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

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.

• Authors: 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
• Journal: Oncogene (Oncogene) Vol. 39 Issue 5 Pg. 1152-1164 (01 2020) ISSN: 1476-5594 [Electronic] England
• PMID: 31570790 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• HNF1B protein, human
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• Thyroid Hormones
• Hepatocyte Nuclear Factor 1-beta
• STK4 protein, human
• Protein Serine-Threonine Kinases
• STK3 protein, human
• Serine-Threonine Kinase 3
• ras Proteins

Topics

• Animals
• Carcinoma, Non-Small-Cell Lung (genetics, pathology)
• Carrier Proteins (metabolism)
• Cell Line, Tumor
• Cell Transformation, Neoplastic
• Disease Models, Animal
• Gene Deletion
• Hepatocyte Nuclear Factor 1-beta (genetics)
• Intracellular Signaling Peptides and Proteins
• Lung (metabolism, pathology)
• Lung Neoplasms (genetics, pathology)
• Membrane Proteins (metabolism)
• Mice
• Mice, Transgenic
• Protein Serine-Threonine Kinases (deficiency, genetics, metabolism)
• Serine-Threonine Kinase 3
• Thyroid Hormones (metabolism)
• ras Proteins (genetics)
• Thyroid Hormone-Binding Proteins