AGING AS A SELECTIVE PRESSURE THAT DRIVES TUMOR PROGRESSION

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PROJECT SUMMARY Aging is the major risk factor for cancer incidence, with more than 60% of cancer diagnoses occurring in those aged 65 and above. In addition, anecdotal observations indicate that age affects prognosis and outcome. Yet, very little experimental data dissect the connection of aging, cancer progression and sensitivity to anti-cancer therapies. In fact, the vast majority of preclinical research that guide the discovery of novel therapeutic targets and clinical trials that lead to anti-cancer treatments approved by the FDA neglect to account for the age of the average patient. This lack of understanding of how aging plays a role in cancer is especially troubling considering that the number of new cancer cases is on the rise globally, a fact that is tied to the increase in the proportion of the older population in the world. Biologically the aging process affects the function of every cell in an organism suggesting that a cancer developing in an aged host is a different disease than a cancer developing in a young one. Using human serum samples, I recently demonstrated that tumor progression and metastasis formation occur, at least in part, as a manifestation of global metabolic deregulation of the aged host. This supports the idea that the role of aging in cancer goes far beyond increased exposure time to mutagens and puts the aging process at the center stage coordinating the different aspects required for the evolution of malignant phenotypes. Therefore, in order to effectively treat cancer, we must look beyond the current framework which neglects the role of the cancer patient’s age. Here, we propose that the aged host tumor microenvironment exerts distinct Darwinian pressures that combined with the decline of the host anti-cancer defenses define how tumor cells evolve within the primary tumor, progress into metastatic disease and respond to anti-cancer therapies. Employing a combination of cutting-edge bulk and single cell technologies we expect to systematically delineate how aging affects the phenotypes and genotypes of cancer cells as well as to characterize the effects of the aging process on the composition and interactions of the different components of the tumor microenvironment. Finally, we will directly evaluate if old age affects the response to FDA-approved chemotherapeutic regiments and immunotherapies, and evaluate if strategies known to rejuvenate old tissues can affect the response to these therapeutic interventions. Through these studies, we aim to build the knowledge infrastructure required to design therapeutic strategies that account for the reprogramming that occurs with aging.