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The effect of mechanical stiffness and the novel ITGA5 targeting peptide in fibroblast activation

Hoen, R.Y. (2022) The effect of mechanical stiffness and the novel ITGA5 targeting peptide in fibroblast activation.

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Abstract:Cancer is one of the leading causes of death in the Netherlands. Pancreatic Ductal Adenocarcinoma is one of the most devastating cancers, with a 10-year survival rate of only 3%. PDAC is known to be a fibrotic tumor which results in a dense, stiff TME. The TME influences the efficacy of therapeutic agents extensively as the TME can function as physical barrier around the tumor. A large portion of the TME consists of cancer-associated fibroblasts (CAFs). CAFs can be characterised by their increased ECM protein production and up-regulated secretion of pro-tumorigenic factors. In PDAC, Pancreatic Stellate Cells (PSCs) largely fill the CAF population. Targeting and potentially inactivating CAFs could prove to positively influence cancer therapeutic efficacy. The key growth factor responsible for PSC recruitment and activation to CAF is Transforming Growth Factor-β. Mechanical stiffness has also been suggested to play a role in fibroblast activation. For fibroblasts, α5β1 integrin is the key integrin that enables mechanosensing. Upon activation, integrins induce cytoskeleton assembly which activates the mechanotransductor effectors of the Hippo pathway: YAP/TAZ. YAP/TAZ activation is recognized by nuclear translocalization where it influences cell proliferation and differentiation. The novel therapeutic peptide, called CyAV3.3, targets the integrin alpha 5 (ITGA5) subunit. This study aims to gain knowledge about the effect of mechanical stiffness in fibroblast activation, and demonstrate the inhibiting capabilities of the novel CyAV3.3 peptide on fibroblast activation in different matrix stiffness conditions. This was examined by comparing mechanical stiffness mediated PSC activation in low (0.2 kPa) and high (32 kPa) matrix stiffness conditions. Furthermore, in the same matrix stiffness conditions, PSCs were treated with CyAV3.3 to investigate activation inhibition. αSMA-, ITGA5- and nuclear YAP/TAZ expression levels were assessed by immunofluorescence staining. The study found significant increase in αSMA expression for high matrix stiffness. The research also demonstrated CyAV3.3 mediated downregulation of αSMA in high matrix stiffness conditions for non-TGF-β treated PSCs. In addition, the inhibiting effect of CyAV3.3 was seen for ITGA5 in TGF-β mediated PSC activation as well. Despite limiting factors, the study offers insight in the effect of mechanical stiffness in PSC activation. Furthermore, the study contributes to previous findings that implicate the inhibiting effect of CyAV3.3 on PSC activation. These findings can prove useful for improving cancer therapeutic efficacy.
Item Type:Essay (Bachelor)
Faculty:TNW: Science and Technology
Subject:50 technical science in general
Programme:Biomedical Technology BSc (56226)
Link to this item:https://purl.utwente.nl/essays/95620
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