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Elucidating the role of TGFβ signalling in drug resistant Hh driven cancers

Morgan, Huw 2018. Elucidating the role of TGFβ signalling in drug resistant Hh driven cancers. PhD Thesis, Cardiff University.
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Targeted therapies for cancer have been developed that block oncogenic pathways that drive tumour growth (e.g. hedgehog, mitogen-activated protein kinases, vascular endothelial growth factor, and the Abelson tyrosine kinase and the chromosome 22 break point cluster fusion gene). For inoperable metastatic disease, targeted therapies provide rapid response, but in most cases are associated with eventual relapse with more aggressive disease. Basal cell carcinoma (BCC) arises from keratinocytes with mutations leading to constitutively active sonic hedgehog (SHh) growth factor signalling. Unlike the multiple genetic lesions required during stepwise carcinogenesis in many other cancers, SHh signalling alone appears to be sufficient to cause BCC, which may explain the absence of precursor lesions and also why BCC is the most common malignancy in Caucasians. As expected hedgehog (Hh) antagonists lead to rapid involution of BCC, but also eventual relapse, and in some cases transformation to squamous cell carcinoma. Thus, BCC represent an ideal model to study relapse after targeted therapy. We show that the TGFβ signalling pathway constituents were amplified in BCC, consistent with increased signalling. TGFβ signalling was evident in a third of untreated BCC cells at the tumour periphery. Cells at the tumour nodule periphery active for TGFβ signalling demonstrated lower rates of proliferation, and upregulation of TGFβ regulated epithelial mesenchymal transition (EMT) genes consistent with tumour invasion. Intriguingly, BCC cancer stem cells that have been previously identified at the tumour nodule periphery consistently demonstrated active TGFβ signalling and enhanced expression of TGFβ dependent EMT genes. We show that as expected, addition of Hh antagonists (GANT-61, Vismodegib, Sonidegib) to primary BCC cells and three Hh driven tumour cell lines (DAOY, UW228-2, SJSA-1), had no significant impact on cell proliferation or survival in vitro. Interestingly, Hh antagonist treatment was associated with increased TGFβ signalling activity as evidenced through nuclear accumulation of pSMAD3 and expression of TGFβ regulated genes. However, blocking the TGFβ signalling pathway, both on its own and in combination with Hh antagonists again had no significant impact on cell proliferation or survival in the cell lines. When trying to elucidate the mechanisms that underlie tumour resistance, we found that Hh antagonist-induced TGFβ signalling was accompanied by destabilisation of the microtubule network. This could subsequently lead to TGFβ-induced EMT/invasion in either the general cell population or stem cell population, and may provide a mechanism through which tumours can promote relapse following treatment, and in rarer cases, induce transformation to more aggressive phenotypes such as SCC. However, additional studies are required to elucidate this mechanism of action further.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Uncontrolled Keywords: Cancer stem cell; Drug resistance; Skin cancer; Basal cell carcinoma; TGFβ signalling; Hh signalling
Funders: Cancer Research Wales
Date of First Compliant Deposit: 10 September 2018
Last Modified: 14 Apr 2021 15:00

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