Investigating hypoxia as a determinant of malignant fates in pancreas cancer

Abstract public domain (NIH RePORTER)

Only one in ten pancreatic cancer patients is alive 5 years after their diagnosis. Unfortunately, this outlook has not improved significantly in decades. This is in stark contrast to most other cancers, which have benefited tremendously from the recent advances in targeted therapies and immunotherapies. Therefore chemotherapies remain as the only option for pancreatic cancer patients, but these therapies are not particularly effective, and they produce significant side effects. Given that pancreatic cancer patients have received little benefit from conventional cancer therapies, there is a need for deeper understanding of the biology of pancreatic cancer. Here, we propose to investigate how low levels of oxygen (hypoxia) promote emergence of aggressive behavior of pancreatic cancer cells. Cancer cells in the same pancreas tumor can show substantial diversity at the molecular level and in how they respond to therapies. The inability to effectively target all cancer cell subsets within a tumor contributes to treatment failure. Pancreas tumors have regions of hypoxia, which are caused by variable access of cancer cells to blood vessels that deliver oxygen to tissues. Our initial results indicate that metabolic adaptations in cancer cells that reside in these hypoxic regions reprogram the cancer cells, so that they become resistant to chemotherapy. In other words, what does not kill the cancer cells makes them stronger. We propose to investigate other possible outcomes of this reprogramming process, including the ability of the cancer cells that experienced hypoxia to contribute to tumor growth as well as their ability to spread into distant parts of the body (metastasis) or resist therapy. The second part of the proposed study will focus on identifying the molecular changes that are induced in the cancer cells by hypoxia. In the third part, we will determine which of these molecular changes enable cancer cells to survive hypoxia and acquire more aggressive behavior. The project will identify fundamental drivers of cell state diversity in pancreatic cancer, which may point to a new generation of targeted therapies that will control the cellular composition of tumors to improve treatment response. We have devised a two-prong research strategy focusing on both the role of the hypoxic pancreatic cancer cells within the tumor and the molecular programs unlocked by hypoxia that promote tumor progression. If successful, this study will (i) fundamentally advance our understanding of the molecular and biological mechanisms underpinning intra-tumoral heterogeneity, tumor progression, and drug resistance; (ii) provide innovative experimental approaches for investigating phenotypic diversity; and (iii) elucidate novel strategies for targeting tumor heterogeneity, malignant progression, and drug resistance in pancreas cancer.

Public health relevance public domain (NIH RePORTER)

An unmet clinical need exists for new therapeutic concepts in pancreatic ductal adenocarcinoma (PDAC), a cancer associated with exceptionally high mortality. We hypothesize that intra-tumoral heterogeneity, progression, metastasis, and drug resistance is driven by hypoxia-mediated reprogramming of PDAC cells. In this study we interrogate the function of hypoxic cells and identify molecular mechanisms that drive adaptation to hypoxia in PDAC tumors in vivo, which may inform future therapeutic strategies.