Project Funding Details

Ageing is a well-known driver of tumor initiation and progression. Thus, understanding how ageing impacts on cancer emergence and evolution may have far-reaching implications in ameliorating the lines of prevention and intervention against tumorigenesis. Despites the relationship between ageing and cancer is a well-recognized fact in oncology, the details of it are still poorly understood, in part because our knowledge of the root causes of ageing is still limited. Here we aim to tackle the issue of how ageing promotes tumorigenesis taking advantage of new model systems we recently developed in our laboratory, allowing to induce accelerated ageing or to reverse natural ageing by acting on the cells of the connective tissue. As shown in Preliminary Results we found that physiological ageing is accompanied by the progressive decline of the activity of the mechanotransducers YAP/TAZ in stromal cells. Functionally, physiological ageing can be halted, or accelerated, by modulating YAP/TAZ activity. Mechanistically, YAP/TAZ mechanotransduction prevents cell senescence by restraining cGAS/STING signaling, a pillar of innate immunity. We will take advantage of the mouse models we developed to control the ageing process in a genetic, deterministic manner, making amenable the dissection of the changes of cell-to-cell communications, stem cell dynamics, immune responses that drive ageing-related tumorigenesis with an unprecedented depth. WP1) Dissecting ageing-promoted tumorigenesis at the cellular and molecular level. For this we will take advantage of mouse models of tumorigenesis of skin (TASK1.1) and pancreas (TASK1.2). We will combine these models with our stromal YAP/TAZ cKO mice to create new animal models of ageing-promoted tumorigenesis. Once established, these models will be dissected in details using single cell transcriptomics (scRNA-seq), to capture the cellular and molecular details associated to ageing-promoted tumorigenesis (TASK1.3). WP2) Stromal rejuvenation as tumor-preventing strategy. If ageing-promoted tumorigenesis is mainly due to accumulation of senescent cells in the connective tissues, then, restraining senescence or blocking the protumorigenic activity of senescent cells should be sufficient to restrain tumor formation and progression. We plan to test this hypothesis by two ways, either inducing stromal rejuvenation by supporting YAP function (TASK2.1), or exploiting the "senomorphic" effects of metformin, a compound known to inhibit SASP induction without killing senescent cells, as a drug restraining ageing-promoted tumorigenesis (TASK2.2). 1) Providing faster and molecular amenable models of ageing-promoted tumor initiation for skin and pancreatic cancer. 2) Unraveling the cellular and molecular players involved in ageing-promoted tumorigenesis. 3) Providing proof-of-principle experiments supporting the idea of preventing cancer initiation by inhibiting cell senescence in the stroma. This study is meant to provide new data for a better understanding of the impact of ageing on cancer. In particular, we aim to understand the cellular and molecular players that shape ageing-promoted tumorigenesis, with a particular emphasis on senescent cells. This study would thus generate reagents and knowledge useful for any further studies on the argument. We will also tackle with the possibility to interfere with these processes using a pharmacological approach; in principle, this may pave the way to future clinical trials to prevent tumor initiation at advanced age.