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NIH grant 1R01CA308069-01A1: Cystine limitation stress in pancreatic cancer tumor growth, progression and metastasis
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Shengyu Yang. Award: $614025.
Start: 2026-07-22T00:00:00.
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.document fetched 2026-08-02 08:24