Transcriptional evidence of neuroendocrine cell plasticity beyond histological boundaries in lung neuroendocrine neoplasms: an in-silico analysis suggesting a progression model

Little is known as to whether there may be a patogenetic continuum among subsets of lung neuroendocrine neoplasms (NENs), including both neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). In this study, transcriptomic data from 205 pulmonary NETs and NECs were collected from four publicly available datasets and analyzed through supervised clustering of a curated 20-gene signature dealing with neuroendocrine differentiation, key oncogenic pathways, chromatin remodeling genes, and lineage-specific transcription factors. Two major clusters were identified, PNEN-A and PNEN-B. Compared to PNEN-A and independently of histological typing, PNEN-B demonstrated reduced neuroendocrine gene expression and increased activation of pulmonary epithelial cell lineages, such as glandular (club/AT2⁺), basal (ΔNp63⁺/p63⁺/CK5⁺), and tuft cell (POU2F3⁺) differentiation. PNEN-B tumors also exhibited features of inflamed but functionally constrained immune microenvironment, with increased expression of immunomodulatory neuropeptides (calcitonin, proopiomelanocortin, and gastrin-releasing peptide), alongside enrichment of T cell exhaustion markers. PNEN-B tumors significantly correlated with poor prognosis in a subset of cases. These findings reveal common transcriptional programs across the entire spectrum of pulmonary NENs, independent of histological typing. Attenuation of neuroendocrine differentiation, activation of alternative cell lineages, and modulation of microenvironment highlight subsets of tumors with potential pathogenetic and clinical implications.