UC San Diego
The combined role of stress and lysophosphatidic acid in pancreatic ductal adenocarcinoma progression
- Author(s): Rakhshandehroo, Taha
- Advisor(s): Cheresh, David A
- et al.
Pancreatic cancers are notoriously aggressive and drug-resistant, and surgical resection is complicated by widespread intraperitoneal dissemination and ascites. One component of malignant ascites is lysophosphatidic acid (LPA), a bioactive lipid that promotes multiple aspects of tumor progression. Here, I report that expression of the cancer stem cell marker αvβ3 integrin is necessary and sufficient for the production of LPA. In turn, LPA was shown to induce the expression of stem genes OCT4 and NANOG and promote anchorage-independent growth. Upon interrogating the LPA metabolic pathway, I found that expression of αvβ3 integrin is necessary and sufficient to promote the expression of cytoplasmic phospholipase A2 (cPLA2), an important enzyme in the production of LPA. Furthermore, αvβ3 integrin forms a physical complex with cPLA2 to stabilize and stimulate its activity. Subsequently, KRAS mutant pancreatic cancer cells utilize LPA to overcome the effects of cellular stress, including cancer therapy. A variety of stress, including nutrient deprivation, oxidative stress, and treatment with standard-of-care chemotherapies, sensitizes cells to LPA-induced migration as well as KRAS-driven advantages such as macropinocytosis in response to nutrient stress and ROS elimination in response to oxidative stress. In order to cope with these stresses, cancer cells selectively upregulate the expression of LPA Receptor 4 (LPAR4). I illustrate that this receptor is necessary and sufficient for adaptation to stress in vitro and tumor progression in vivo. I showed that LPAR4 is necessary and sufficient to activate the Gαs/cAMP/PKA signaling pathway and that this pathway is required for LPA-mediated protection from stress. This is accomplished through activation of Vasodilator Stimulated Phosphoprotein (VASP), an enzyme involved in actin polymerization. Ultimately, I found that VASP is necessary for stress-mediated and LPAR4-mediate migration and macropinocytosis. My work highlights how stress changes the repertoire of LPA receptors, leading to dependence on LPAR4 by virtue of its stress mitigating functions, such as macropinocytosis and ROS elimination. Furthermore, my findings illustrate that αvβ3 integrin expressing cancer stem-like cells can secrete the bioactive lipid LPA through cPLA2 upregulation. Subsequently, cellular stress drives a more aggressive cancer phenotype by priming pancreatic cells to be highly responsive to LPA.