Dysregulated Tgfbr2/ERK-Smad4/SOX2 Signaling Promotes Lung Squamous Cell Carcinoma Formation

Abstract

Lung squamous cell carcinoma (SCC) is a common type of lung cancer. There is limited information on the genes and pathways that initiate lung SCC. Here, we report that loss of <i>TGFβ type II receptor</i> (<i>Tgfbr2</i>), frequently deleted in human lung cancer, led to predominant lung SCC development in <i>Kras^G12D</i> mice with a short latency, high penetrance, and extensive metastases. <i>Tgfbr2</i>-loss-driven lung SCCs resembled the salient features of human lung SCC, including histopathology, inflammatory microenvironment, and biomarker expression. Surprisingly, loss of <i>Smad4</i>, a key mediator of Tgfbr2, failed to drive lung SCC; instead, low levels of phosphorylated ERK1/2, a Smad-independent downstream effector of Tgfbr2, were tightly associated with lung SCC in both mouse and human. Mechanistically, inhibition of phosphorylated ERK1/2 significantly upregulated the expression of <i>SOX2</i>, an oncogenic driver of lung SCC, and cooperated with SMAD4 repression to elevate <i>SOX2</i>. Inhibition of ERK1/2 in <i>Smad4^fl/fl</i> ;<i>Kras^G12D</i> mice led to extensive lung SCC formation that resembled the SCC phenotype of <i>Tgfbr2</i>-deficient mice. Overall, we reveal a key role of ERK1/2 in suppressing SCC formation and demonstrate that dysregulated Tgfbr2/ERK-Smad4/SOX2 signaling drives lung SCC formation. We also present a mouse model of metastatic lung SCC that may be valuable for screening therapeutic targets. SIGNIFICANCE: This study sheds new light on the mechanisms underlying lung SCC formation driven by mutated <i>Kras</i>.