Full Project 1: Defining Mechanisms of MICAL-dependent Pancreatic Cancer Cell Migration

PROJECT SUMMARY/ ABSTRACT – PROJECT 1 Pancreatic duct adenocarcinoma (PDAC) takes the life of an American approximately every 12 minutes and disproportionately affects African American and Hispanic patients, who experience higher rates of morbidity and mortality compared to non-Hispanic white patients. Since the incidence of PDAC is relatively modest, even

among higher risk groups, screening is not feasible. Thus, improvements in outcomes require an improved understanding of PDAC biology to guide development of effective therapies. Here, the partnering PI’s complementary expertise in PDAC biology and modeling cellular biophysical properties converge to investigate

mechanisms of PDAC cell migration and metastasis, the primary cause of death in this patient population. The Lowy laboratory focused on identifying therapeutic targets by performing unbiased discovery in PDAC vs. normal pancreas. They hypothesized that super enhancer associated genes, which define cell identity, would

be effective therapeutic targets for PDAC. One differentially acetylated enhancer region was mapped to the MICAL2 gene, that encodes a flavin monooxygenase. This protein drives F-actin depolymerization, that in the cytosol can restructure the actin myosin machinery used to migrate and respond to external mechanical and

biochemical signals. MICAL2 also plays a role in linking nuclear actin dynamics to serum response factor (SRF) transcription. Myocardin-related transcription factors (MTRFs) are co-activators of SRF; when nuclear actin depolymerization is induced by MICAL2, globular actin is targeted for nuclear export, freeing MTRF to

bind SRF and activate transcription of genes important for cell adhesion and migration. Studies in PDAC cells reveal that silencing MICAL2 expression impairs cell migration and metastasis. The Katira laboratory in collaboration with Dr. Engler’s group have reported that cell adhesiveness serves as a

biophysical marker for metastatic potential, and both adhesiveness and contractility enable adurotaxis, the ability of cells to migrate regardless of a stiffness gradient. To goal of this project is to define how MICAL2 influences properties of adhesiveness and durotaxis, and how it may regulate properties, not only of the cancer

cell, but of the tumor microenvironment through regulation of gene expression. We hypothesize that MICAL2 promotes PDAC cell invasion and metastasis by cell autonomous and non-cell autonomous mechanisms. We will test this hypothesis in three specific aims; 1) Determine how MICAL2 modulates adherence and durotaxis in pancreatic cancer cells, 2) Determine how MICAL2 promotes pancreatic cancer

cell migration and metastasis, and 3) Determine how MICAL2 related signaling from cancer an stromal cells modulates the tumor microenvironment. As a putative therapeutic target, our goal is to determine how MICAL2 functionally regulates cell migration and metastatic capacity during PDAC progression. This knowledge will be

key to understanding how and when MICAL2 activity can be targeted in PDAC.