Abstract In a recent study published in Cancer Discovery, Hsu and colleagues employ an elegant combination of single-cell and bulk RNA sequencing experiments from mouse and human colorectal cancer samples, patient-derived organoids, two-dimensional in vitro systems, and in vivo validation in genetically engineered colorectal cancer mouse models to investigate how mutant KRAS (KRAS*) impacts the tumor microenvironment. They identify a molecular signaling cascade downstream of KRAS* that activates a specific program of lipid-rich cancer-associated fibroblasts, promoting tumor angiogenesis and progression. These findings may lead to new therapeutic strategies for patients with colorectal cancer with KRAS*.