A pro-metastatic secretory program activated by epithelial-to-mesenchymal transition

Project Summary/Abstract Candidate: Dr. Xiao has received broad training in cell and cancer biology, including postdoctoral training at UT-­ Southwestern Medical Center (UTSW) and MD Anderson Cancer Center (MDACC). He seeks to understand how epithelial-­to-­mesenchymal transition (EMT) drives malignant secretion to promote lung cancer metastasis. Dr. Xiao is a highly productive investigator, with 4 first-­authored peer-­reviewed papers. As recognition of his achievements, he received numerous awards during his doctoral and postdoctoral training. Career Development/Training: Dr. Xiao’s primary mentor is Dr. Jonathan Kurie, a physician-­scientist with expertise in cancer biology and mouse modeling of human lung adenocarcinoma (LUAD). His co-­mentor is Dr. Sandra Schmid, who was his mentor at UTSW and is a leader in the field of endocytic vesicle trafficking. Additional input will come from Dr. Angela Wandinger-­Ness (University of New Mexico), who identified Rab GTPases as regulators of endosomal trafficking and is developing GTPase-­targeted therapies for cancer. These investigators have designed a training program centered on their key scientific disciplines that will strengthen Dr. Xiao’s abilities in their respective fields and provide the skills needed for a smooth transition to independence. Research: EMT induction in cancer cells initiates the metastatic cascade by promoting motility and invasiveness through cell-­autonomous mechanisms. Our group has shown that EMT also increases the secretion of proteins that maintain LUAD cell viability and create an immunosuppressive and fibrotic tumor microenvironment (TME) that facilitates LUAD metastasis. These findings are the basis for our hypothesis that EMT promotes LUAD metastasis through dual cell-­autonomous and non-­autonomous mechanisms. The objective of my proposal is to elucidate the molecular underpinnings of EMT-­dependent secretion in LUAD. In my preliminary results, I show that the EMT-­activating transcription factor ZEB1 upregulates the expression of Rab6A and Rab8A by silencing microRNAs that target these effectors. I show that ZEB1 requires Rab6A and Rab8A to drive polarized trafficking of secretory vesicles toward the leading edge of migrating LUAD cells, to increase cytokine secretion, to generate an immunosuppressive TME, and to promote LUAD cell migration, invasion, and metastasis. Because secretory vesicle exocytosis occurs at hot spots juxtaposed to focal adhesions, I hypothesize that ZEB1 coordinately regulates anterograde trafficking of secretory vesicles and remodeling of actin-­based cytoskeletal structures to initiate polarized secretion of pro-­tumorigenic effector proteins that drive LUAD progression. I will test this hypothesis by determining how ZEB1 coordinately regulates anterograde vesicle trafficking and cytoskeletal remodeling to drive polarized secretion of pro-­tumorigenic effector proteins and LUAD progression. In sum, my proposal will address the clinical problem of LUAD metastasis. The novelty rests in preliminary results that demonstrate a transcriptional governance of polarized vesicular transport, providing the potential to target ZEB1-­driven secretory pathways for the purpose of blocking metastasis in LUAD.