The intestinal epithelium continuously self-renew through the activity of a dedicated population of intestinal stem cells. Unlike the bulk of cells that populate this tissue, intestinal stem cells are long-lived and generate cellular progeny throughout life that regenerates the multiple specialized, short-lived cells that ultimately perform intestinal-specific functions. Analogous to renewal of healthy intestine, colorectal cancer (CRC) growth is fueled by tumor stem cells, which are believed to be responsible for important clinical observations such as the almost inevitable recurrence of tumors after initially successful chemotherapy. However, the analysis of stem cell hierarchies in human cancer has been hampered by the impossibility of identifying or tracking this tumor cell populations in an intact environment. Recently, we have made use of patient derived organoids and CRISPR/Cas9 technology to study CRC stem cells in unperturbed tumors. This strategy has provided insights into cancer stem cell, renewal, quiescence and plasticity. Our lab has also embarked in the development of therapies that target specifically CRC stem cells.
Another major challenge remains treatment of CRC patients at late stages when tumor cells have already disseminated. Current therapies are poorly effective for metastatic disease, the main cause of death in CRC. We discovered that transforming growth factor (TGF)-beta is the major architect of the microenvironment of poor-prognosis CRCs. Disseminated tumor cells rely on a TGF-beta-activated stroma during the establishment and subsequent expansion of metastasis. This dependency could be exploited to cure the disease at advanced stages.