Experimental models reveal HNF4α's role in lineage plasticity and tumor progression in lung adenocarcinoma, suggesting treatment pathways.
Lineage plasticity drives treatment resistance in lung adenocarcinoma (LUAD) as cancer cells adopt new identities. In this issue of Genes & Development , Fort and colleagues (doi:10.1101/gad.352742.125) report HNF4α as a key regulator of hybrid identity states and tumor progression in NKX2-1-positive LUAD. Using murine and human models, they show that HNF4α promotes gastrointestinal/liver-like programs and suppresses pulmonary identity by modulating cell identity-specific binding of NKX2-1. In addition, RAS/MEK signaling was implicated in maintenance of this hybrid identity state by regulating NKX2-1 chromatin binding in LUAD. These findings nominate HNF4α as a driver of LUAD plasticity and a potential therapeutic target to overcome resistance.
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Feng et al. (2025) studied this question.
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