Cystine limitation stress in pancreatic cancer tumor growth, progression and metastasis

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY The goal of this proposal is to uncover the mechanism underlying cystine limitation stress adaptation (CLSA) in PDAC and to identify exploitable therapeutic vulnerabilities in CLSA PDAC. The tumor microenvironment in PDAC is characteristically nutrient deprived due to desmoplasia, poor vascularization and hyperactive cancer metabolism. These environmental stresses exert evolutionary pressure on PDAC cells and profoundly affect PDAC tumor growth, progression and metastasis. Cystine and cysteine are important amino acid nutrients critical for antioxidant response and synthesis of many sulfur metabolites. In the tumor microenvironment in PDAC, the availability of cystine is limited. The mechanisms by which PDAC cells adapt to cystine limitation stress (CLS) and maintain rapid tumor growth are poorly understood. In preliminary studies, we found that CLSA promotes PDAC cell proliferation, tumor growth and liver metastasis. PDAC cells adapt to CLS through translational and metabolic reprograming, which upregulates pentose phosphate pathway and increases the de novo synthesis of nucleotides and lipids to promote tumor cell proliferation and to confer ferroptosis resistance. Through unbiased drug screening, we identify dysregulated lipid metabolism as a potential therapeutic vulnerability in CLSA PDAC. In Aim 1 we will interrogate the mechanism by which CLSA activates pentose phosphate pathway through translational reprogramming and RNA methylation. In Aim 2, we will examine mechanism by which CLSA reprograms lipid metabolism in PDAC and the feasibility to exploit lipotoxicity as a potential therapeutic vulnerability in PDAC. Mice will be used for the proposed tumor initiation experiment and xenograft metastasis study in Aim 1 and Aim 2, since there are no in vitro systems or invertebrate animal models that would be comparable or that would allow us to examine the role of CLSA response PDAC progression and metastasis in vivo. The success of this proposal will not only shed new light on the role of nutrient stress on PDAC progression, but also potentially provide a new avenue for PDAC treatment.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE PUBLIC HEALTH RELEVENCE: This project investigates the mechanisms by which limitation promotes pancreatic cancer metastasis, which accounts for more than 90% of pancreatic cancer-related death. The anticipated results from this proposal will significantly advance our understanding of pancreatic cancer metastasis, and potentially provide novel strategy for preventing metastatic progression in pancreatic cancer.