Final Report Summary - CRC PROGRAMME (Dissecting the roles of the beta-catenin and Tcf genetic programmes during colorectal cancer progression)
In 2002 we originally proposed that alterations in the biology of colon stem cells (CoSCs) may be at the heart of the pathophysiology of various intestinal disorders, including CRC. Over the first part of the ERC StG we focused our efforts towards the purification and gene expression profiling of normal and cancerous intestinal stem cells (ISCs). We have developed technology that for the first time allows the purification and in vitro expansion of human normal and cancerous ISCs. Through the characterization of both types of stem cells we have discovered that CRCs are caricatures of the normal process of tissue renewal and are organized through a hierarchy of cells with distinct tumorigenic potential. The expression of ISC genes defines a tumor cell population within human CRCs that resemble normal ISCs. Functional experiments demonstrated that purified ISC-like tumor cells from CRC biopsies possess long-term self-renewal capacity and show robust tumor initiation capacity when transplanted into immunodeficient hosts. High expression levels of the ISC- signature in primary tumors predict disease relapse upon intended curative treatment. Altogether, these data imply that CRCs share a common hierarchy and organization with the normal intestinal epithelium and that ISC-like tumor cells are probable candidates to mediate disease relapse and metastasis. This work is key for the clinical management of CRC patients, since it may allow to identify patients at high risk of disease recurrence. Likewise, it demonstrates unequivocally and for the first time the connection between adult stem cells from a certain organ and recurrence of a cancer derived from the same organ. In addition, it represents the first characterization and in vitro expansion of human CoSCs, a work that paves the way for their use in regenerative medicine and to understand their role in disease, current aspects of the research in my laboratory (Jung et al., Nature Medicine, 2011; Merlos Suárez et al., 2011).
In the second part of the ERC StG we have characterized the signalling pathways downstream of EphB receptors in colorectal cancer. This investigation revealed that one mechanism of cell compartmentalization downstream of EphB signalling involves the destruction of adherens junctions in adjacent cells through shedding of E-cadherin by ADAM10 metalloproteinase (Solanas et al., Nature Cell Biology, 2011).
The analysis of EphB-ephrinB interactions between tumor and stromal cells, led us to investigate the role of TGF-beta signalling during CRC progression. We discovered that colonization of foreign organs in CRC depends on a prometastatic program induced by TGF-beta in the tumor microenvironment. Low stromal TGF-beta signalling is a robust predictor of disease-free survival after therapy. Furthermore, pharmacological blockade of TGF-beta stromal signalling prevents metastasis initiation in animal models. Thus TGF-beta may be a target for therapeutic intervention at early time points of the metastatic process (Calon et al., Cancer Cell, 2012). This work has given rise to a technology transfer project that aims to develop a test that will estimate the likelihood of cancer reappearance with a high degree of reliability in a given patient suffering CRC.
In the second part of the ERC StG we have characterized the signalling pathways downstream of EphB receptors in colorectal cancer. This investigation revealed that one mechanism of cell compartmentalization downstream of EphB signalling involves the destruction of adherens junctions in adjacent cells through shedding of E-cadherin by ADAM10 metalloproteinase (Solanas et al., Nature Cell Biology, 2011).
The analysis of EphB-ephrinB interactions between tumor and stromal cells, led us to investigate the role of TGF-beta signalling during CRC progression. We discovered that colonization of foreign organs in CRC depends on a prometastatic program induced by TGF-beta in the tumor microenvironment. Low stromal TGF-beta signalling is a robust predictor of disease-free survival after therapy. Furthermore, pharmacological blockade of TGF-beta stromal signalling prevents metastasis initiation in animal models. Thus TGF-beta may be a target for therapeutic intervention at early time points of the metastatic process (Calon et al., Cancer Cell, 2012). This work has given rise to a technology transfer project that aims to develop a test that will estimate the likelihood of cancer reappearance with a high degree of reliability in a given patient suffering CRC.