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Metabolic Dynamics in Colorectal Cancer

Periodic Reporting for period 1 - MDCRC (Metabolic Dynamics in Colorectal Cancer)

Reporting period: 2018-05-01 to 2020-04-30

Colorectal carcinoma (CRC) is the second most common cancer in Europe and the third most common cancer worldwide. Despite several genetic and transcriptomic studies have provided valuable information contributing to the improvement in the diagnosis and treatment of CRC, its outcome still remains poor, with a 5-year survival rate of 60% and approximately half of the patients dying of their disease despite curative resection. These poor treatment outcomes highlight the need to better understand the mechanisms that account for CRC initiation, progression and spreading.
Colorectal tumors are highly heterogeneous and they are continuously maintained by a small population of cells with stem cell activity, the so-called cancer stem cells (CSCs). These tumor initiating cells or CSCs derive from stem cells present in the normal intestinal epithelium, named intestinal stem cells (ISCs). Therefore, elucidating the molecular mechanisms involved in the expansion of the ISC pool and regulating the acquisition and maintenance of tumor-initiating cells will provide us with a better understanding of how intestinal tumors originate and propagate, a key step for metastatic dissemination and tumor relapse. In this context, our previous work and preliminary data obtained before starting this project demonstrated a prominent role of glucose metabolism on CRC. Based on this, we sought to study the role of glucose metabolism on ISCs dynamics and its role in CRC initiation and progression. To explore this, I proposed two specific aims:
1. To analyze the role of metabolic reprogramming in ISCs and its contribution to CRC
2. To study the metabolic evolution of CRC.
The completion of this project has revealed a novel subtype of ISC displaying a very active glucose metabolism. These cells have strong stem cell potential and can give rise to intestinal and colon tumors in a mouse model of colorectal cancer. Furthermore, we have found that these highly glycolytic cells are also present in human colorectal tumors and might be involved in tumor progression. These studies have provided a comprehensive picture of the role of metabolism on CRC tumorigenesis, which will potentially provide the rationale to target metabolism in CRC to improve current therapies and reduce CRC incidence and mortality.
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.
The results derived from this action provide new insights into the metabolic complexity and dynamics of tumors, which will help in designing more efficient therapeutic strategies targeting metabolic vulnerabilities of cancer cells. This is particularly relevant in the case of CRC, as it represents the second more common cancer in Europe and the third most common cancer worldwide. Although recent advances in the molecular genetics of CRC have helped to design new targeted therapies, most patients relapse and succumb to this deadly disease, which represents a big economic burden to national health systems and highlights the need for new therapeutic approaches. Finally, the metabolic reporter we have generated is one of a kind and will help the scientific community to address the role of glucose metabolism on a variety of biological processes, from development and stem cell biology to cancer and immunology.