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Cues from the extracellular space: matrix proteins regulate melanoma invasion

Grahovac, Jelena (2012) Cues from the extracellular space: matrix proteins regulate melanoma invasion. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Grahovac, Jelenajeg80@pitt.eduJEG80
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSaunders, William Swsaund@pitt.eduWSAUND
Committee MemberBecker, Dorotheadbecker@pitt.eduDBECKER
Committee MemberSmithgall, Thomas Etsmithga@pitt.eduTSMITHGA
Committee MemberHildebrand, Jeffreyjeffh@pitt.eduJEFFH
Thesis AdvisorWells, Alanwellsa@msx.upmc.eduAHW6
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

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