Fra-1: a safeguard protecting tumor cells from oncogenic stress

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Across species and tumors our preliminary data provide robust evidence for the co-selection/co-expression of the transcription factors Fra-1, a member of the AP-1 family, and MYC, an oncogene with relevance for most cancers, especially in context of oncogenic KRAS. Therefore, we hypothesize that Fra-1 is a "safeguard" needed in tumor cells with supra-physiological MYC activity to cope with MYC-dependent oncogenic stress pathways. Using PDAC as a bona fide KRAS-driven cancer, we aim to decipher and understand the function of Fra-1 and elucidate how Fra-1 protects against MYC-dependent oncogenic stress. Since context matters, we will also analyze whether the molecular functions detected in KRAS-driven PDAC is evident in KRAS-driven NSCLC models. We propose that the detailed understanding of Fra-1 will allow to develop novel therapeutic concepts for a subtype of KRAS-driven cancers by the targeting of "safeguard" functions of Fra-1, which we plan to test in up-to-date human model systems of PDAC.