Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation

Abstract

Oncogenic mutations regulate signaling within both tumor cells and adjacent stromal cells. Here, we show that oncogenic KRAS (KRAS[superscript G12D]) also regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with multivariate phosphoproteomics, we analyzed heterocellular KRAS[superscript G12D] signaling in pancreatic ductal adenocarcinoma (PDA) cells. Tumor cell KRAS[superscript 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[superscript G12D]. Consequently, reciprocal KRAS[superscript G12D] produces a tumor cell phosphoproteome and total proteome that is distinct from cell-autonomous KRAS[superscript 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.