Adaptation to cystine limitation stress promotes PDAC tumor growth and metastasis through translational upregulation of OxPPP.

Cystine/cysteine is critical for antioxidant response and sulfur metabolism in cancer cells and is one of the most depleted amino acids in the PDAC microenvironment. The effects of cystine limitation stress (CLS) on PDAC progression are poorly understood. Here we report that adaptation to CLS (CLSA) promotes PDAC cell proliferation and tumor growth through translational upregulation of the oxidative pentose phosphate pathway (OxPPP). OxPPP activates the synthesis of nucleotides and fatty acids to support tumor growth. Our data suggested that much like hypoxia, CLS in the tumor microenvironment could promote PDAC tumor growth and metastasis through upregulating anabolic metabolism of nucleotides and lipids.