Assistant Professor University of Utah Salt Lake City, Utah, United States
Michelle Mendoza (University of Utah)| Kelley Ingram (University of Utah)| Shiela Samson (University of Utah)
Lung cancer remains a leading cause of cancer death, with unclear mechanisms driving the transition to aggressive cancer with poor prognosis. The RAS/RAF/MEK/ERK pathway is hyper-activated in ~50% of human lung adenocarcinoma (LUAD). An initial activating mutation induces homeostatic feedback mechanisms that limit ERK activity. Additional, undefined genetic hits overcome the feedback, leading to high ERK activity that drives malignant progression. At detection, the majority of LUADs express the homeobox transcription factor NKX2-1, which also limits malignant progression. NKX2-1 constrains LUAD, in part, by maintaining a state of well-differentiation. We asked if loss of NKX2-1 might also contribute to the release of ERK activity that drives tumor progression. Using human tissue samples and cell lines, xenografts, and genetic mouse models, we show that NKX2-1 induces the ERK phosphatase DUSP6. In cells with silenced NKX2-1, re-introduction of NKX2-1 induces DUSP6 and inhibits cell proliferation and migration and tumor growth and metastasis. Our CRISPR knockout studies show that DUSP6 is necessary for NKX2-1-mediated inhibition of ERK activity and tumor progression. Further, DUSP6 expression is sufficient to inhibit RAS-driven LUAD. We conclude that NKX2-1 silencing, and thereby DUSP6 silencing, is a mechanism by which early LUAD can unleash ERK hyperactivation for tumor progression.
Support or Funding Information
M.C.M was supported by K01CA168850, an American Lung Association Research Grant, American Cancer Society RSG CSM130435, and R21CA215891.