Oncogenic RAS promotes malignant progression by altering stem cell cross-talk with the microenvironment.

  • Major Finding: Oncogenic RAS promotes malignant progression by altering stem cell cross-talk with the microenvironment.

  • Concept: Cancer stem cells induce angiogenesis, which brings TGFβ to the tumor microenvironment and activates leptin receptor and PI3K–AKT–mTOR signaling.

  • Impact: This study suggests that aberrant stem cell/microenvironment cross-talk can elevate common pathways seen in highly mutated cancers.

Aberrant RAS–MAPK signaling promotes the progression of benign papilloma to invasive disease in many cancers, including squamous cell carcinomas (SCC), but with high mutational burden, it has not been possible to decipher the relative importance of mutations versus the tumor microenvironment. Here, Yuan and colleagues devised a mouse model to clonally activate a single HRASG12V oncogene in a skin stem cell and monitored it as it progressed to form first a benign and then malignant, invasive SCC. Single-cell RNA sequencing showed that oncogenic RAS activation rewired cancer stem cell (CSC) gene expression leading to altered signaling cross-talk with the tissue microenvironment. As the CSCs formed benign tumors, they activated VEGFa, bringing to the microenvironment a low level of angiogenesis and active TGFβ from the perivasculature. TGFβ signaling triggered further changes in the CSCs, elevating a cohort of angiogenesis factors, immunomodulatory factors, and leptin receptor (LEPR), induced in part by the rise in TGFβ signaling. The rise in angiogenesis increased circulating leptin levels in the tumor microenvironment, elevating PI3K–AKT–mTOR signaling and malignant progression. Further evaluation revealed that LEPR signaling promoted larger colony formation in vitro and higher tumor incidence in an in vivo serial dilution transplantation assay, indicating a role for this pathway in enhancing stemness and tumor-initiating capabilities. Additionally, when LEPR was removed from the CSCs, tumor initiation and progression were reduced. In summary, this study shows the impact of aberrant cross-talk between CSCs and the tumor microenvironment and uncovers its ability to dramatically elevate pathways often seen in human metastatic cancers with high mutational burden. Together, this suggests the possibility that mutational burden may lock pathways into place that were already established by aberrant CSC cross-talk with the tumor microenvironment.

Yuan S, Stewart KS, Yang Y, Abdusselamoglu MD, Parigi SM, Feinberg TY, et al. Ras drives malignancy through stem cell crosstalk with the microenvironment. Nature 2022 Nov 30 [Epub ahead of print].

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