Signaling Response to Early Oncogenesis by a Novel Panel of Murine Mutant Kras Alleles in the Mouse Lung Transcriptome [I]

Despite over 50 oncogenic RAS mutations, specific mutations track with distinct cancer types. To elucidate the underlying contribution of oncogenic signaling to RAS mutation patterns we globally activated a novel panel of endogenous murine Kras alleles with biochemically distinct mutations encoded with native or common codons producing low or high protein levels. Each induced unique tumor patterns, with quantitative signaling favoring hematopoietic tumors, qualitative signaling favoring squamous tumors, while carcinomas tended to be a combination of both types of signaling. Mechanistically, these mutants generated very different levels of active Kras and cellular responses, with low Kras activity yielding transcriptional features of a multipotent state while high activity had all the hallmarks of potent oncogenic activity and resultant stress and an inflammatory response. We thus suggest that the RAS mutational bias to specific cancer types is a result of tissue-specific responses of normal cells to either or both quantitative and qualitative signaling differences imparted by the selected mutant. Overall design: Lung transcriptome of three male and female adult mice from KrasnatG12D, and KrascomQ61R allele in the Rosa26Cre-ERT2 background 1 week after tamoxifen injection