1. Connecting stem cells to colorectal cancer
Tissues such as the intestinal epithelium and the hematopoietic system continuously self-renew through the activity of a dedicated population of tissue-specific stem cells. Unlike the bulk of the cells that populate these tissues, adult stem cells are long-lived and generate cellular progeny throughout life to regenerate the multiple specialized, short-lived cells that ultimately perform tissue-specific functions. The cancer stem cell (CSCs) theory states that tumor growth is similarly fueled by small numbers of tumor stem cells hidden in cancers. It explains clinical obser¬vations, such as the almost inevitable recurrence of tumors after initially successful chemotherapy and/or radiation therapy, the phenomenon of tumor dormancy, and metastasis. Our laboratory pioneers the notion that colorectal cancers retain a cell hierarchy similar to that of the normal intestinal mucosa. We have characterized extensively tumor stem cell population in CRCs and its role in chemotherapy resistance and relapse. We are currently pursuing the following questions:

- How does the tumor niche specify the CSC state?
- To which extent are tumor-cell phenotypes reversible or interchangeable?
- What type of ‘regenerative’ responses occur upon CSC loss in a tumor, and how are these controlled?
- Which are the intermedi¬ate states adopted by tumor cells during invasion?
- How metabolic states of tumor stem cells controlled, and what are their effects?

2. Tumor microenvironment, immune evasion and metastasis
A large proportion of deaths by colorectal cancer are the consequence of metastasis. This process involves the regeneration of a full-blown tumor from disseminated cancer cells and it is intrinsically inefficient mainly due to the inability of isolated tumor cells to colonize host tissues and reinitiate tumor growth in a different environment. The most accepted view is that competences to overcome this bottleneck result from clonal selection of appropriate genetic alterations in cancer cells. However, primary CRCs and metastases do not differ significantly in their mutational content and none of the main alterations in driver oncogenes and tumor suppressor genes correlate significantly with patient outcome. Our laboratory recently discovered that the key genetic programs associated to poor prognosis in CRC patients are expressed in cells of the tumor microenvironment (TME). TGF-beta signaling is the main architect of the TME in metastatic CRC and appears to help metastatic cancer cells evade the immune system. This finding opens up the development of new therapeutic and diagnostic tools for advanced CRC patients based on targeting the TME. Key questions and research lines in this area include:

- Why some CRCs develop a TGF-beta-activated TME and others don’t?
- How cancer associated fibroblasts mediate the phenomenon of immune exclusion?
- Genetic analysis of the metastatic niche.
- How systemic factors influence cancer recurrence?