Wang, Victoria Min-Yi; (2019) Characterisation of CD9 as a functional marker of cancer stem cells in pancreatic ductal adenocarcinoma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common and most aggressive type of pancreatic cancer, with a five-year survival rate of approximately 5%. PDAC tumours are heterogeneous, containing morphologically, genetically and epigenetically distinct cancer cells, as well as large numbers of stromal and immune cells. To date there is no consensus on any well-defined cancer stem or tumour- initiating cell (CSC/TIC) in PDAC that might explain the tumour cell heterogeneity. Our laboratory recently identified the tetraspanin protein CD9 as a marker of PDAC CSCs/TICs. In this thesis, I further characterised CD9 as being a functional marker of these cells: in vitro, knocking down or overexpressing CD9 in mouse PDAC organoids decreased or increased organoid growth, respectively. These growth differences were recapitulated in tumour grafts in immuno-compromised mice. Furthermore, heterozygous deletion of CD9 in the embryonic pancreas in the commonly used Pdx1-Cre; LSL-KRasG12D; p53F/F and Pdx1-Cre; LSL-KRasG12D; p53F/+ mice prolonged overall survival. CD9 was therefore important in PDAC tumour initiation. Knocking out CD9 heterozygously in already-established tumours using a dual-recombinase genetic system showed that CD9 is also involved in tumour maintenance. Human PDAC patients with high levels of CD9 expression have a worse overall survival than patients with low levels of CD9 expression. Additionally, about 10% of patients have genomic amplifications of the CD9 locus. Mechanistically, CD9 interacted with several metabolite transporters in primary PDAC cells. In particular, CD9 promoted the plasma membrane localisation of the glutamine transporter ASCT2, which enhanced glutamine uptake. ASCT2 overexpression could rescue the growth defect of CD9-depleted PDAC cells, and CD9-depleted PDAC cells were more sensitive to a glutaminase inhibitor in vitro, supporting the functional link between CD9 and ASCT2. Overall, this work identifies the tetraspanin CD9 as an important functional marker of PDAC CSCs, which may have therapeutic implications in pancreatic cancer patients.

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