Chawla, Pooja
(2024)
MRTF-dependent Paracrine Regulation of Osteoclast Differentiation and Bone Colonization of Breast Cancer Cells.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
Bone is a frequent site for breast cancer metastasis. Conditioning of the local tumor microenvironment through crosstalk between tumor cells and bone resident cells in the metastatic niche is a major driving force for bone colonization of cancer cells. The vast majority of breast cancer-associated metastasis is osteolytic in nature due to dysregulated action of osteoclasts (OCL). Osteoclastogenesis and OCL survival are greatly enhanced by increased secreted levels of RANKL and other soluble factors contributed by tumor cells, osteocytes, osteoblasts, and immune cells. Increased bone resorption promotes the release and activation of ECM-bound growth factors and cytokines, further amplifying this loop and stimulating tumor cell proliferation and metastatic colonization of tumor cells. The present study investigates the role of Myocardin-related transcription factor (MRTF - a major cofactor for the transcription factor serum-response factor, SRF) in tumor-cell directed paracrine modulation of OCL differentiation and metastatic colonization of breast cancer cells. We herein demonstrate that MRTF depletion in breast cancer cells severely impairs experimental bone colonization of breast cancer cells in vivo. We further show that MRTF plays a key role in tumor-cell directed paracrine modulation of RANKL-induced OCL differentiation of bone marrow-derived macrophages (BMDMs). Luminex and transcriptomic analyses revealed that MRTF depletion in breast cancer cells impacts a broad range of cell secreted osteoclast regulatory factors. Rescue experiments demonstrated that downregulation of pro-osteoclastogenic matricellular protein connective tissue growth factor (CTGF) partly underlie the repressive effect of MRTF-depletion in breast cancer cells on RANKL-induced OCL differentiation of BMDMs. SRF’s interaction is critical for MRTF-dependent regulation of CTGF. A strong positive correlation between CTGF expression and MRTF gene signature in human breast cancer further establishes the clinical relevance of our findings. In conclusion, this study uncovers a novel functional aspect of MRTF in bone colonization of cancer cells, and we propose that MRTF inhibition could be a novel strategy to suppress OCL activity and skeletal involvement in metastatic breast cancer.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
6 September 2024 |
| Date Type: |
Publication |
| Defense Date: |
10 July 2024 |
| Approval Date: |
6 September 2024 |
| Submission Date: |
30 June 2024 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
77 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Bioengineering |
| Degree: |
MS - Master of Science |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Breast Cancer, MRTF, Osteoclast |
| Date Deposited: |
06 Sep 2024 19:57 |
| Last Modified: |
06 Sep 2024 19:57 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46641 |
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