HNF4α controls growth, identity, and KRAS inhibitor response in invasive mucinous adenocarcinoma of the lung
Headtlove Essel Dadzie, Yangsook Song Green, Soledad A. Camolotto, Henry U. Arnold, Matthew Gumbleton, Minzhe Guo, Mari Mino-Kenudson, Yutaka Maeda, Benjamin T. Spike, Eric L. Snyder
Headtlove Essel Dadzie, Yangsook Song Green, Soledad A. Camolotto, Henry U. Arnold, Matthew Gumbleton, Minzhe Guo, Mari Mino-Kenudson, Yutaka Maeda, Benjamin T. Spike, Eric L. Snyder
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Research Article Oncology Pulmonology

HNF4α controls growth, identity, and KRAS inhibitor response in invasive mucinous adenocarcinoma of the lung

Abstract

Cellular plasticity is a hallmark of cancer, enabling tumor cells to alter identity and evade therapeutic pressure. In invasive mucinous adenocarcinoma of the lung (IMA), NK2 homeobox 1 (NKX2-1) loss triggers a pulmonary to gastric switch marked by aberrant activation of hepatocyte nuclear factor 4 alpha (HNF4α), a master regulator of gastrointestinal/hepatic differentiation. We show that HNF4α promoted IMA growth and activated a gastric pit cell–like program. Loss of HNF4α enabled forkhead box A1 and A2 (FoxA1/2) transcription factors to bind de novo sites and activate alternative, nongastric identities in IMA. HNF4α also established a mucinous program associated with tolerance to KRAS blockade, and loss of HNF4α enhanced response to KRASG12D inhibition. Mechanistically, HNF4α blocked cell-cycle exit in drug-tolerant persister cells and promoted activity of the antioxidant transcription factor nuclear factor erythroid 2–related factor 2 (NRF2). NRF2 activation partially rescued the effects of Hnf4a deletion on KRASG12D inhibition, whereas NRF2 inhibition enhanced sensitivity to KRASG12D blockade. Thus, HNF4α is a key regulator of growth, identity, and primary response to KRASG12D inhibition in IMA.

Authors

Headtlove Essel Dadzie, Yangsook Song Green, Soledad A. Camolotto, Henry U. Arnold, Matthew Gumbleton, Minzhe Guo, Mari Mino-Kenudson, Yutaka Maeda, Benjamin T. Spike, Eric L. Snyder

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Figure 5

HNF4α sustains a stomach-like gastric lineage program in IMA at single-cell resolution.

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HNF4α sustains a stomach-like gastric lineage program in IMA at single-c...
(A) UMAPs of representative HNF4α target genes (Lgals4, Eps8l3, Gkn1, and Tff1). (B) UMAPs of the Takada et al. corpus dataset (PMID: 37386010), with KN and KNH tumor cells mapped by Seurat label transfer. (C) Proportion of KN and KNH tumor cells mapping to corpus clusters. (D) Feature plots of corpus pit, antral pit, and mature pit cell markers in IMA tumor cells. (E) UMAPs of gene module scores along the isthmus-to-pit trajectory. (F) UMAPs of gene modules associated with alternative cell types in KNH tumors. (G) UMAP of CytoTRACE1 scores (0–1), with lower values indicating greater differentiation. (H) Violin plot of iPSC and ESC gene signatures in KN and KNH tumor cells (group B). (I) UMAPs of fetal intestinal stem cell markers (Ly6a, Tacstd2, Anxa1, and Clu).