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Gene expression profiling has revealed transcriptional heterogeneity across NEPC, but this is rarely considered in the context of variation between pathologies. Diagnosis typically relies on immunohistochemical markers (CHGA, SYP, NCAM1) and genomic alterations in RB1, PTEN and TP53. We hypothesized that NEPC pathologies have unique transcriptional features. Single\u2010cell RNA sequencing of 18\u2009632 tumour cells from nine patient\u2010derived xenograft models representing five pathologies (small\u2010cell and large\u2010cell neuroendocrine carcinomas, focal neuroendocrine differentiation (Focal NED), low\u2010grade neuroendocrine and amphicrine) demonstrated pathway\u2010specific enrichment. Focal NED and amphicrine tumours exhibited cellular subpopulations enriched for KRAS, IL2\u2010STAT5 and TNF signalling pathways, absent in small\u2010 and large\u2010cell carcinomas, which were instead enriched for Myc and E2F pathways. 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