Obscurin-Deficient Breast Epithelia Generate Secreted Factors that Prime Lung Vascular Smooth Muscle Cell Pre-metastatic Microenvironment Formation

点击翻译按钮获取中文摘要

Project Summary/Abstract: New therapies blocking metastatic spread are greatly needed to improve breast cancer patient survival. Pre-metastatic niche development has been identified as a key milestone to successful metastasis, generated in response to a growing tumor’s release of secreted factors. Critical to the pre-metastatic niche is the pre- metastatic microenvironment (PMM) composed of extracellular matrix (ECM) proteins, deposited by resident stromal cells, that enhance metastasis. To date, PMM development has been studied solely in the context of highly metastatic tumor models using cell lines rich in tumor suppressor and oncogene mutations, however no direct mechanistic connections between metastatic driver genes and PMM formation have yet been deciphered. Obscurins have recently been pinned as potent metastasis suppressors in breast cancer. Biochemical evidence from our group has mechanistically linked obscurin loss to PI3K/Akt2 activation in breast epithelial cells, driving oncogenesis and metastatic spread. However, no study has yet drawn the connection between the loss of obscurin in breast epithelia and PMM development. This study will test the novel hypothesis that loss of obscurin in breast epithelia primes vascular smooth muscle cell (vSMC)-derived fibronectin and collagen 1a1 deposition in the PMM through secreted factors, potentiating metastasis. The goal of my application is to investigate the potential of obscurin-deficient breast epithelia secreted factors (OBEFs) to drive vSMC ECM fibronectin and collagen 1a1 deposition. OBEFs will be isolated from OBSCN knock-out (KO) MCF10A cell clones, while the human pulmonary artery smooth muscle cell (HPASMC) line will be the representative PMM cell population for the following reasons: 1) Lung PMM development is dependent on phenotypically activated lung vSMC-derived ECM production, and 2) Pre-metastatic lung, vSMC- derived ECM has been shown to enhance metastatic lung seeding in the pre-metastatic lung parenchyma. In particular, I will investigate potential changes in OBEF-driven vSMC-derived ECM fibronectin and collagen 1a1 and their connection to enhanced lung metastatic seeding (Aim 1). Then, I will identify the responsible secreted factors (Aim 2) that drive the subsequent vSMC ECM fibronectin and collagen 1a1 production in the lung PMM. Together, these studies will connect our knowledge of PMM development back to a major suppressor of primary tumor metastasis, indicating the first targetable tumor biomarker linked to the stromal component of PMM generation.