The risk of metastatic disease in colorectal cancer is determined by a gene program expressed in the tumor stroma
About 40% of Colorectal Cancer (CRC) patients with locally advanced disease show resistance to therapy and eventually develop metastasis. Current CRC staging based on histopathology and imaging has limited ability to predict disease progression or patient prognosis. A major advance has been the recent elaboration of molecular classifications based on global gene expression profiles, which have defined CRC subtypes displaying resistance to therapy and poor prognosis. In this work, we evaluated various molecular classifications and discovered that in all cases, their predictive power arises from genes expressed by cancer-associated fibroblasts (CAFs) rather than by tumor cells themselves. We found that such stromal gene program is driven by TGF-beta signaling and is expressed by virtually all poor prognosis CRCs. Functional dissection of CRC progression demonstrated that the presence of CAFs facilitates tumor initiation, an effect that is dramatically enhanced by transforming growth factor (TGF)-ß signaling. Using patient-derived tumor organoids and xenografts, we showed that the use of TGF-ß signaling inhibitors to block the cross-talk between cancer cells and the microenvironment prevented metastasis formation. Overall, our work reveals that CRC metastasis rely on a cancer cell non-autonomous program driven by TGF-ß in the tumor microenvironment. This dependency suggests that patients with advanced CRC cancers could benefit from the use TGF-ß signaling inhibitors. In addition, our work paves the way for new methods of patient classification based on the existence of distinct tumor microenvironments.