Jazwinska, Dorota Elzbieta
(2024)
Mesothelial Barrier Dysfunction in Ovarian Cancer Metastasis.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
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Abstract
Ovarian cancer is the leading cause of death among all gynecological cancers, with most patients being diagnosed with metastatic disease. For metastatic implants to form, mesothelial interactions are critical in many steps of the metastatic cascade. However, the mechanisms by which mesothelial barrier integrity is impaired, as well as how mesothelial cells respond to environmental and treatment-induced stress, are not well understood. We utilized multiple models both in vitro and ex vivo to study ovarian cancer cell adhesion and transmigration. We first employed pharmacological approaches to strengthen the mesothelial barrier using the cAMP agonist forskolin, which has been previously utilized in endothelial and epithelial monolayers. Our findings reveal that forskolin treatment reduced ovarian cancer spheroid transmigration by decreasing mesothelial contractility and enhancing cell-cell junction organization. Conversely, upregulation of mesothelial cell contractility using calyculin A led to increased spheroid transmigration and weakening of mesothelial cell-cell junctions. Next, we utilized platinum-based chemotherapy to induce clinically-relevant therapeutic stress in mesothelial cells. We found that treating the mesothelial monolayers with cisplatin resulted in increased ovarian spheroid transmigration. Inhibition of STAT3 protected mesothelial cells from chemotherapy without compromising the cytotoxic efficacy of cisplatin on ovarian cancer spheroids. Finally, we investigated how a major environmental stress stimulus, hypoxia in the tumor microenvironment, perturbs mesothelial barrier integrity. Utilizing a microfluidic model with a mesothelial monolayer formed in one channel and ovarian cancer cells seeded in the other, we found that hypoxic conditions drove mesothelial cell invasion into the collagen gel toward the cancer cells. Inhibition of SRC signaling using the FDA-approved agent saracatinib under hypoxia reduced mesothelial cell invasion into the collagen gel. Overall, our findings demonstrate that strengthening the mesothelial barrier and targeting mesothelial cell responses to environmental or chemotherapy-induced stress signaling block ovarian cancer spheroid metastatic potential. Our work has important implications for discovering new therapeutic targets in the peritoneal microenvironment and developing mesothelial-targeted combination therapies to reduce ovarian cancer metastatic progression.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
6 September 2024 |
| Date Type: |
Publication |
| Defense Date: |
17 July 2024 |
| Approval Date: |
6 September 2024 |
| Submission Date: |
5 July 2024 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
149 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Bioengineering |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Microfluidic, Ovarian Cancer, Metastasis |
| Date Deposited: |
06 Sep 2024 19:58 |
| Last Modified: |
06 Sep 2024 19:58 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46657 |
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