Pancreatic ductal adenocarcinoma (PDAC) cancer cells proliferate within particularly fibrotic and poorly vascularized tumors. Although PDAC cells exist within a tumor environment with limited nutrients and oxygen, these cells nevertheless aggressively proliferate and grow. Limited electron transport chain (ETC) activity caused by oxygen limitation in this environment creates a redox balance problem such that NADH cannot be recycled by the ETC to NAD+. Under these conditions, NAD+ can become limiting for growth, a condition we term electron acceptor insufficiency. Cells proliferating under hypoxic conditions must overcome this electron acceptor insufficiency in order to proliferate. We hypothesize that oxygen limitation leads to reliance on alternative metabolic pathways to maintain redox balance, biomass synthesis and proliferation. While many studies have focused on aberrant PDAC metabolism triggered by genetic alterations common to this malignancy, there is little understanding of the environment- dependent alterations in tumor cell metabolism that are required for PDAC proliferation in harsh oxygen and nutrient limiting conditions. The proposed work will identify the metabolic requirements of PDAC cells brought on by hypoxia. First I will test whether otherwise unexplained PDAC metabolic phenotypes might drive reactions that allow these cells to proliferate in limited oxygen. Specifically, I will test the hypotheses that proline and fatty acid metabolism allow hypoxic PDAC cells to overcome electron acceptor insufficiency and are functionally important for hypoxic PDAC proliferation. Lastly, I will perform a metabolic gene targeted CRISPR/Cas9 screen, to identify the set of metabolic enzymes that are required for PDAC redox homeostasis and proliferation under environmental hypoxia. The results of these studies will be the first to identify metabolic pathways that PDAC cells require for redox balance under hypoxia. This will provide a metabolic basis for understanding how PDAC cells continue to proliferate under conditions that otherwise severely limit perturb cellular redox balance and synthesis of metabolites required for growth. This is important as targeted inhibition of the set of reactions that PDAC cells use to maintain redox balance and prevent electron acceptor insufficiency may selectively prevent PDAC cell proliferation and have therapeutic value. Thus, this work may reveal ways to target PDAC based on the environmental context of these cancers.

Public Health Relevance

Cancer cells proliferate rapidly and require a constant supply of building blocks needed to generate new cells, namely fats, amino acids and nucleotides. Pancreatic cancer cells are able to proliferate rapidly, even though their environment limits access to nutrients and oxygen normally used to generate these building blocks. Thus, in their harsh environment, pancreatic cancer cells are likely to rely upon alternative metabolic pathways to generate metabolites needed for growth. Targeting these metabolic pathways may inhibit pancreatic tumor growth and have therapeutic potential. Here, we propose to identify the metabolic pathways that pancreatic cancer cells specifically require to grow in nutrient and oxygen limiting environments. This knowledge will generate new insight into cancer metabolism and potentially lead to new chemotherapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA213810-02
Application #
9420462
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mcguirl, Michele
Project Start
2017-02-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Miscellaneous
Type
Organized Research Units
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
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