Study of the metabolic reprogramming associated to metastasis in colon cancer

Abstract

Metastasis is the main cause of cancer-related deaths and it is of great biomedical importance to develop new therapeutic strategies that specifically target metastatic cells. Therefore, a better comprehension of the process of how the disseminated tumour cells manage to survive the circulation and initiate new tumours is crucial. Genetic alterations are established to be the main driving force of tumorigenesis, while when it comes to metastasis, fewer genetic changes are identified and the metabolic adaptation emerges as an important hallmark. With the aim to elucidate the metabolic reprogramming supporting metastasis in colorectal cancer, we performed a thorough metabolic characterisation in vitro and in vivo of a primary colon cancer cell line (SW480), a cell line derived from the lymph node metastasis of the same patient (SW620) and a metastatically enriched derivative of the latter (LiM2). We revealed that the metastatic cell lines present enhanced glucose, glutamine and mitochondrial metabolism, and present higher metabolic flexibility. Additionally, from a systems biology approach, the metabolic dependencies of the metastatic cell lines were identified and validated in vitro, using a healthy colon cell line (NCM460). Specifically, we determined that the metastatic cell lines are selectively vulnerable to the inhibition of cysteine import and folate metabolism, among other targets. Together, the thesis presented here contributes to the knowledge of the mechanisms underlying metastasis as well as the development of new therapies capable of selectively blocking the metastatic spread of colorectal cancer.