Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation

Oncogenic mutations regulate signaling within both tumor cells and adjacent stromal cells. Here, we show that oncogenicKRAS(KRAS G12D) also regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with multivariate phosphoproteomics, we analyzed heterocellular KRAS G12D signaling in pancreatic ductal adenocarcinoma (PDA) cells. Tumor cell KRAS G12D engages heterotypic fibroblasts, which subsequently instigate reciprocal signaling in the tumor cells. Reciprocal signaling employs additional kinases and doubles the number of regulated signaling nodes from cell-autonomous KRAS G12D. Consequently, reciprocal KRAS G12D produces a tumor cell phosphoproteome and total proteome that is distinct from cell-autonomous KRAS G12D alone. Reciprocal signaling regulates tumor cell proliferation and apoptosis and increases mitochondrial capacity via an IGF1R/AXL-AKT axis. These results demonstrate that oncogene signaling should be viewed as a heterocellular process and that our existing cell-autonomous perspective underrepresents the extent of oncogene signaling in cancer.