POU2F3 (POU Class 2 Homeobox 3)

Pcdh20 is a POU2F3 target gene in tuft cells, critical to maintain the rigid microvillar apparatus. These findings, together with the shared expression of mechanosensory components like TMC1, support the hypothesis that tuft cells could have mechanosensory capabilities analogous to cochlear hair cells.

These results demonstrate that LCNEC-P represents a distinct subgroup of LCNEC that is characterized by a specific morphological, immunohistochemical, and genetic profile, closely resembling SCLC-P. This study provides insights into the biology of LCNEC-P and supports its classification as a unique entity within LCNEC.

Methylation analysis confirmed the proximity of the two cases with other skin cancers. To conclude, we report herein the first description of primary cutaneous small cell carcinoma POU2F3 subtype.

Both components showed concordant aberrant tumor-suppressor immunoprofiles (p53 overexpression and Rb loss), and high-risk HPV RNA in situ hybridization (RNAscope) was negative. This case expands the recognized morphologic spectrum of bladder neuroendocrine carcinoma to include POU2F3-defined non-small cell neuroendocrine carcinoma with basaloid architecture, supporting the practical value of incorporating POU2F3 into immunohistochemical panels for poorly differentiated basaloid bladder tumors.

SEZ6expression is higher in SCLC than in NE tumors, with notable heterogeneity by subtype, warranting consideration of expanded use of SEZ6-directed therapy. Translational Relevance Statement: This study establishes SEZ6 as a promising therapeutic target in small cell lung cancer (SCLC) and transformed non-small cell lung cancer (NSCLC), demonstrating its significantly elevated expression compared to neuroendocrine (NE) tumors and NSCLC. The positive correlation of SEZ6 expression with NE lineage markers, particularly in ASCL1 and NEUROD1 subtypes, highlights its role as a lineage-specific marker, guiding the development of SEZ6-targeted antibody-drug conjugates (ADCs). Additionally, the increased SEZ6 expression following NSCLC-to-SCLC transformation suggests that SEZ6-targeted therapies could address resistance mechanisms in transformed tumors. Importantly, the association between high SEZ6 expression and shorter survival indicates that integrating SEZ6 status into diagnostic workflows could help stratify patients by risk and guide therapeutic decision-making. The findings from this study will inform future clinical trials, aiming to implement SEZ6-targeted treatments as part of precision oncology strategies for aggressive NE malignancies.

Unlike SCLC, lung carcinoids and EP-NETs completely lack the expression of POU2F3 and YAP1, which offers diagnostic applications. Our findings also nominate ASCL1 and NEUROD1 as site of origin markers for lung versus digestive NETs/carcinoids, respectively. Finally, the divergent expression of DLL3 in lung carcinoids and EP-NETs has therapeutic implications.

TNIK inhibition is more effective in c-MYChigh SCLC, acting through downregulation of c-MYC levels. It also decreases the production of CCL2, supporting the rationale for combination therapy with immune checkpoint inhibitors in c-MYChigh SCLC.

The ASCL1/INSM1-NLR composite biomarker stratifies survival outcomes for unresectable SCLC patients treated with first-line chemoimmunotherapy with or without radiotherapy. Prospective multicenter validation is required.

We applied CyTOF and a 20-marker antibody panel to detect and phenotype CTCs directly in liquid biopsies of 51 SCLC patients (treatment-naïve, chemotherapy and immunotherapy-treated, and tarlatamab-treated), of which a subset were longitudinally tracked...Our study demonstrates the utility of CyTOF for high-resolution CTC profiling, offering dynamic insights into CTC heterogeneity, treatment response, and resistance mechanisms. CTCs can be detected, subtyped and phenotyped in SCLC liquid biopsies using CyTOFCTC subtypes and EMT states are differentially associated with treatment modalityCTC DLL3 levels and epithelial features increase following anti-DLL3 BiTE therapyCyTOF CTC subtyping can predict disease aggressivenessLongitudinal tracking reveals CTC plasticity and therapy response correlations.

YAP1 and HNF4A expression correlated significantly with large-cell morphology.

Cases with Ki-67 > 10% require careful evaluation. At minimum, patients should undergo close surveillance, with treatment plans reassessed if rapid progression or PET changes are observed.

We further employ deep mutational scanning to assess the functional impact of 4,218 missense variants in POU2F3 and OCA-T1, uncovering both mutation-sensitive hotspots and structurally constrained regions critical for tumor cell fitness. These findings define a transcriptional complex that integrates DNA recognition with coactivator recruitment and nominate POU2F3-OCA-T as a structurally tractable vulnerability in tuft cell-like carcinomas.