Dissecting the role of extra centrosomes-induced exosome secretion in PDAC microenvironment

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Despite progress, cancer is still a serious challenge in medicine. This is particularly true for pancreatic cancer, which has a dismal 5-year survival rate of <5%. This highly aggressive behaviour is cause in part caused by fibrosis, which forms a barrier around the tumour that hinders drug delivery and efficacy. This barrier is cause by changes in a cell population, named stellate cells, induced by the tumour. Combating fibrosis in pancreatic cancer is thus considered to be an important area for therapeutic intervention. We recently found that a population of cancer cells that carries amplification of a cellular organelle called centrosome is able to activate stellate cells. Centrosome amplification, an aberration that exists in cancer cells, was described in later 1800s as a possible cause of tumourigenesis. We now know that these abnormalities are a common feature of human tumours and can actively contribute to tumour formation. Published work from our lab was the first to identify a novel function of these abnormalities in influencing the surrounding cells (Arnandis et al., 2018). This work demonstrates that cancer cells with amplified centrosomes have a broader role in tumourigenesis than previously anticipated by communicating and changing other cells within tumours. In particular our new unpublished data shows that this communication between cancer cells with extra centrosomes and pancreatic stellate cells leads to their activation, which could contribute to fibrosis in PDAC. This is mediated via the release of small vesicles from cells with extra centrosomes, exosomes, that are packed with factors that will instruct stellate cells to become activated. Thus, understanding how cells with extra centrosomes activate stellate cells could help understanding fibrosis and lead to therapeutic strategies to treat pancreatic cancer patients.In this research proposal we aim to determine how centrosome amplification induces the release of exosomes and in turn how these vesicles activate stellate cells. We will use a combination of approaches, including live cell imaging, to identify the mechanisms responsible for exosome release. Furthermore, using well-established methods to identify the factors contained in these exosomes, we propose to uncover the molecules responsible for stellate cell activation. We will test if blocking the identified factors prevents stellate activation and fibrosis using 3-D culture models that mimic the interaction between cancer and stellate cells in tumours. Changes in signalling induced by exosomes in stellate cells will also be studied to understand the mechanisms of activate. This could be important to identify signatures of stellate cell activation and fibrosis in pancreatic tumours and will provide another opportunity to identify potential therapeutic targets to block fibrosis. Finally, we will use mouse models to test our findings in vivo. This will provide relevant pre-clinical models to assess the importance of our findings and test response to therapy. Thus, our work will not only contribute to understand for the first time the role of centrosomes amplification in tumour microenvironment but could also have a major impact in developing therapeutic strategies that target fibrosis to treat patients that suffer from pancreatic cancer.