RAB11A in distinguishing SCLC patients from healthy controls (AUC = 0.91, 95% CI 0.79-1.00, P = 0.0004), with a sensitivity of 85% and specificity of 92%. RAB11A also showed significant potential in monitoring treatment response (AUC = 0.86, 95% CI 0.69-1.00, P = 0.0019) and disease relapse (AUC = 0.90, 95% CI 0.76-1.00, P = 0.0005). Immunohistochemistry showed significantly higher RAB11A expression in SCLC tissues compared to adjacent normal tissues (70% vs. 33% positive expression, P = 0.043).
CONCLUSION: Urinary exosomal RAB11A shows promise as a non-invasive biomarker for SCLC diagnosis, treatment response monitoring, and early detection of relapse, potentially improving clinical management of SCLC patients. The findings provide insights into SCLC pathogenesis and offer a non-invasive approach for patient monitoring, which could improve clinical management strategies.

Keywords:  Biomarker; Proteomics; RAB11A; Small cell lung cancer (SCLC); Urinary exosomes

DOI:  https://doi.org/10.1186/s12014-025-09554-4
Dev Cell. 2025 Aug 25. pii: S1534-5807(25)00499-X. [Epub ahead of print]

Loss of NOTCH2 creates a TRIM28-dependent vulnerability in small cell lung cancer.

Deli Hong, Ying Lyu, Richa Nayak, Justin S Becker, Matthew A Booker, Keita Masuzawa, Zoe Devos, Tianchu Wang, Shin Saito, Qi Liu, Yixiang Li, Zhaorong Li, Eric H Knelson, Tran Thai, Leslie Duplaquet, Yasmin N Laimon, Gabriel Roberti De Oliveira, Sabina Signoretti, John G Doench, David A Barbie, Michael Y Tolystorukov, Jun Qi, Bradley E Bernstein, Yejing Ge, Matthew G Oser.

  Small cell lung cancer (SCLC) is a highly aggressive malignancy that lacks effective targeted therapies, in part due to frequent loss-of-function mutations in tumor suppressors and the absence of recurrent oncogenic drivers. Approximately 15% of SCLCs harbor inactivating mutations in NOTCH1 or NOTCH2, and most neuroendocrine-high SCLCs exhibit low NOTCH activity. Using CRISPR-Cas9 screening in primary cell lines derived from NOTCH1/2-isogenic SCLC genetically engineered mouse models, we identified TRIM28 as a synthetic lethal dependency in NOTCH2-inactivated SCLCs. Loss of TRIM28 in this context robustly induced expression of endogenous retroviruses (ERVs), activated viral sensing pathways, and triggered a type I interferon response. Mechanistically, NOTCH2 inactivation increased reliance on TRIM28-mediated ERV silencing, creating a hyperdependence on TRIM28 via the STING-MAVS-TBK1 axis. Notably, TRIM28 was essential for tumor growth only in the setting of NOTCH2 loss. These findings identify TRIM28 as a potential therapeutic target in NOTCH2-deficient or low-NOTCH2-expressing SCLC.

Keywords:  CRISPR-Cas9 screening; NOTCH2; TRIM28; endogenous retroviruses; small cell lung cancer; synthetic lethality; viral sensing

DOI:  https://doi.org/10.1016/j.devcel.2025.07.023
Histochem Cell Biol. 2025 Aug 26. 163(1): 83

Proneural gene Mash1 (Ascl1) is expressed in multiple lineages and regulates their differentiation and specification.

Yoko Kameda.

  Ascl1 (Mash1), a bHLH transcription factor, is widely expressed by neuronal progenitors. The gene plays a key role in the differentiation of the autonomic nervous system, i.e., sympathetic, parasympathetic, and enteric ganglia; all of which are derived from neural crest cells. In Ascl1-null mutants, defective development of these ganglia is induced. The differentiation of neuroendocrine cells, including the carotid body, ultimobranchial body and thyroid C cells, the neuroepithelial body in the lung, and the adrenal medulla, is also controlled by Ascl1. Although the carotid body glomus cells and adrenal medulla are derived from neural crest, the ultimobranchial body is from pharyngeal endoderm and the neuroepithelial body is from endodermal epithelium. A targeted mutation of Ascl1 results in complete loss or failure in differentiation of these neuroendocrine cells. Furthermore, the development of olfactory epithelium and bulbus is regulated by Ascl1. In the central nervous system, Ascl1 is expressed in the arcuate and ventromedial nuclei, telencephalon, and dopaminergic neurons such as locus coeruleus and nucleus tractus solitarius. The elimination or atrophy of these regions are induced in Ascl1-null mutants. All cells and tissues affected by the deficiency of Ascl1 express catecholamines and/or serotonin. The Phox2b or/and Hes1 genes are required for regulation of Ascl1 expression. Phox2b stimulates the expression of Ascl1, whereas Hes1 represses gene expression.

Keywords:  Ascl1-null mutant mice; Autonomic nervous system; Catecholamines and/or 5-HT; Neuroendocrine cells; Olfactory epithelium and bulbus; Phox2b and/or Hes1

DOI:  https://doi.org/10.1007/s00418-025-02412-2
Endocr Relat Cancer. 2025 Aug 27. pii: ERC-25-0073. [Epub ahead of print]

Anti-tumor potential of combinatory GSK3 inhibition in human 3D models of pancreatic neuroendocrine tumors and patient-derived GEP-NET primary cultures.

Svenja Nölting, Edlira Luca, Igor Shapiro, Katharina Wang, Christoph J Auernhammer, Felix Beuschlein, Kathrin Zitzmann, Huguette Debaix, Constanze Hantel.

  Activation of signaling pathways that regulate survival, proliferation, motility, inflammation, metabolism and stemness fuel tumor growth, metastasis and recurrence. Therapies targeting signaling pathway components including candidates such as GSK3 and TNFα drastically affect cellular viability in preclinical cancer models but have limited success in the clinic. However, in recent years, spheroids and organoids have been demonstrated to more accurately reflect tumor characteristics and to be better predictors of therapeutic response than monolayer cultures. Here, we used 3D models from the pancreatic neuroendocrine tumor (pNET) model BON1 to evaluate the effect of GSK3 inhibition along with TNFα or insulin and extended our results in primary gastroenteropancreatic (GEP-)NET culture. The multidimensional configuration of BON1 spheroids imparted aggressive characteristics and a lack of anti-proliferative effects upon single treatments. However, GSK3 inhibition alone resulted in dispersion of spheroids indicating that GSK3 is necessary for cell-cell adhesions and participates in spheroid architecture. Interestingly, GSK3 inhibition in combination with TNFα or insulin led to drastically reduced cell proliferation. In fresh patient-derived 2D primary cultures from (GEP-)NETs, we demonstrate that insulin has tumor-promoting effects while GSK3 inhibition and metformin display significant anti-tumor activity, mediated through common effects on GSK3/insulin signaling. Both agents show strong efficacy in a patient-derived insulinoma without affecting the corresponding normal pancreatic tissue. We conclude that treatment efficacy depends on three-dimensional architecture and that combinatorial treatments which target cellular dispersion in addition to cellular viability might have beneficial clinical applications, but metatastatic potential of remaining single cells needs further characterization before clinical implementation.

Keywords:  BON1; GSK3; TNFα; Wnt/β-catenin; gastroenteropancreatic (GEP-)NETs; insulin; pancreatic neuroendocrine tumor; spheroids

DOI:  https://doi.org/10.1530/ERC-25-0073