Oncogenic RAS triggers stem cell: microenvironment crosstalk to drive malignant progression [scRNA-Seq]

Oncogenic RAS/MAPK signaling drives metastatic squamous cell carcinomas (SCCs). These cancers are typified by high mutational burden, often featuring activating mutations in phosphatidylinositol-3-kinase (PI3K). Here we show that early in skin HRASG12V-induced oncogenesis, transitions from benign to malignant states are also marked by PI3K, this time super-activated through a temporal cascade of non-genetic events. Coupling clonal skin SCC genetic models with bulk and single-cell transcriptomics, chromatin-landscaping, lentiviral reporters, and lineage-tracing, we trace its roots. We show that following HRASG12V activation, oncogenic stem cells rewire their gene expression program. Initially, they produce an array of angiogenic factors, triggering a striking influx of vasculature and TGFß into the microenvironment. Sparked by TGFß-signaling, the stem cells induce leptin receptor (LEPR), which through the angiogenic influx activates LEPR-signaling to launch downstream PI3K-AKT-mTOR signaling. Our findings show how dynamic temporal crosstalk with the microenvironment, orchestrated by the stem cells, can drive the path to malignancy. Overall design: FACS sorted tumor cells were sorted directly into SMARTSeq2 lysis buffer in 96-well plates and snap frozen.