Early Stage Researcher (PhD student) in Cancer Metabolism

TRANSMIT - TRANSlating the role of Mitochondria in Tumorigenesis

The consolidation of the knowledge that cancer is not only a genetic, but also a metabolic disease, has led scientists to investigate the intricate metabolic plasticity that transformed cells must undergo to survive the adverse tumor microenvironment conditions, and the contribution of oncogenes and tumor suppressors in shaping metabolism. In this scenario, genetic, biochemical and clinical evidences place mitochondria as key actors in cancer metabolic restructuring, not only because these organelles have a crucial role in the energy and biosynthetic intermediates production but also because occurrence of mutations in metabolic enzymes encoded by both nuclear and mitochondrial DNA has been associated to different types of cancer. TRANSMIT aims to dissect the metabolic remodeling in human cancers, placing the focus on the role of mitochondria and bridging basic research to the improvement/development of therapeutic strategies. Further, TRANSMIT fosters the communication of this emerging field to the patients and their families. To these aims, TRANSMIT will create a network of seven different countries, among which world-leading basic science and clinical centers of excellence, several industrial partners with up-todate omics technologies, as well as non-profit foundations and associations who care for cancer patients. By creating the critical mass of scientific excellence, TRANSMIT will allow to transfer the current knowledge into the wide field of cancer research, translating scientific and technical advances into the education and training of eleven Early Stage Researchers. TRANSMIT will implement training-through-research dedicated to unravel the metabolic features of cancer, as well as to provide a full portfolio of complementary skills through the creation of a network of basic, translational and industrial laboratories, devoted to a multidisciplinary/multisectorial education of young scientists.

Project Description

Job Summary

The PhD student will conduct experimental research in the field of tumor metabolism. He/she will lead his/her own research program under the direction of Prof. Pierre Sonveaux and the direct supervision of a post-doc, with the assistance of a lab technician.

Job description

In primary tumors, natural selection is known to foster the emergence of metastatic progenitor cells. Because its thorough understanding could ultimately be translated in treatments aimed to prevent metastasis, the metastatic switch is the subject of intense investigation. In previous work, we tested whether mitochondrial metabolism could promote tumor metastasis. We identified two different metabolic alterations, a TCA cycle overload and bottlenecking of the mitochondrial electron transport chain (ETC), which trigger tumor cell migration, invasion, clonogenicity, metastatic take and, overall, spontaneous metastasis (Porporato PE et al., Cell Reports 2014;8:754-766). We further found that these pro-metastatic phenotypic features are primarily conferred by an enhanced mitochondrial production of mtROS in both systems, and can be countered with mitochondria-targeted ROS scavengers. For the open position, using our well established models, the PhD student will aim to identify the exact nature of mtROS promoting tumor metastasis, their molecular origin and the signaling pathways by which altered mitochondria drive the metastatic process. The combination of specific sensors, scavengers, antioxidants and RNA interference will allow him/her to discriminate specific activities of superoxide from that of H₂O₂. Mitochondrial dysfunctions will be traced back to mtDNA and ETC complexes abnormalities. Altered expression/activity of specific enzymes and proteins known to regulate TCA cycle and the coupling between ETC activity and ATP synthesis will be investigated. Finally, based on early evidence indicating that focal adhesion kinase (FAK) family member Pyk2 executes at least in part the metastatic program triggered by mtROS, the PhD student will further characterize the activation of the mtROS-FAK axis in metastatic cancer cells, its inhibition by mtROS scavengers, and the consequences of its inhibition on the metastatic program in vitro and in vivo.

Subject area of PhD program in which the ESR will be enrolled and PhD program duration

PhD in Biomedical and Pharmaceutical Sciences (3 years)

Host University that will provide the PhD degree

Université catholique de Louvain (UCL)

PhD program starting date

October 1^st, 2017

Applications, in English, should include CV, detailed academic transcripts, a summary of the thesis (abstract), a motivation letter and a reference letter, which are all to be submitted as a single PDF file by email to c.remacle@uclouvain.be