bims-necame 2025-09-14 papers

Issue of 2025–09–14
five papers selected by
Grigor Varuzhanyan, UCLA

Nature. 2025 Sep 10.

Functional synapses between neurons and small cell lung cancer.

Vignesh Sakthivelu, Anna Schmitt, Franka Odenthal, Kristiano Ndoci, Marian Touet, Ali H Shaib, Abdulla Chihab, Gulzar A Wani, Pascal Nieper, Griffin G Hartmann, Isabel Pintelon, Ilmars Kisis, Maike Boecker, Naja M Eckert, Manoela Ianicelli Caiaffa, Olta Ibruli, Julia Weber, Roman Maresch, Christina M Bebber, Ali Chitsaz, Anna Lütz, Mira Kim Alves Carpinteiro, Kaylee M Morris, Camilla A Franchino, Jonas Benz, Laura Pérez-Revuelta, Jorge A Soriano-Campos, Maxim A Huetzen, Jonas Goergens, Milica Jevtic, Hannah M Jahn-Kelleter, Hans Zempel, Aleksandra Placzek, Alexandru A Hennrich, Karl-Klaus Conzelmann, Hannah L Tumbrink, Pascal Hunold, Joerg Isensee, Lisa Werr, Felix Gaedke, Astrid Schauss, Marielle Minère, Marie Müller, Henning Fenselau, Yin Liu, Alena Heimsoeth, Gülce S Gülcüler Balta, Henning Walczak, Christian Frezza, Ron D Jachimowicz, Julie George, Marcel Schmiel, Johannes Brägelmann, Tim Hucho, Silvia von Karstedt, Martin Peifer, Alessandro Annibaldi, Robert Hänsel-Hertsch, Thorsten Persigehl, Holger Grüll, Martin L Sos, Guido Reifenberger, Matthias Fischer, Dirk Adriaensen, Reinhard Büttner, Julien Sage, Inge Brouns, Roland Rad, Roman K Thomas, Max Anstötz, Silvio O Rizzoli, Matteo Bergami, Elisa Motori, Hans Christian Reinhardt, Filippo Beleggia.

Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer, characterized by rapid proliferation, early metastatic spread, frequent early relapse and a high mortality rate1-3. Recent evidence has suggested that innervation has an important role in the development and progression of several types of cancer4,5. Cancer-to-neuron synapses have been reported in gliomas6,7, but whether peripheral tumours can form such structures is unknown. Here we show that SCLC cells can form functional synapses and receive synaptic transmission. Using in vivo insertional mutagenesis screening in conjunction with cross-species genomic and transcriptomic validation, we identified neuronal, synaptic and glutamatergic signalling gene sets in mouse and human SCLC. Further experiments revealed the ability of SCLC cells to form synaptic structures with neurons in vitro and in vivo. Electrophysiology and optogenetic experiments confirmed that cancer cells can receive NMDA receptor- and GABAA receptor-mediated synaptic inputs. Fitting with a potential oncogenic role of neuron-SCLC interactions, we showed that SCLC cells derive a proliferation advantage when co-cultured with vagal sensory or cortical neurons. Moreover, inhibition of glutamate signalling had therapeutic efficacy in an autochthonous mouse model of SCLC. Therefore, following malignant transformation, SCLC cells seem to hijack synaptic signalling to promote tumour growth, thereby exposing a new route for therapeutic intervention.

DOI: https://doi.org/10.1038/s41586-025-09434-9

Nature. 2025 Sep 10.

Neuronal activity-dependent mechanisms of small cell lung cancer pathogenesis.

Neural activity is increasingly recognized as a crucial regulator of cancer growth. In the brain, neuronal activity robustly influences glioma growth through paracrine mechanisms1 and by electrochemical integration of malignant cells into neural circuitry via neuron-to-glioma synapses2,3. Outside of the central nervous system, innervation of tumours such as prostate, head and neck, breast, pancreatic, and gastrointestinal cancers by peripheral nerves similarly regulates cancer progression4-12. However, the extent to which the nervous system regulates small cell lung cancer (SCLC) progression, either in the lung or when growing within the brain, is less well understood. SCLC is a lethal high-grade neuroendocrine tumour that exhibits a strong propensity to metastasize to the brain. Here we demonstrate that in the lung, vagus nerve transection markedly inhibits primary lung tumour development and progression, highlighting a critical role for innervation in SCLC growth. In the brain, SCLC cells co-opt neuronal activity-regulated mechanisms to stimulate growth and progression. Glutamatergic and GABAergic (γ-aminobutyric acid-producing) cortical neuronal activity each drive proliferation of SCLC in the brain through paracrine and synaptic neuron-cancer interactions. SCLC cells form bona fide neuron-to-SCLC synapses and exhibit depolarizing currents with consequent calcium transients in response to neuronal activity; such SCLC cell membrane depolarization is sufficient to promote the growth of intracranial tumours. Together, these findings illustrate that neuronal activity has a crucial role in dictating SCLC pathogenesis.

DOI: https://doi.org/10.1038/s41586-025-09492-z

Ann Med. 2025 Dec;57(1): 2556253

Prognostic values and clinical significance of POU2F3 expression in neuroendocrine carcinomas: a meta-analysis with a focus on small cell lung cancer.

Yeoun Eun Sung, Meejeong Kim, Jihye Kim, Sung Hak Lee, Younghoon Kim.

BACKGROUND: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine carcinoma (NEC) with poor prognosis due to chemotherapy resistance. Molecular subtypes, including ASCL1, NEUROD1, YAP1 and POU2F3, have distinct clinical implications. POU2F3, linked to a tuft cell-like lineage, represents a non-neuroendocrine subtype found in SCLC and extrapulmonary NECs. However, its prognostic and clinical significance remain unclear.
METHODS: A meta-analysis was performed to assess the relationship between POU2F3 expression and clinical outcomes in SCLC and NECs. Studies reporting clinicopathological or survival data related to POU2F3 expression, identified via immunohistochemistry, were included. This review was performed following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and was registered on the International Prospective Register of Systematic Reviews (registration number: CRD42023478789).
RESULTS: Sixteen studies involving 2011 patients met inclusion criteria. Pooled analysis revealed that POU2F3 expression in SCLC significantly improved OS (HR = 0.74, 95% CI = 0.61-0.90, p < .01 and PFS/RFS (HR = 0.69, 95% CI = 0.53-0.90, p < .01). Subgroup analyses associated POU2F3 positivity with favourable survival when surgical specimen or whole slide analysis was used, or when studies with chemotherapy regimen were included. POU2F3 expression also correlated with younger age (p = .02) and male sex (p = .03) but not with smoking history, tumour stage, nodal involvement, or vascular invasion.
CONCLUSION: POU2F3 expression is associated with improved survival and correlates with younger age and male sex in SCLC, highlighting distinct clinical and biological characteristics of this tuft cell-originated subtype. Data on extrapulmonary NECs were limited, precluding definitive conclusions for this population.

Keywords: POU2F3; meta-analysis; neuroendocrine carcinoma; prognosis; small cell lung cancer

DOI: https://doi.org/10.1080/07853890.2025.2556253

BMC Res Notes. 2025 Sep 08. 18(1): 385

Imaging mass cytometry dataset of small-cell lung cancer tumors and tumor microenvironments.

France Rose, Olta Ibruli, Luca Lichius, Martha Kiljan, Gokcen Gozum, Manoela Iannicelli Caiaffa, Jiali Cai, Li-Na Niu, Jan M Herter, Holger Grüll, Reinhard Büttner, Filippo Beleggia, Graziella Bosco, Julie George, Grit S Herter-Sprie, Hans Christian Reinhardt, Katarzyna Bozek.

OBJECTIVES: Small cell lung cancer (SCLC) accounts for approximately 15% of lung tumors and is marked by aggressive growth and early metastatic spread. In this study, we used two SCLC mouse models with differing tumor mutation burdens (TMB). To investigate tumor composition, spatial architecture, and interactions with the surrounding microenvironment, we acquired multiplexed images of mouse lung tumors using imaging mass cytometry (IMC). These data build upon a previously published characterization of the mouse model.
DATA DESCRIPTION: After tumor detection, mice were assigned to one of five treatment groups. Lung tumor tissues were imaged with a 37-marker IMC panel designed to identify major cell types-tumor, immune, and structural-as well as their functional states. When possible, each tumor was sampled both at its center and border regions. Tumor masks in the form of binary images are provided to delineate tumor areas. Additional metadata include tumor onset and endpoint dates to support downstream correlation or predictive analyses based on the image data. This dataset offers a valuable resource for studying the histological and cellular complexity of SCLC in a genetically controlled mouse model across multiple therapeutic conditions.

Keywords: Hyperion; IMC; MIBI-TOF; Mouse models; SCLC; Tumor microenvironment

DOI: https://doi.org/10.1186/s13104-025-07460-4

Signal Transduct Target Ther. 2025 Sep 10. 10(1): 290

Characterization of the extrinsic and intrinsic signatures and therapeutic vulnerability of small cell lung cancers.

Small-cell lung cancer (SCLC), an aggressive neuroendocrine tumor strongly associated with exposure to tobacco carcinogens, is characterized by early dissemination and dismal prognosis with a five-year overall survival of less than 7%. High-frequency gain-of-function mutations in oncogenes are rarely reported, and intratumor heterogeneity (ITH) remains to be determined in SCLC. Here, via multiomics analyses of 314 SCLCs, we found that the ASCL1+/MKI67+ and ASCL1+/CRIP2+ clusters accounted for 74.38% of the 190,313 SCLC cancer cells from 39 patients, with the ASCL1+SOX1+ stem-like cell cluster across SCLC subtypes. The major histocompatibility complex (MHC) class I molecules were expressed at low levels in six and high levels in five cancer cell clusters and were inversely associated with the KI67 expression level. Abnormal splicing of mRNAs was a feature of SCLC, with focal adhesion kinase (FAK) splicing variants identified in 119 (77.3%) of 154 patients. FAK variants exhibited elevated kinase activity, were associated with the worst prognosis, and were sensitive to FAK inhibitors in patient-derived organoids and xenograft models. Eleven high-frequency mutations were identified in addition to TP53 and RB1, and smoking status and tumor stage did not affect microbiota variance in SCLC. Taken together, our data further revealed the complicated ITH and discovered that FAK splicing variants represent high-frequency gain-of-function alterations in oncogene in SCLC and potential therapeutic targets for this recalcitrant cancer.

DOI: https://doi.org/10.1038/s41392-025-02378-6