Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a 5-year survival rate of only 10%. The low survival rate is driven by extreme resistance of PDAC to treatments such as chemo- and immunotherapies. Thus, novel drug targets and treatment modalities are urgently needed to control PDACs and allow management of this disease.

Most approaches for identifying therapeutic targets in pancreatic cancer are based on identifying and targeting those cellular processes that isolated pancreatic cancer cells divorced from tumors and cultured in standard laboratory conditions require for growth and survival. However, increasingly we understand that the cellular processes of PDAC cells need are not constant but instead are strongly dependent on their environment. PDAC cells normally inhabit a densely fibrotic tumor microenvironment (TME) that is substantially different than both standard laboratory conditions and normal healthy tissues. Thus, the TME influences what can be targeted effectively treat PDAC cells. Therefore, to find effective therapies for PDAC, it is not sufficient to consider PDAC cells alone, but rather we must develop a sophisticated understanding of the TME and how this impacts PDAC cells to identify effective PDAC therapies. Our research group seeks to identify the cellular processes PDAC cells use to survive in the TME and understand how they enable PDAC pathology, with the goal of identifying better targets for PDAC therapy.

One highly abnormal aspect of the PDAC TME is its vasculature, the system of blood vessels that deliver nutrients to tissues and tumors. Due to fibrosis in the TME, PDAC blood vessels are largely dysfunctional, with only ~30% of blood vessels actively transporting blood. Thus, compared to normal tissues that are well fed by functional vasculature, the non-functional blood vessels of PDAC limit nutrient delivery from cells within these tumors, resulting in a TME with abnormal nutrient availability. We have built a system to study how cells function when fed levels of nutrients in the PDAC TME. With the generous support of the Cancer Research Foundation (CRF), we have used this system to: (1) identify the processes that PDAC cells need to cope with abnormal TME nutrient levels and (2) determine if tumor nutrition negatively impacts anti-cancer immune cells and contributes to immunotherapy resistance in this disease.

Towards the first goal, CRF support enabled us to perform in-depth transcriptomic analysis of PDAC cells growing under TME nutrient levels. We used the resulting data to identify novel cellular pathways that become upregulated upon exposure to such conditions, with the hypothesis that these upregulated pathways may be critical for PDAC cells in the TME. One upregulated pathway we identified was arginine metabolism. Arginine is a critical amino acid that all cells need to make proteins. We found this pathway was indeed critical for PDAC cells in the TME, as the TME is starved of amino acids like arginine. Thus, PDAC tumors have to make their own arginine to grow. These exciting findings have identified a key stress in the TME of PDAC tumors as well as the mechanism by which PDAC cells cope.

Towards the second goal, we have established a long term collaboration with Dr. Greg Delgoffe at the University of Pittsburgh to study the impact of TME nutrition on anti-cancer immune cells. TME nutrition severely impairs immune cells and we have made major strides in identifying the TME nutrients that block immune cell function. We are also gaining an understanding of how these nutrients block immune function. These exciting findings confirm that tumor nutrition is a key factor that impairs immunotherapy in PDAC and suggests exciting dietary and metabolic interventions to improve immunotherapy in this disease. Altogether, CRF support has enabled us to understand

how both cancer and immune cells function (or dysfunction) with abnormal TME nutrition, suggesting promising future avenues for metabolic therapies to target cancer cells and improve immune function in this disease.