The Aging Pancreas as a Pro-tumorigenic Niche

PROJECT SUMMARY Age is a major risk factor for pancreatic ductal adenocarcinoma (PDAC), with the incidence of PDAC rising sharply with increasing age. Most PDAC cases occur in individuals who are over the age of 60, and the risk continues to increase with each decade of life. The median age at diagnosis and death for PDAC is around 70

and 72-years old, respectively. Although PDAC can occur at any age, it is relatively rare in younger individuals, and it is uncommon for people under the age of 40 to develop PDAC. It is not clear why age is a significant risk factor for PDAC but like other age-associated cancers there are likely multiple variables at play. Like other

diseases, we use sophisticated mouse models to study PDAC, but none have been used to address the impact of aging on disease initiation or progression. This proposal is based on our preliminary data demonstrating that PDAC progression is accelerated in old animals. We have found that increased organismal age significantly

enhances the growth of primary PDAC tumors and increases metastasis. Remarkably, we find that the immune landscape is vastly different in tumors generated in young versus old animals, and that intratumoral desmoplasia is heightened with age. Our findings are in line with the established prominence and importance of the PDAC

tumor stroma in tumor progression and suggest that aging substantially affects the functional characteristics of the stromal cells. Most of the stromal cells within a PDAC tumor are cancer-associated fibroblasts (CAFs) and how the functionality of these CAFs changes with age is totally unexplored. Moreover, whether other aspects of

PDAC biology, such as tumor initiation, are affected by age remains an unanswered question. Based on our preliminary data, our central hypothesis is that age plays a critical role in PDAC by accelerating tumor initiation and progression. In this proposal, we will 1) examine the influence of the aging stroma on tumor growth and

progression, and 2) investigate the impact of age on the intrinsic oncogenic potential of the pancreas. This project

will be of great significance, novelty, and impact, as it will constitute the first evaluation of the impact of aging on PDAC initiation and progression. Our work will establish new paradigms for the study of PDAC, and will set the framework for evaluating potential PDAC therapies from a patient-centric perspective.