Elizabeth Martin
LSU, Department of Biological and Agricultural Engineering
Project Title
Evaluation of Subtype Specific Collagen Remodeling in Breast Cancer Progression.
Mentors
Bridgette Collins-Burow, M.D., Ph.D., Tulane University, Department of Medicine, Hematology/Oncology
Joseph Francis, Ph.D., Louisiana State University, Department of Comparative Biomedical Sciences
Funding Period
Project (May 1, 2021 - February 28, 2024)
Biosketch
My diverse training in engineering, breast cancer, and regenerative medicine has led to my current work: investigating subtype specific breast cancer progression and remodeling of the tumor microenvironment. I strongly feel that my prior work in three different developmental/regenerative medicine based labs combined with my graduate and post-doctoral studies in breast cancer and my current position as faculty in Biological Engineering provides an innovative perspective in the study of breast cancer biology. I plan to integrate these disciplines to establish a connection between tumor architecture, stromal remodeling, and progression to a drug resistant breast cancer phenotype. While training in regenerative medicine I acquired skills on tissue decellularization and proteomic analysis of tissue matrix. I used these techniques to identify novel mechanism to evaluate tumor structure, through the development of a tumor decellularization model. Encompassed within this is evaluating how the tumor microenvironment may facilitate cell dormancy and a cancer stem phenotype. Currently I am using the skills acquired in engineering to develop physiologically relevant tumor models that more accurately mimic specific patient populations. I believe that I am uniquely positioned to develop these ideas as I have had extensive training in the fields of cancer, regenerative medicine, and engineering. The project proposed here will provide a paradigm shift from treating breast cancer cells to the evaluation and treatment of the surrounding stroma.
Abstract
Currently there are no available therapies designed to appropriately target the triple negative/basal breast cancer subtype (TNBC). Due to the risk of recurrence and metastasis following primary therapy, novel avenues of intervention must be pursued. The tumor matrix, the material cancer cells are grown on, modulates cellular proliferation and survival, however a link between a TNBC subtype specific extracellular matrix (ECM) and mechanisms of TNBC drug resistance has not yet been made. This proposal will identify novel mechanism of matrix induced drug resistance in TNBC. Using a combination of 3D in vitro screens, murine models of TNBC, and primary patient samples, Dr. Martin will interrogate novel matrix proteins (collagen IV, XII, and fibronectin) involved in TNBC drug resistance. The hypothesis of this proposals is: TNBC extracellular matrix enhances drug resistance through the induction of cellular dormancy. Dr. Martin will use in vitro 3D tumor models to screen the effects of matrix composition on induction of cellular dormancy and a cancer stem cell phenotype in TNBC. Furthermore Dr. Martin will determine how cancer cells grown on different matrix composites alter immune cell activation and proliferation, providing new insight on matrix induced immune evasion. These in vitro screens will be validated in vivo through the construction and evaluation of conditional knock out of matrix proteins (collagen IV, XII, fibronectin) in the mammary fat pad of transgenic murine models. Finally the clinical significant of this study will be verified through the interrogation and histological evaluation of matrix composition, immune infiltration, and occurrence of cell dormancy in a panel TNBC primary tumors. Dr. Martin will use proteomics to evaluate the matrix composition of primary TNBC and adjacent matched tissue and correlate these finding with observed immune infiltration. Additional histological evaluation and confirmation will also be performed. This will be investigated through the following specific aims: Specific Aim 1. Evaluate the effect of ECM composition on TNBC drug resistance. Specific Aim 2. Determine the translational relevance of subtype specific ECM composition.