Lineage rewiring in lung adenocarcinoma via HNF4α and NKX2-1 dynamics.

Lineage plasticity drives treatment resistance in lung adenocarcinoma (LUAD) as cancer cells adopt new identities. In this issue of , 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.