Oncogenic Ras activation in permissive somatic cells triggers rapid-onset phenotypic plasticity and elicits a tumor-promoting neutrophil response
Year: 2025
Type: article
Abstract: 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 HRAS G12V -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.
Source: Cell Reports
Authors: Abigail M. Elliot, Isabel Ribeiro Bravo, Yiyi Zhao, Zhuorui Wang, Jeanette Astorga Johansson, Esme Hutton, Richard Cunningham, Henna Myllymäki, Kai Yee Chang, Justyna Cholewa-Waclaw, Lisa Kelly, Mariana Beltran, Amy Lewis, Philip M. Elks, Carsten Gram Hansen, Neil C. Henderson, Yi Feng
Language: English
Topic: Cancer Cells and Metastasis
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
Awards: Investigation of antifibrotic targets in human liver fibrosis using a single cell transcriptomics approach., G1399669356, G2263456784, G2298236389, G3218722679, Investigation of antifibrotic targets in human liver fibrosis using a single cell transcriptomics approach., DTP Bid Led by University of Edinburgh, G388216973, G5442472037, G560035560, Live imaging and genetic analysis of the inflammatory response upon oncogene induced tissue homeostasis disruption and its contribution to tumour initiation in zebrafish larvae ., Manipulation of host hypoxia signalling as a therapeutic strategy for mycobacterial infection, Live imaging and genetic analysis of the inflammatory response upon oncogene induced tissue homeostasis disruption and its contribution to tumour initiation in zebrafish larvae ., G7423961978, G7457959702, G7982776177, G8037778031, G9000134720
OpenAlex ID: W4415533984