Our preliminary results suggested that glucose metabolism could regulate stem cell fate in the intestine leading to tumor development. We have followed up these observations to determine the precise role of glucose metabolism on ISCs fate as well as its implications in CRC. To identify intestinal epithelial cells with different glycolytic metabolism, we have developed a metabolic reporter based on the expression of a fluorescent marker under the control of a key glycolytic gene. In this system, cells with an active glucose metabolism can be identified, tracked and isolated by means of the fluorescent marker. Using this approach, we have found a novel, exquisitely glycolytic cell type characterized by high levels of glucose metabolism. These cells have strong stem cell potential, and these specific metabolic properties are required to regulate their stemness. Importantly, our results strongly suggest that these cells can give rise to tumor initiating cells in a mouse model of colorectal cancer and, together with my previous findings, provide novel insights into the role of metabolism in driving normal intestinal stem cells and early stages of intestinal cancer.
In order to translate our findings to human CRC and shed light on the role of glucose metabolism during tumor progression, we took advantage of a unique resource of CRC patients-derived tumors obtained by our Institute. We used these tumors to derive 3D cultures in vitro (organoids), which we engineered to carry the fluorescent metabolic reporter described above. Transplantation of these organoids into the cecum of mice led to the formation of colorectal tumors in their native environment. By following the expression of the fluorescent marker, we have found that, similar to what we observed in mouse models of CRC, human colorectal tumors also contain a small fraction of highly glycolytic cells. Remarkably, these cells are present in metastatic lesions and its number increases at later stages of tumorigenesis, suggesting that they might be involved in driving tumor progression.
Exploitation and dissemination of the results obtained during the action
I have been actively engaged in exploiting and disseminating my research by several means. I have presented the results derived from this project at several international meetings, which have enhanced the visibility of my research. As a result, I have been invited to give several lectures and to write a review article covering the topic of CRC and metabolism. Furthermore, I have set up a “Cancer Metabolism Club”, a monthly seminar series bringing together more than 50 researchers working on cancer metabolism in the Turin area, which has fostered several fruitful collaborations. Remarkably, some results obtained in this project are part of a manuscript currently being evaluated for publication and have been the basis for successful grant applications.
No public website has been developed for this project.
Impact on the researcher’s career
Being awarded with this prestigious fellowship has been fruitful in many professional aspects. First, it allowed me to establish my own laboratory and independent research lines, which helped me in obtaining further funding for my laboratory. It also allowed me to establish several collaborations with both internal and external researchers promoting a bi-directional transfer of knowledge, which has been highly beneficial for my training. Together, all these achievements have been instrumental in granting me a senior position at the University of Barcelona by being awarded with a Beatriz Galindo professorship at the Department of Cell Biology, Physiology and Immunology (starting date September 1st), which will enable me to maintain an active and successful research program.
