Mst1/2 kinases restrain transformation in a novel transgenic model of Ras driven non-small cell lung cancer

Kanchan Singh, Melissa A. Pruski, Kishore Polireddy, Neal C. Jones, Qingzheng Chen, Jun Yao, Wasim A. Dar, Florencia McAllister, Cynthia Ju, Holger K. Eltzschig, Mamoun Younes, Cesar Moran, Harry Karmouty-Quintana, Haoqiang Ying, Jennifer M. Bailey

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Non-small cell lung cancer remains a highly lethal malignancy. Using the tamoxifen inducible Hnf1b:CreERT2 (H) transgenic mouse crossed to the LsL-KrasG12D (K) transgenic mouse, we recently discovered that an Hnf1b positive cell type in the lung is sensitive to adenoma formation when expressing a mutant KrasG12D allele. In these mice, we observe adenoma formation over a time frame of three to six months. To study specificity of the inducible Hnf1b:CreERT2 in the lung, we employed lineage tracing using an mTmG (G) reporter allele. This technique revealed recombined, GFP+ cells were predominantly SPC+. We further employed this technique in HKG mice to determine Hnf1b+ cells give rise to adenomas that express SPC and TTF1. Review of murine lung tissue confirmed a diagnosis of adenoma and early adenocarcinoma, a pathologic subtype of non-small cell lung cancer. Our expanded mouse model revealed loss of Mst1/2 promotes aggressive lung adenocarcinoma and large-scale proteomic analysis revealed upregulation of PKM2 in the lungs of mice with genetic deletion of Mst1/2. PKM2 is a known metabolic regulator in proliferating cells and cancer. Using a human lung adenocarcinoma cell line, we show pharmacologic inhibition of Mst1/2 increases the abundance of PKM2, indicating genetic loss or pharmacologic inhibition of Mst1/2 directly modulates the abundance of PKM2. In conclusion, here we report a novel model of non-small cell lung cancer driven by a mutation in Kras and deletion of Mst1/2 kinases. Tumor development is restricted to a subset of alveolar type II cells expressing Hnf1b. Our data show loss of Mst1/2 regulates levels of a potent metabolic regulator, PKM2.

Original languageEnglish (US)
Pages (from-to)1152-1164
Number of pages13
JournalOncogene
Volume39
Issue number5
DOIs
StatePublished - Jan 30 2020

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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