SRP105485 PRJNA382611 Specific integrin functions regulating the interplay between cancer cells and their microenvironment In many cancer types, integrin-mediated signaling regulates proliferation, survival, and invasion of tumorigenic cells1–3. However, it is still unclear how integrins crosstalk with oncogenes to regulate tumorigenesis and metastasis. Here, we show that oncogenic K-RasV12 upregulates a6-integrin expression in Madin-Darby canine kidney (MDCK) cells via activation of the mitogen-activated protein kinase (MAPK) / extracellular signal-regulated kinase (ERK) / Fos-related antigen 1 (FOSL1)-signaling cascade. Activated a6-integrins promoted anoikis resistance and led to perturbed growth and polarity of MDCK cysts. Transcriptomic analysis of K-RasV12-transformed MDCK cells also revealed robust downregulation of aV-class integrins. Re-expression of aV-integrin in K-RasV12-transformed MDCK cells synergistically upregulated the expression of Zinc finger E-box-binding homeobox 1 (ZEB1) and Twist-related protein 1 (TWIST1) and triggered epithelial-mesenchymal transition (EMT) leading to induced cell motility and invasion. Taken together, these results delineate the signaling cascades connecting oncogenic K-RasV12with a6- and aV-integrin functions to modulate cancer cell survival and tumorigenesis and reveal new possible strategies to target highly oncogenic K-RasV12-mutants. Canis lupus familiaris