NANOTUMOR
CANCER RESEARCH

The cellular organization and organelle morphology reflect the integrated action of the expressed proteins directed by the genetic and epigenetic program of a given cell type. The cellular ultrastructure is affected by metabolic or pathologic changes and therefore informs us about the physio-pathological state of the cell. Deciphering the links between morphology and disease could therefore help to establish a diagnosis and/or determine the stage of a large number of human diseases and particularly in cancer cells (Rozenblatt-Rosen et al., 2020). The pathway between one – or a collection of – point mutation(s) identified in a patient to the actual cellular defect is often not straightforward since cells behave like multicomponent networks in which the alteration of one or several component(s) may have distal, antagonist or synergic effects which are difficult to predict. Thus, an adequate cure might not be to replace the exact function of the altered protein(s), but to remedy more general downstream effects that may be revealed by cell morphology. Consequently, an atlas of normal and pathologic cell morphology parameters may guide researchers studying an unknown disease towards altered pathways for which treatments exist.

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One major goal of the Nanotumor Consortium is thus to provide the nanoscale maps of cancer cells, at different steps of the metastasis cascade, from tumor initiation to metastasis formation. We ambition to characterize tumor subcellular processes and cellular organelles at high resolution. Cells are occupied by numerous organelles which carry important cellular functions and are constantly remodeled to exchange molecules. In addition to be responsible for the viscoelastic behavior of any cell (Pu et al., 2016), these organelles are notably under extreme mechanical stress when tumors cells are subjected to high compression or tension forces which they need to cope with (van Bergeijk et al., 2016). A careful evaluation of the effect of mechanical forces and metastatic steps on cellular organelles is crucial and would allow to understand their effects on important organelle-carried cellular functions, in addition to identifying organelles and cytoskeletal elements that are responsible for rheological responses and differences. Furthermore, since organelles represent hierarchical structures of molecular networks, studying their alteration in cancer could provide a framework for network stratification. Key to this project is thus to shed light on the alterations of intracellular organelles during cancer progression and to use this higher order modules to delineate basic mechanisms driving tumorigenesis. We aim at establishing an unprecedented top-down strategy to stratify protein networks driving cancer and exploit key protein interactions and complexes for vulnerabilities of therapeutic relevance. We anticipate major insights into the underlying tumor biology allowing rational design of antitumor strategies.

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Another major goal of the Nanotumor consortium is to identify, characterize and determine the atomic structure of multi-subunit macromolecular complexes involved in the cancer cascade, either identified as a result of the top-down strategy, or already studied by the members of the consortium. This will enable us, in the medium term, to initiate our drug research efforts. Major technological progresses now allow to identify major cellular nano-machines in terms of protein composition, post-translational modifications, functional dissection, and structure determination at close to atomic resolution. The biochemical and structural characterization of the cancer-induced and time-resolved alterations of molecular complexes will be validated in-vivo, their structure used for in-silico drug design (ie. PPI) and purified for in-vitro screening / optimization.

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For the NANOTUMOR coordination, Jacky G. Goetz and Patrick Schultz