Grahovac, Jelena
(2012)
Cues from the extracellular space: matrix proteins regulate melanoma invasion.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
Melanoma is the most aggressive type of skin cancer with increasing incidence rates. To date, there are no effective therapies that can ensure disease free or even progression free survival of melanoma patients. While early stage primary melanoma is curable by surgical resection, survival of patients with metastatic melanoma is measured in months. Therefore it is of utmost importance to decipher molecular events that precede and/or induce the switch towards the invasive melanoma phenotype. In pursue of efficient therapy, attention has to be given not only to the cancer cells themselves but also to the microenvironment that nurtures and promotes malignant behavior. Aggressive melanoma cells drastically remodel their microenvironment. We found that expression of two extracellular matrix (ECM) proteins was significantly altered in melanoma compared to uninvolved patient skin: Tenascin C (TNC) was markedly increased, while small proteoglycan Decorin (DCN) was decreased. We found that invasion of the melanoma cells correlates with TNC expression levels and that cells present TNC asymmetrically at the invasive fronts. We also found that Epidermal Growth Factor-Like (EGFL) repeats of TNC promote melanoma cell invasiveness by activating Rho-associated kinase and increasing cell contractility, thus allowing mesenchymal to amoeboidal switch in mode of migration. Interestingly, TNC and DCN have both been shown to affect signaling through Epidermal Growth Factor receptor (EGFR), but with opposite outcomes on cell proliferation, migration and survival. We adapted skin organ cultures to test the influence of these two proteins on melanoma invasion and found that DCN can ameliorate TNC induced melanoma invasion. Taken together, our findings imply that ECM composition has a significant role in the regulation of melanoma invasiveness and that even in the presence of increased pro-invasive TNC signaling DCN can be a promising moiety for melanoma therapy.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
18 December 2012 |
| Date Type: |
Publication |
| Defense Date: |
27 November 2012 |
| Approval Date: |
18 December 2012 |
| Submission Date: |
4 December 2012 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
152 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Integrative Molecular Biology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
melanoma, extracellular matrix, tenascin c, decorin, migration, adhesion, ROCK |
| Date Deposited: |
18 Dec 2012 12:52 |
| Last Modified: |
19 Dec 2016 14:40 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/16769 |
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Cues from the extracellular space: matrix proteins regulate melanoma invasion. (deposited 18 Dec 2012 12:52)
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