"Neuroendocrine (NE) cancers are aggressive tumours found throughout the body, including in the lung, prostate, pancreas and gastrointestinal tract15,16. A tuft-like subset of these tumours depends on the lineage-specific oncogene POU2F32,3,4,5,6,7,17. Although tuft-like cancers are not yet clinically distinguished, they are transcriptionally distinct from other NE types and may respond uniquely to therapies. The origins of tuft-like cancers and the genetic alterations that drive them are poorly understood, partly because of a lack of representative models."
"Small cell lung cancer (SCLC) is among the deadliest NE cancers, with a 5-year survival rate below 7%20,21. SCLC comprises distinct molecular subtypes: SCLC-A (ASCL1+), SCLC-N (NEUROD1+) and SCLC-P (POU2F3+), as well as a controversial fourth group that lacks these markers and has been described as YAP1+, mesenchymal and/or inflammatory8,9,20,21,22,23,24,25. Human SCLC displays intratumoural subtype heterogeneity and plasticity, especially among the A, N and Y states8,26,27,28,29,30,31. Whether SCLC-P arises through plasticity remains unknown."
Tumour cell plasticity drives cell fate diversity, tumour progression and therapy resistance, while the cues governing plasticity and the influence of cell-of-origin remain largely undefined. Neuroendocrine cancers occur across organs, and a tuft-like subset depends on the lineage-specific oncogene POU2F3. Tuft-like cancers are transcriptionally distinct and may respond differently to therapies, yet origins and genetic drivers are poorly characterized because of limited models. Small cell lung cancer has a 5-year survival below 7% and comprises subtypes SCLC-A, SCLC-N and SCLC-P, plus a controversial YAP1/mesenchymal/inflammatory group. Human SCLC shows intratumoural heterogeneity and plasticity, and SCLC-P, driven by tuft-lineage factors, may arise from tuft/brush cells rather than pulmonary neuroendocrine cells.
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