bims-necame 2025-11-02 papers

bims-necame

Biomed News

on Metabolism in small cell neuroendocrine cancers

Issue of 2025–11–02
eleven papers selected by
Grigor Varuzhanyan, UCLA

ERRγ impedes neuroendocrine prostate cancer development.
S100A9 enhances tumor immune suppression and cancer cell survival in small cell lung cancer.
Targeting the CCL5/CCR5 axis in tumor-stromal crosstalk to overcome cisplatin resistance in neuroendocrine prostate cancer.
Transcription Factor Dynamics in Neuroendocrine Prostate Cancer Development.
Bridging Knowledge Gaps in Small Cell Lung Cancer: Data, Challenges and Priorities.
Prognostic Utility of Cachexia in Lung Cancer: A Multicenter Cohort Analysis.
Patient-Derived Organoids from Pancreatic Neuroendocrine Tumors: A Systematic Review of PDO Take Rates, Molecular-Biological Characteristics, and Potential for Clinical Utility.
Targeting CXCR2 in prostate cancer cells can block CD47-SIRPα interaction and reverse M2 macrophage polarization in the TME.
Tumor Growth Rate in Neuroendocrine Neoplasms: An Additional Tool for Treatment Strategies?
Per-Lesion Assessment of Individual MRI Sequences and 68Ga-DOTATATE PET in Neuroendocrine Liver Metastases.
Y90 radioembolization in advanced liver cancer of rarely treated tumor entities: prediction of treatment response and survival by clinical and imaging features.

Genes Dev. 2025 Oct 29.

ERRγ impedes neuroendocrine prostate cancer development.

Ting Li, Catherine R Dufour, Lingwei Han, Anthony Alfonso, Mirna Farhat, Annabelle Beaumier, Qian Chen, Jin-Jian Lu, Vincent Giguère.

  Neuroendocrine prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (CRPC). The molecular mechanisms underlying the progression of CRPC toward NEPC remain incompletely understood, and effective treatments remain to be discovered. Here, we report that loss of the nuclear receptor ERRγ promotes neuroendocrine differentiation in a Pten-deficient mouse model of prostate adenocarcinoma. These findings were recapitulated in advanced cellular and xenograft models of human prostate cancer. Critically, we show that ERRγ gain of function can reverse instilled NEPC features accompanied by suppression of growth and oncogenic metabolic reprogramming. Activation of a neuroendocrine transcriptional program enabled by ERRγ deficiency unveiled a targetable vulnerability exploited by the combined pharmacological inhibition of EZH2 and RET kinase that effectively inhibited the growth of ERRγ-deficient tumor organoids and cells. Collectively, our findings demonstrate that ERRγ downregulation facilitates prostate cancer adeno-to-neuroendocrine transformation and offer potential therapeutic strategies to prevent/treat the development of poor outcome NEPC.

Keywords:  ChIP-seq; EZH2; NEPC; PROX1; RET; RNA-seq; adenocarcinoma; lineage plasticity; metabolism; nuclear receptor; transcription

DOI:  https://doi.org/10.1101/gad.353024.125
Cell Death Dis. 2025 Oct 31. 16(1): 774

S100A9 enhances tumor immune suppression and cancer cell survival in small cell lung cancer.

Manish Charan, Sanjay Mishra, Konstantin Shilo, Xiaoli Zhang, Ajeet K Verma, Pratyusha Ghanta, Amy Webb, Ramesh K Ganju.

Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer associated with a poor prognosis. However, there have been few advancements in improving the survival of SCLC patients in recent decades. This study shows that the S100A9 protein is highly expressed in SCLC patients and several highly aggressive SCLC cell lines. Furthermore, we showed that S100A9 expression inversely correlates with overall survival in SCLC patients. S100A9 increases the survival and migration of SCLC cells by activating Akt and GSK3α/β/Snail pathways. In addition, S100A9 reduces tumor cell autophagy through MAGE-A3. S100A9 depletion or pharmacological inhibition using tasquinimod reduced tumor growth and metastasis in vivo. Importantly, we observed that S100A9 downregulation or tasquinimod treatment alone or combined with cisplatin reduces the recruitment of MDSCs. Furthermore, tasquinimod treatment alone or combined with cisplatin significantly enhanced tumor infiltration of activated CD8+ (CD69-positive) T cells. Overall, our results, for the first time, show that S100A9 enhances SCLC progression and metastasis by altering the tumor microenvironment, and its inhibition using tasquinimod alone or in combination with chemotherapy could be developed as a promising therapeutic strategy for SCLC.

DOI: https://doi.org/10.1038/s41419-025-08102-0
J Exp Clin Cancer Res. 2025 Oct 28. 44(1): 296

Targeting the CCL5/CCR5 axis in tumor-stromal crosstalk to overcome cisplatin resistance in neuroendocrine prostate cancer.

Bo Liu, Weiwei Zhang, Yiyi Ji, Jiajin Wu, Ruopeng Su, Xinyu Liu, Ang Li, Kai Shen, Xinyu Chai, Haotian Wu, Zehua Ma, Cong Hu, Zhou Jiang, Liang Dong, Yinjie Zhu, Baijun Dong, Wei Xue, Jiahua Pan, Qi Wang.

   BACKGROUND: Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer with limited therapeutic options. Although cisplatin is recommended as a first-line treatment, its clinical efficacy is hindered by the rapid development of drug resistance, highlighting the urgent need for effective strategies to overcome cisplatin resistance.
METHODS: We established a NEPC mouse allograft model and performed RNA sequencing to identify genes associated with cisplatin resistance. The role of CCL5 in tumor-stromal crosstalk was investigated using immunofluorescence, ELISA assays, co-culture assays, and CCL5 knockout mice. Mechanistic studies were conducted to explore CCL5/CCR5-mediated signaling pathways. The therapeutic efficacy of cisplatin combined with maraviroc, an FDA-approved CCR5 antagonist, was evaluated in vitro using NEPC cell lines and patient-derived organoids, and in vivo using NEPC mouse models.
RESULTS: Here, we identify a tumor-stromal interaction mediated by the CCL5/CCR5 axis that drives cisplatin resistance in NEPC. Cisplatin-induced DNA damage promotes a cGAS-STING-dependent senescence program in cancer-associated fibroblasts (CAFs), resulting in the secretion of CCL5, a key senescence-associated secretory phenotype factor. CCL5 from CAFs binds to CCR5 on tumor cells, promoting the formation of a CCR5/β-arrestin1/p85 complex that activates the PI3K/AKT pathway. This activation enhances DNA repair, protecting tumor cells from cisplatin-induced apoptosis. Pharmacologic inhibition of the CCL5/CCR5 pathway using maraviroc, an FDA-approved CCR5 antagonist, sensitizes NEPC cells to cisplatin treatment and significantly prolongs survival in NEPC mouse models.
CONCLUSIONS: Our findings identify the CCL5/CCR5 axis as a key mediator of tumor-stromal crosstalk driving cisplatin resistance in NEPC. Mechanistically, CAF-derived CCL5 activates AKT signaling in tumor cells by promoting the formation of the CCR5/β-arrestin1/p85 complex. Targeting this pathway with maraviroc in combination with cisplatin offers a promising therapeutic strategy for overcoming drug resistance in NEPC.

Keywords:  CCL5; Cancer-associated fibroblasts; Cisplatin resistance; Maraviroc; Neuroendocrine prostate cancer

DOI:  https://doi.org/10.1186/s13046-025-03552-y
Holist Integr Oncol. 2025 ;4(1): 65

Transcription Factor Dynamics in Neuroendocrine Prostate Cancer Development.

Yu Wang, Yuzhuo Wang.

  Treatment-induced neuroendocrine prostate cancer (NEPC) represents a lethal evolution of prostate adenocarcinoma under androgen receptor pathway inhibition, posing a significant clinical challenge. In a recent landmark study, Wang et al. introduced an innovative internal Z-score based approach to comprehensively characterize the transcription factor (TF) landscape in prostate cancer progression, uncovering distinct TF profiles associated with adenocarcinoma and NEPC lineages. Notably, the study proposes a three-phase model of NEPC transdifferentiation-comprising de-differentiation, dormancy, and re-differentiation-revealing dynamic shifts in TF expression that underpin lineage plasticity and therapeutic resistance. This commentary critically evaluates the methodological advancements, the functional significance of the identified TF signatures, and the broader implications of these findings for developing novel therapeutic strategies. By delineating the molecular events driving the transition from androgen receptor (AR)-dependent adenocarcinoma to treatment-resistant NEPC, this work underscores the potential of targeting early and dormant phases of transdifferentiation to improve patient outcomes.

Keywords:  Lineage plasticity; Neuroendocrine prostate cancer (NEPC); Prostate cancer; Three-phase hypothesis; Transcription factors; Tumor dormancy

DOI:  https://doi.org/10.1007/s44178-025-00197-x
Curr Oncol. 2025 Sep 25. pii: 536. [Epub ahead of print]32(10):

Bridging Knowledge Gaps in Small Cell Lung Cancer: Data, Challenges and Priorities.

Chiara Catania, Priscilla Cascetta, Alessandro Russo, Emily Governini, Marzia Bendoni, Alice Laffi, Ilaria Piloni, Fabio Conforti, Laura Pala, Emilia Cocorocchio, Giovanni Ceresoli, Marzia Locatelli, Daniele Laszlo, Flaminia Facella, Tommaso De Pas.

  Small Cell Lung Cancer (SCLC) is an aggressive neuroendocrine malignancy representing approximately 15% of all lung cancers. Characterized by rapid progression, early metastasis, and high circulating tumor cell burden, SCLC has a poor prognosis. Although initial responses to chemotherapy, radiotherapy, and immunotherapy are common, relapse due to acquired resistance is nearly inevitable. Molecular studies have identified four transcription factor-driven subtypes-ASCL1, NEUROD1, POU2F3, and YAP1-each with distinct biological traits and therapeutic vulnerabilities. However, clinical classification remains largely homogeneous, limiting precision treatment strategies. Immunotherapy has modestly improved survival, as demonstrated in trials like IMpower133, CASPIAN, and ADRIATIC. Yet only a small subset of patients-approximately 12%-achieve long-term survival beyond five years. Understanding the biological and immunological profiles of these exceptional responders is critical. Future research should prioritize comprehensive biomarker integration, including PD-L1, TMB, DLL3, CD3, and emerging targets. Novel agents such as tarlatamab (DLL3-targeting) and ifinatamab deruxtecan (B7-H3-targeting) have shown encouraging efficacy in early-phase trials, though predictive markers remain elusive. A multi-dimensional approach combining tissue, blood, and immune profiling is essential to advance precision oncology in SCLC and improve patient selection for emerging therapies.

Keywords:  immunotherapy; molecular subtype; precision oncology; small cell lung cancer

DOI:  https://doi.org/10.3390/curroncol32100536
Clin Nutr ESPEN. 2025 Oct 29. pii: S2405-4577(25)02976-6. [Epub ahead of print]

Prognostic Utility of Cachexia in Lung Cancer: A Multicenter Cohort Analysis.

Lishuang Wei, Guotian Ruan, Heyang Zhang, Hanping Shi, Hailun Xie.

   BACKGROUND: The clinical significance of the Asian Working Group on Cachexia (AWGC) criteria, as a novel diagnostic standard for cachexia, remains underexplored. This study aims to investigate the prognostic value of the AWGC criteria and to propose a scoring system for stratifying the severity of cachexia in lung cancer patients.
METHODS: Survival curves were generated using Kaplan-Meier analysis with log-rank tests. Cox proportional hazards models were employed for survival analysis, providing hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Logistic regression analysis was utilized to assess the independent association between cachexia and 90-day mortality, presenting the results as odds ratios (ORs) with 95% CIs.
RESULTS: This study enrolled a total of 3,424 lung cancer patients, comprising 86.6% with non-small cell lung cancer (NSCLC) and 13.4% with small cell lung cancer (SCLC). Patients with AWGC-defined cachexia had significantly poorer survival (55.8% vs. 39.3%, p < 0.001). Cachectic patients exhibited considerably worse survival rates in both SCLC (42.9% vs. 25.4%, p < 0.001) and NSCLC (57.8% vs. 41.4%, p < 0.001). Cox regression analysis indicated that AWGC-defined cachexia is an independent risk factor for survival in lung cancer patients (HR: 1.436, 95% CI: 1.306-1.580, p < 0.001). Moreover, AWGC-defined cachexia was significantly associated with poor prognosis in both SCLC (HR: 1.307, 95% CI: 1.007-1.698, p = 0.044) and NSCLC (HR: 1.377, 95% CI: 1.234-1.538, p < 0.001) patients. AWGC-defined cachexia was also found to be an independent risk factor for 90-day mortality in lung cancer patients (OR = 3.060, 95% CI: 2.254-4.155, p < 0.001). We developed a severity grading system for categorizing cachexia into Mild, Moderate, and Severe. Survival rates gradually decreased as the severity grading score increased (63.2% vs. 49.1% vs. 37.0% vs. 30.0%, p < 0.001).
CONCLUSIONS: AWGC-defined cachexia is an independent risk factor for both long-term prognosis and 90-day mortality in lung cancer patients.

Keywords:  Asian Working Group for Cachexia criteria; Cancer cachexia; Lung cancer; Prognostic

DOI:  https://doi.org/10.1016/j.clnesp.2025.10.017
Cancers (Basel). 2025 Oct 18. pii: 3364. [Epub ahead of print]17(20):

Patient-Derived Organoids from Pancreatic Neuroendocrine Tumors: A Systematic Review of PDO Take Rates, Molecular-Biological Characteristics, and Potential for Clinical Utility.

Celine Oanæs, Marcus T T Roalsø, Marina Alexeeva, Kjetil Søreide.

  Background: Pancreatic neuroendocrine neoplasia (PanNEN) comprises a spectrum, from well-differentiated (i.e., G1, G2) pancreatic neuroendocrine tumors (PanNETs) to poorly differentiated carcinomas (PanNECs). Therapeutic progress is limited by the lack of representative preclinical models. Patient-derived organoids (PDOs) offer potential as translational models, but evidence remains scattered. Methods: We conducted a systematic review of PubMed (Jan 2009-Aug 2025) for original studies reporting on PDOs from PanNEN patients. Eligible studies were screened using the Rayyan software and data extracted from PDO take rates, validation methods, and clinical applications. Results: Twelve studies were included for qualitative and quantitative analyses. PDOs were successfully generated from both PanNETs (G1-G3; n = 26) and PanNECs (n = 6), primarily derived from primary tumors, but several studies also included metastatic sites. Take rates ranged from 33% to 100%, for a cumulative 33 PDOs from 44 attempts (overall take rate: 75%). Validation consistently employed histology, immunohistochemistry, and molecular profiling, with several studies incorporating xenotransplantation or omics approaches. PDOs demonstrated variable culture durations, from short-term (<3 weeks) to long-term (>20 passages). Drug screening studies (n = 7) revealed heterogenous responses to standard agents and pathways (everolimus, sunitinib, and temozolomide) and identified novel vulnerabilities, including EZH2 dependency, PI3K/CDK4/6 synergy, and Bcl-2-linked sensitivities in PanNECs. One study provided evidence of concordance between PDO drug sensitivity and patient responses. Conclusions: Research into PanNEN organoids remains limited. However, PDOs can preserve key histological and molecular features, enable pharmacotyping, and uncover candidate biomarkers for therapy. Despite feasibility across subtypes, progress is constrained by variability in culture success. Standardization and prospective validation are essential to advance PDOs as tools for personalized medicine in PanNENs.

Keywords:  NEC; NET; PDO; PanNEN; neuroendocrine carcinoma; neuroendocrine tumor; pancreatic neuroendocrine neoplasm; patient-derived organoid; spheroid; tumoroid

DOI:  https://doi.org/10.3390/cancers17203364
Mol Cancer. 2025 Oct 30. 24(1): 273

Targeting CXCR2 in prostate cancer cells can block CD47-SIRPα interaction and reverse M2 macrophage polarization in the TME.

Yi Sun, Shangqing Ren, Wei Wen, Jun Jing, Xu Luo, Shuai Shao, Ruiqi Duan, Guohua Zeng, Ju Guo.

  Neuroendocrine prostate cancer (NEPC) exhibits strong immune evasion and plays a critical role in regulating metabolic reprogramming within prostate cancer. High infiltration of CD36 + M2 tumour-associated macrophages (TAMs) and elevated CD47 expression in NEPC cells are often associated with poor progression-free survival in cancer patients. Understanding the mechanisms that regulate CD36 + M2 TAM infiltration and high CD47 expression in tumour cells within the prostate cancer tumour microenvironment (TME) is essential. Using cell models and two animal models, we discovered that the IL-8/CXCR2 pathway increases acetyl-CoA levels through metabolic reprogramming, which subsequently increases CD47 expression via acetylation. Moreover, this pathway modulates the membrane localization of CD47 by stimulating tumour cells to secrete palmitic acid and utilize palmitoylation mechanisms, thereby protecting tumour cells from macrophage-mediated phagocytosis. The IL-8/CXCR2 pathway also reshapes the metabolic microenvironment of the TME, increasing the infiltration of ω-3/6 polyunsaturated fatty acids (PUFAs) in the TME, which promotes the recruitment of CD36 + M2 TAMs. Preclinical studies in both NSG and C57BL/6 animal models demonstrated that targeting CXCR2 restored TAM phagocytic activity and significantly reduced tumour growth. These findings suggest that CXCR2-targeted immunotherapy holds promising therapeutic potential for prostate cancer and underscores its importance in translational medicine.

Keywords:  CD36; CD47; IL-8/CXCR2; Lipid metabolism; Macrophage; Prostate cancer

DOI:  https://doi.org/10.1186/s12943-025-02436-1
Medicina (Kaunas). 2025 Oct 16. pii: 1852. [Epub ahead of print]61(10):

Tumor Growth Rate in Neuroendocrine Neoplasms: An Additional Tool for Treatment Strategies?

Roberta Modica, Alessia Liccardi, Elio Benevento, Roberto Minotta, Gianfranco Di Iasi, Massimo Di Nola, Michele Coletta, Annamaria Colao.

  Background and Objectives: Neuroendocrine neoplasms (NENs) are rare, mainly gastro-entero-pancreatic tumors with heterogeneous biology and multiple therapeutic options. Assessing treatment response remains challenging. Standard evaluation relies on RECIST 1.1, although its limitations are well recognized. Tumor growth rate (TGR), defined as the monthly percentage change in tumor size between two imaging assessments, has been proposed as a dynamic parameter to complement conventional criteria. This review explores the role of TGR in NEN. Results: Two different evaluations of TGR, once conducted between baseline diagnostic scan and a radiological assessment 12-24 weeks after (TGR0), and another conducted between baseline scan and a diagnostic evaluation three months after (TGR3m), proved to be well correlated to progression free survival (PFS) in G1 and low-G2 NEN, with cut off of 4%/month and 0.8%/month, respectively. Conclusions: TGR offers additional insights into tumor kinetics and may help refine treatment monitoring in NEN. While retrospective evidence supports its prognostic utility, prospective studies are required to validate TGR as a standard clinical tool.

Keywords:  chemotherapy; neuroendocrine neoplasms; neuroendocrine tumors; radioligand therapy; somatostatin analog; target therapy; tumor growth rate

DOI:  https://doi.org/10.3390/medicina61101852
Invest Radiol. 2025 Oct 27.

Per-Lesion Assessment of Individual MRI Sequences and 68Ga-DOTATATE PET in Neuroendocrine Liver Metastases.

Alexander Herold, Azadeh Hajati, Yihan Cao, Kevin P Fialkowski, Soumyadeep Ghosh, Francis Delaney, Pedram Heidari, Maria Picchio, Paola Mapelli, Arturo Chiti, Mark A Anderson, Valeria Peña-Trujillo, Avinash Kambadakone, Michael A Blake, Steven Shufflebeam, Ciprian Catana, Peter Caravan, Michael Weber, Susie Y Huang, Onofrio A Catalano.

   OBJECTIVES: To explore magnetic resonance imaging (MRI) and gallium-68 (68Ga)-DOTATATE positron emission tomography (PET) performance in the assessment of neuroendocrine liver metastases (NELMs) on a per-lesion basis, with particular attention to the contribution of individual MRI sequences and assessment of other factors that might influence their detection.
MATERIALS AND METHODS: This observational retrospective study included patients with histologically confirmed neuroendocrine tumors who underwent both contrast-enhanced MRI and 68Ga-DOTATATE PET within 12 weeks between August 2017 and December 2023. Three readers in consensus assessed individual MRI sequences [diffusion-weighted imaging (DWI), dynamic contrast-enhanced imaging (DCE), and hepatobiliary phase (HBP) imaging when available], entire MRI data set, and PET in random order. The reference standard was histopathology or follow-up imaging. Diagnostic performance metrics were calculated using generalized estimating equations with Bonferroni correction. Correlations were assessed using Pearson correlation coefficients.
RESULTS: A total of 1249 lesions, comprising 1050 metastases, were analyzed in 60 patients (mean age: 64.9±11.5 years; 56.7% male). Compared with PET, MRI demonstrated superior sensitivity (93% vs. 59%, P<0.001) and accuracy (93% vs. 63%, P<0.001), with DWI and HBP providing the highest sensitivity (89% and 92%). Size-stratified analysis showed that MRI outperformed PET, particularly for metastases <5 mm (81.6% vs. 19.7%) and 5 to 10 mm (96.1% vs. 61.8%) (P<0.001). Arterial enhancement and portal venous washout were present in 67.8% and 23.7% of metastases, respectively, with only portal venous washout showing size dependence (11.9% in <5 mm to 55.6% in >20 mm lesions, P<0.01). PET-negative metastases were smaller than PET-positives (5.0 vs. 8.0 mm, P=0.001), with lesion size correlating with maximum standardized uptake values and normalized uptake ratios (r=0.54 to 0.59, P<0.001).
CONCLUSIONS: MRI outperformed 68Ga-DOTATATE PET in detecting NELMs, with DWI and HBP providing particularly high sensitivity for small metastases.

Keywords:  DOTATATE; MRI; PET; diagnostic performance; neuroendocrine liver metastases

DOI:  https://doi.org/10.1097/RLI.0000000000001248
Nucl Med Commun. 2025 Oct 30.

Y90 radioembolization in advanced liver cancer of rarely treated tumor entities: prediction of treatment response and survival by clinical and imaging features.

Carola Maria Bregenzer, Bianca Herm, Christine March, Maximilian Thormann, Romy Damm, Jazan Omari, Maciej Pech, Robert Damm.

   BACKGROUND: Radioembolization is classically used in patients with hepatocellular carcinoma and secondary hepatic malignancies like colorectal cancer and neuroendocrine tumors. Up to now, data for other hepatic metastasized tumor entities are rare, and it is not clear which clinical and imaging features could predict the outcome.
METHODS: Data of 60 patients exceptionally treated with radioembolization through the decision of an interdisciplinary board with tumor entities usually not treated by radioembolization were retrospectively analyzed. Hepatic features on cross-sectional preprocedural imaging, for example, like hypervascularization, hepatic tumor burden, maximum diameter, and clinical data, were also analyzed during follow-up. Predictive factors were calculated.
RESULTS: Univariate Cox regression showed a significant impact of different features on overall survival, for example, primary malignancy histology in the case of sarcoma, with 25 months median vs. 6 months median overall survival (P = 0.015). Multivariate Cox regression revealed the two key factors for overall survival: arterial hypervascularization more than rim enhancement (15 vs. 6 months, P = 0.011, hazard ratio: 0.339) and hepatic tumor burden below 10% (18 vs. 5 months, P < 0.001, hazard ratio: 1.04).
CONCLUSION: Preprocedural hypervascularization of liver malignancies and hepatic tumor burden are overall survival predicting factors in tumor entities rarely treated by radioembolization. Consideration of these factors can help to carry out suitable patient selection in the interdisciplinary board for radioembolization.

Keywords:  predictive factor; radioembolization; secondary hepatic malignancies

DOI:  https://doi.org/10.1097/MNM.0000000000002070