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

> **NIH NIH F30** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $47,091

## Abstract

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.

## Key facts

- **NIH application ID:** 10912529
- **Project number:** 5F30CA278384-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Matthew Kent Eason
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $47,091
- **Award type:** 5
- **Project period:** 2023-07-15 → 2026-07-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10912529

## Citation

> US National Institutes of Health, RePORTER application 10912529, Obscurin-Deficient Breast Epithelia Generate Secreted Factors that Prime Lung Vascular Smooth Muscle Cell Pre-metastatic Microenvironment Formation (5F30CA278384-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10912529. Licensed CC0.

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