MEN1 deficiency leads to neuroendocrine differentiation of lung cancer and disrupts the DNA damage response

The MEN1 gene, a tumor suppressor gene that encodes the protein menin, is mutated at high frequencies in neuroendocrine (NE) tumors; however, the biological importance of this gene in NE-type lung cancer in vivo remains unclear. Here, we established an ATII-specific KrasG12D/+/Men1−/− driven genetically engineered mouse model and show that deficiency of menin results in the accumulation of DNA damage and antagonizes oncogenic Kras-induced senescence and the epithelial-to-mesenchymal transition during lung tumorigenesis. The loss of menin expression in certain human primary lung cancers correlates with elevated NE profiles and reduced overall survival. Loss ofMEN1 results in an inherited multiple endocrine neoplastic type 1 syndrome. Here, the authors generate an alveolar type II cell MEN1 knockout mouse model and show that on a Kras mutant background the mice develop lung tumors with features of neuroendocrine differentiation.