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Title page for ETD etd-04282017-095747


Type of Document Dissertation
Author Loomans, Holli Ann
Author's Email Address holli.loomans@gmail.com
URN etd-04282017-095747
Title Loss of ACVRIB-dependent Activin A signaling induces esophageal and head and neck carcinoma aggressiveness
Degree PhD
Department Cancer Biology
Advisory Committee
Advisor Name Title
J. Ann Richmond Committee Chair
Alissa Weaver Committee Member
Andries Zijlstra Committee Member
Hal Moses Committee Member
Keywords
  • adhesion
  • three-dimensional culture
  • dysplasia
  • fibroblast
  • cell invasion
  • extracellular matrix
Date of Defense 2017-04-18
Availability unrestricted
Abstract
It was been well established that the Activin A signaling pathway plays a pivotal role in the developing, adult, and diseased organism, commonly acting as a growth inhibitor. Though prevalent in embryonic tissues, Activin A secretion is downregulated in post-natal tissues. Contrary to its function, Activin A expression is often upregulated in cancer, and, of particular interest, in esophageal (ESCC) and head and neck squamous (HNSCC) cell carcinomas. Therefore, we investigated the function of Activin A in these contexts. Interestingly, we found that Activin A acts as an inhibitor of invasion and regulator of the extracellular matrix on dysplastic and ESCC cell lines that retain expression of Activin A receptor type IB, ACVRIB. When ACVRIB is lost, Activin A no longer exerts these effects, though the other components of the Activin A receptor complex remained intact. Consequently, we decided to further define the functional effects of loss of ACVRIB in HNSCC and ESCC cells using CRISPR/Cas9 and siRNA, respectively. In the absence of ACVRIB, we found increased proliferation, migration, and invasion. Using an organoptypic culture system and immunofluorescence staining, we observed altered expression of proteins responsible for cell-cell and cell-extracellular matrix adhesion. We conclude that ACVRIB-dependent Activin A signaling is necessary to regulate ESCC and HNSCC progression.
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