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Title page for ETD etd-03272011-124925

Type of Document Dissertation
Author Ruppender, Nazanin Sabine
Author's Email Address nazanin.s.ruppender@vanderbilt.edu
URN etd-03272011-124925
Title Matrix Mechanical Properties and the Invasive Potential of Metastatic Cancer
Degree PhD
Department Chemical Engineering
Advisory Committee
Advisor Name Title
Scott Guelcher Committee Chair
Clare McCabe Committee Member
Jeffry Nyman Committee Member
Kane Jennings Committee Member
  • bone metastasis
  • mechanotransduction
  • cancer
  • biomaterials
Date of Defense 2011-03-10
Availability unrestricted
Recent studies suggest that cancer cells undergo genotypic and phenotypic changes in response to the rigidity of the extracellular matrix (ECM). These studies have focused largely on non-mineralized tissues in the kPa range (corresponding to soft tissue), while many tissues important in the progression of cancer, such as mineralized bone (O(109 Pa)) and the basement membrane (O(106 Pa)), far exceed those values. In this work, we employed the use of in vitro culture systems spanning the entire range of tissue elasticity (103-109 Pa) to study the invasive potential of breast cancer. Here, we demonstrate that cancer cells can sense a wide range of rigidities, and show increased ECM degradation by invadopodia in response to rigidity. Furthermore, we show that the rigidity of bone, a preferential target for breast cancer, specifically induces changes in parathyroid hormone related protein (PTHrP) and its transcription factor Gli2 in the cancer cell to facilitate degradation and invasion of the bone matrix. We find that these genotypic changes are mediated by mechanotransduction, as bone-like matrix rigidity induced clustering of β3 integrin and TGF-β receptor type II (TGF-βRII) to stimulate expression of PTHrP and Gli2 through Src, Rho-kinase (ROCK) and mitogen activated protein kinase (MAPK). These observations demonstrate the need for physiologically relevant in vitro culture systems and suggest a role for the differential rigidity of the mineralized bone microenvironment in early stages of tumor-induced osteolysis. These findings could lead to new clinical targets for the treatment of bone metastases, a major contributor in the lethality of metastatic cancer, for which no effective therapies exist to date.
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