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.