Collaborative Research: Integrated Analysis of Mechanical and Biochemical Effects in Breast Tumor Microenvironment

Regents Of The University Of Michigan - Ann Arbor, Ann Arbor MI

Investigators

Abstract

This project will study how breast cancer cells respond to the local tumor environment and invade adjacent tissue. In breast tumors, biochemical signals lead to cancer cells invading nearby healthy tissue. The cells that produce these signals are called fibroblasts. Fibroblast cells also make tumors stiffer. It is known that patients with stiffer breast tumors typically have poorer outcomes. Past research on these tumors has studied biochemical signaling and mechanical stiffness separately. As such, the combined effects of these two processes on cancer cell invasion remain unknown. The goal of the project is to understand how biochemical and mechanical inputs together enable invasion of healthy tissue. The interdisciplinary research team will use state-of-the-art bioengineered breast tumor models and imaging biosensors. The work will measure both cell signaling and mechanical forces. Findings from this research may eventually help develop new treatment strategies that reduce metastasis. Through a range of educational activities, this project will broaden participation of underrepresented minorities in STEM fields. Therefore, this project will also benefit society by providing new training and research opportunities for the next generation of leaders in STEM fields. Carcinoma-associated fibroblasts (CAFs) remodel the extracellular matrix (ECM) and secrete signaling molecules that promote invasion and metastasis in multiple malignancies. While these events are commonly considered as independent entities, their integrated effects in altering the tumor environments are unknown. The investigators hypothesize that cancer cells establish a memory of mechanical environments that shapes responses to biochemical signals from CAFs and the ability of cancer cells to invade into adjacent tissue. Focusing on breast cancer, this project will develop and apply quantitative imaging biosensors for single-cell and subcellular force measurements and signaling outputs, and a tissue-engineered breast tumor model for phenotypic and whole tumor-level measurements. The research team will quantitatively (i) determine how the interplay between matrix contraction and paracrine signaling of CAFs promotes an invasive mesenchymal phenotype in cancer cells and alters their responses to targeted therapies; and (ii) establish effects of matrix composition and stiffness on nuclear architecture and chromatic condensation that enable cancer cells to retain a signaling memory of their mechanical environment. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.