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

Cancer Res. 2019 Sep 1;79(17):4466-4479. doi: 10.1158/0008-5472.CAN-19-0161. Epub 2019 Jun 17.

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 TGFβ type II receptor (Tgfbr2), frequently deleted in human lung cancer, led to predominant lung SCC development in KrasG12D mice with a short latency, high penetrance, and extensive metastases. Tgfbr2-loss-driven lung SCCs resembled the salient features of human lung SCC, including histopathology, inflammatory microenvironment, and biomarker expression. Surprisingly, loss of Smad4, 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 SOX2, an oncogenic driver of lung SCC, and cooperated with SMAD4 repression to elevate SOX2. Inhibition of ERK1/2 in Smad4fl/fl ;KrasG12D mice led to extensive lung SCC formation that resembled the SCC phenotype of Tgfbr2-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 Kras.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / mortality
  • Carcinoma, Squamous Cell / pathology*
  • Cell Line, Tumor
  • Humans
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology*
  • MAP Kinase Signaling System / genetics
  • Mice
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / pathology
  • Phosphorylation
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Receptor, Transforming Growth Factor-beta Type II / genetics
  • Receptor, Transforming Growth Factor-beta Type II / metabolism*
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism*
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism*

Substances

  • SMAD4 protein, human
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • Smad4 Protein
  • Smad4 protein, mouse
  • Receptor, Transforming Growth Factor-beta Type II
  • TGFBR2 protein, human
  • Tgfbr2 protein, mouse
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)