Date of Award
Summer 8-15-2025
Level of Access Assigned by Author
Open-Access Thesis
Degree Name
Doctor of Philosophy (PhD)
Department
Biochemistry and Molecular Biology
First Committee Advisor
Guangwen Ren
Second Committee Member
Lenny Shultz
Third Committee Member
Chih-Hao Chang
Additional Committee Members
Sheng Li
Xia Liu
Abstract
Aging is a major risk factor for breast cancer metastasis, yet the mechanisms by which it alters distant organ microenvironments remain poorly understood. Here, we used murine models of pre-metastatic lung niche to investigate how aging reprograms stromal and immune compartments to promote pulmonary metastasis.
Single-cell RNA sequencing revealed that fibroblasts in aged lungs acquire immunoregulatory functions, including upregulation of antigen presentation genes and interferon-stimulated pathways, but lack costimulatory signals, potentially inducing T cell anergy or Treg expansion.
Aged fibroblasts also showed elevated prostaglandin E2 (PGE2) production, which may impair dendritic cell activation and promote suppressive neutrophil phenotypes in co-culture. In parallel, myeloid cells exhibited functional shifts: alveolar macrophages showed ECM remodeling signatures, dendritic cells had reduced antigen-presenting capacity, and neutrophils displayed enhanced NETosis and immunecheckpoint expression. Together, these alterations formed a self-reinforcing loop of stromal–myeloid crosstalk that established an immunosuppressive, pro-metastatic niche.
Our results underscore the importance of aging fibroblasts in shaping an immunosuppressive lung environment and provide potential targets such as the PGE2–EP axis for therapeutic intervention to mitigate metastatic risk in elderly cancer patients.
Recommended Citation
He, Jiatai, "The Impact of Aging on The Lung Stromal-Immune Microenvironment in Breast Cancer Metastasis" (2025). Electronic Theses and Dissertations. 4252.
https://digitalcommons.library.umaine.edu/etd/4252