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Addressing MITochondrial Import by Glioblastoma cells to rewire respiratory metabolism

Periodic Reporting for period 1 - MITIG (Addressing MITochondrial Import by Glioblastoma cells to rewire respiratory metabolism)

Reporting period: 2019-03-01 to 2021-02-28

Addressing the mechanisms that drive pathology is key to provide innovative therapeutic paths against currently untreatable diseases. That makes the case for certain cancer types such as glioblastoma, still associated with a dire prognosis derived from a very limited therapeutic handling. Unveiling how so far unaddressed mechanisms account for glioblastoma progression is thus key to face the high health and socio-economic burden this disease represents. A growing body of evidence is consolidating intercellular networking and sharing of organelles, as well as a consequent physiological rewiring as central to control the oncogenic process, thus revealing central for novel strategies aimed at curtailing glioblastoma development. Departing from these premises, MITIG has explored the missing link on how glioma cells rewire their metabolism and survival upon the acquisition of exogenous mitochondria, organelles that master respiration, metabolism and cell fate. To this end, MITIG training and research objectives have focused on the mechanisms by which glioblastoma import exogenous mitochondria, and its consequences in the remodelling of the native mitochondrial content and metabolism. Capitalizing on a wide range of techniques, MITIG has settled unprecedented approaches to analyse this biological process and unveil how it impacts mitochondrial morphology, function and metabolism in gliomas, which in turn define cancer cell growth. By tackling these objectives, MITIG will serve to provide a major advance in novel therapeutic strategies that impinge in the so far unappreciated mitochondrial transfer, with the final goal to improve the survival and quality of life of patients.
MITIG has tackled how glioma communicate and acquire functional mitochondria to reconfigure their metabolism, as these organelles are master regulators of respiration and processing of nutrients in the cell. MITIG has set a wide range of dedicated and innovative genetic, pharmacological, ultrastructural, morphological and functional approaches and analyses. As a result, we show that glioma cells acquire mitochondria through their intercellular transfer or importation from neighbour cells, highlighting their acquisition from astrocytes as donors. The incorporation of exogenous mitochondria reconfigures the morphology and ultrastructure of the native mitochondrial network in acceptor glioma cells. Importantly, exogenous mitochondrial DNA and proteins integrate the composition of the whole native network, resulting in a diverted mitochondrial function. Consequently, glioma cells rewire the way they respire and derive nutrients towards a processing control exerted by mitochondria, at the expense of other metabolic paths that become less relevant for glioma development. The change in the respiration and fuel usage by glioma cells deeply impact their fate, whereby the survival of tumour cells is shortcut by interfering with the acquisition of mitochondria, causing a major impact in the development of brain tumours. Altogether, MITIG has tackled a key path underscoring the communication and rewiring of mitochondrial content, respiration and metabolism that leads to glioblastoma progression. The results arising from MITIG, disseminated through the project webpage and several contributions in media, meetings and scientific manuscripts, foresees major biomedical applications in glioblastoma oncology.
MITIG has set a series of cutting-edge experimental analysis and conceptual advances in the understanding of how intercellular transfer and acquisition of exogenous mitochondria accounts for cancer progression. Capitalizing on such innovative traits, MITIG has solved a so far missing deep characterization on how mitochondrial acquisition rewires the morphology, function, metabolism and development of glioblastomas. Departing from MITIG results, new strategies are in place to fulfil the scientific community and patients with a valuable technical and conceptual framework, key to dissect the biomedical impact of mitochondrial transfer with unprecedented efficiency and resolution. MITIG hence provides the first comprehensive characterization of mitochondrial acquisition and metabolic remodelling in glioblastoma, paving the way to overcome current therapeutic limitations in oncology. Besides providing scientific advance, the novel results from MITIG aim to face currently untreatable cancers, that still represent a major global socio-economic and healthcare challenge. From a broader view, the innovation provided by MITIG is intended to serve as a valuable reference for novel therapeutic strategies aimed to reconfigure cellular physiology in disabling diseases primed by mitochondrial dysfunction.
MITIG technical summary