The Role of Extracellular Matrix Alterations Induced by Radiation Therapy in Modulating  Breast Cancer Recurrence

Zhu, Tian

The Role of Extracellular Matrix Alterations Induced by Radiation Therapy in Modulating Breast Cancer Recurrence

dc.contributor.committeeChair	Rafat, Marjan
dc.creator	Zhu, Tian
dc.creator.orcid	0000-0002-9471-4711
dc.date.accessioned	2025-06-06T09:46:54Z
dc.date.available	2025-06-06T09:46:54Z
dc.date.created	2025-05
dc.date.issued	2025-03-24
dc.date.submitted	May 2025
dc.description.abstract	Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high metastatic potential, and radiation therapy (RT) is a crucial treatment strategy. However, despite its effectiveness in reducing recurrence overall, many patients with TNBC experience relapse, suggesting that irradiation may play a significant role in promoting a pro-tumor microenvironment. This dissertation investigates the impact of RT-induced extracellular matrix (ECM) remodeling on tumor recurrence, with a focus on structural, molecular, and mechanical properties of the ECM. We employed a combination of in vivo and ex vivo irradiated models, including non-tumor bearing and tumor-bearing models, to assess how RT affects ECM properties that regulate cancer and immune cell behavior. Our analysis of murine mammary fat pads revealed significant ECM alterations following RT, including increased collagen deposition, enhanced fiber density, increased tissue stiffness, and changes in the expression of key ECM components such as collagen I, IV, VI, and fibronectin. Utilizing decellularized ECM (dECM) hydrogels, we successfully replicated the in vivo irradiated microenvironment and studied its effects on tumor and immune cell proliferation, invasion, and function. Our results demonstrate that RT-induced ECM structure and composition modifications create a permissive platform for breast cancer cell growth, invasion, and immune modulation, especially in an immunocompromised context known to correlate with post-RT relapse. Notably, TNBC cells co-cultured with macrophages in irradiated dECM hydrogels led to macrophage polarization toward an immunosuppressive phenotype, which further enhanced tumor cell proliferation in both ex vivo irradiated and in vivo irradiated tumor-bearing models. Additionally, RT-induced ECM remodeling promoted cancer and immune cell metabolic reprogramming and facilitated ECM uptake. In conclusion, our study underscores the critical role of ECM remodeling in the RT response, highlighting its contribution to tumor growth and invasion as well as immune suppression in TNBC. These findings provide new insights into how targeting ECM-immune cell interactions may improve RT outcomes and reduce the likelihood of cancer recurrence.
dc.format.mimetype	application/pdf
dc.identifier.uri	https://hdl.handle.net/1803/19753
dc.language.iso	en
dc.subject	Breast cancer
dc.subject	Extracellular matrix
dc.subject	Radiation therapy
dc.title	The Role of Extracellular Matrix Alterations Induced by Radiation Therapy in Modulating Breast Cancer Recurrence
dc.type	Thesis
dc.type.material	text
thesis.degree.discipline	Chemical Engineering
thesis.degree.grantor	Vanderbilt University Graduate School
thesis.degree.level	Doctoral
thesis.degree.name	PhD