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TRANSlating the role of Mitochondria in Tumorigenesis

Periodic Reporting for period 2 - TRANSMIT (TRANSlating the role of Mitochondria in Tumorigenesis)

Reporting period: 2019-01-01 to 2021-06-30

TRANSMIT is a multi-partner project that intends to mobilize the critical mass of expertise, by linking partners from 7 different countries, among which world-leading basic science and clinical centers of excellence, SMEs as full partners, as well as non-profit foundations with a long-lasting history of dealing with the societal consequences of cancer in patients and their families. It is estimated that one in 3-4 individuals will develop a form of cancer during their lifetime, making this complex disease a heavy burden for the health system, with societal implications and new challenges. 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.
During the project, TRANSMIT investigated the metabolic changes that characterize human cancers, with emphasis on the role of mitochondria, bridging basic research to the improvement/development of therapeutic strategies, and ultimately fostering the communication of this rapidly emerging field of innovative research to the general public.
Further, TRANSMIT fostered the communication of this emerging field to the patients and their families. Thanks to its multi-partners Consortium, TRANSMIT project allowed 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 in the field of cancer biology.
TRANSMIT Consortium dissected and unravelled the role of mitochondria in the metabolic reprogramming of several solid human cancers. Taking advantage of the scientific expertise of the TRANSMIT’s members and the excellent training through research and complementary skills of the 11 ESRs, the following main scientific activities were performed and related fulfilled results were achieved:
1) to educate young researchers (ESRs) in the multifaceted aspects of human cancer metabolism. In particular, ESRs showed that bioenergetic reprogramming in terms of glutaminolysis versus glycolysis and mitochondrial metabolic biomarkers strongly contribute to malignant transformation in lung and prostate cancer at least. Further, they reported the pivotal role of oxidative metabolism enzymes and their regulators (namely fumarate hydratase, respiratory complex I and PGC1) in the modulation of both metabolic and epigenetic profiles triggering tumor progression and chemoresistance. Finally, the decrease in cancer cells growth was reported by using cell permeable αKG ester analogues, ROS prevention and ketogenic diet. These potential metabolic-based anticancer strategies were proved in vitro (2D and 3D cancer cell models) and in vivo (xenografts in immunodeficient mice).
2) to implement innovative technologies and integrated methodologies in the field of mitochondrial physiopathology to dissect the molecular mechanisms underlying cancer. This activity led TRANSMIT to develop and exploit different in vitro and in vivo solid cancer models with different hystotypes. In particular, 2D and 3D cancer cells models were developed and improved. Cancer cell lines lacking of pivotal oxidative enzymes using genome editing were generated and characterized. These models were also used to develop xenografts in immunodeficient mice. Further, the use biochemical, metabolomic, proteomic and bioinformatic integrated technologies allowed TRANSMIT to evaluate the bioenergetic, metabolic and epigenetic rewiring in several solid cancer models and define the mitochondria as hub to sustain cancer cell survival and proliferation.
3) to provide a full portfolio of complementary skills through the creation of a network of basic, translational and industrial laboratories. First, this activity exposed ESRs to a multidisciplinary/multisectorial industrial field allowing them to learn how to design and produce cancer-related tools as commercially exploitable output. Then, the interaction with Associate partners such as FUV and Dynamo Camp sensitized ESRs towards both scientific dissemination and fundraiser. Indeed, ESRs were personally involved in organizing the patients Symposium and a crowdfunding campaign. These two dissemination activities tightly connected with the research training markedly impact on the scientific oncological community, as well as on the patients, their families, the international patients’ associations and the entire society.
The bulk of data obtained during the TRANSMIT project clearly underline and support the pivotal role of mitochondria in metabolic and epigenetic adaptation in tumorigenesis. Further, through the use and improvement of innovative and integrated methods and technologies and exploiting the scientific expertise of Consortium, TRANSMIT has revealed novel possible biomarkers and molecular mechanisms that are involved in the metabolic and epigenetic reprogramming in a wide and different range of solid tumors. Finally, TRANSMIT proposed a metabolic-based strategy as adjuvant anticancer therapy. Thus, these results will impact the scientific field in terms of identification of metabolic and genetic targets, discovery of novel biomarkers and testing of novel anticancer therapeutic strategies. The tight connection among Academic and Industrial partners generated an excellent multidisciplinary/multisectoral training that will make ESRs appealing candidates for highly selective positions at the frontiers of Industrial and/or Academic research in life sciences and biomedical research, enhancing the fellow’s career perspectives and employability. Further, the intense collaboration among partners located in different European universities will promote new and future intra-or inter-sectorial network collaboration in terms of teaching, lectures and students internships at the Academic level. A huge benefit coming from the integrated work with industrial partners will make the project’s outputs immediately useful as research tools, either by partners within the Consortium or by third parties. TRANSMIT will also impact at European level with the formation of a joint educational structure in the multi-disciplinary field of cancer and metabolism that fostered both the scientific communication and the problem-solving capacities. The TRANSMIT Consortium believed that communicating science can provide a stronger understanding of current research and its trials, and, most importantly, its wider relevance to society. For this reason, fellows attended some training activities and events specifically devoted to the science communication and organized and managed the TRANSMIT Symposium and the crowdfunding campaign “NOW” to support 4 associations of oncological patients. Delivering the outcomes of the TRANSMIT projects to patients and their associations and balance optimistic expectations and realistic progresses was an important task to fulfil during the Symposium mostly. Overall, all these scientific and dissemination activities allowed TRANSMIT outputs to actively contribute to one of the challenges of public health namely the fight against cancer.
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