Oncogenic Ras activation in permissive somatic cells triggers rapid-onset phenotypic plasticity and elicits a tumor-promoting neutrophil response.

Oncogenic driver mutations are common in normal tissues, indicating that non-genetic factors are necessary for tumorigenesis. Phenotypic plasticity is a crucial gateway to malignancy, and inflammation can fuel tumorigenesis; however, little is known about the timing and mechanisms by which these hallmarks first emerge. Using single-cell transcriptomics and in vivo live imaging, we characterized the immediate cell-intrinsic and innate immune responses during the first 24 h following oncogenic Ras activation in a zebrafish model of HRASG12V-mediated skin tumor initiation. We found that in a subset of basal keratinocytes, RAS alone drives phenotypic plasticity, and these cells undergo dedifferentiation and partial epithelial-to-mesenchymal transition (EMT), resembling malignant cells in human squamous cell carcinoma. Strikingly, these cells also drive a tumor-promoting neutrophil program, which in turn enhances preneoplastic cell proliferation. Thus, oncogenic Ras effects are dictated by the cell of origin, and we revealed a link between unlocking plasticity and the onset of tumor-promoting inflammation.