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Title: BMP-SMAD1/4 upregulates HNF4α in a subset of heterogeneous mouse pancreatic cancer cells while under metabolic stress
Author: Heung, Man Yeung
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2013
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It is not known whether pancreatic cancers evolve from a single or multiple cells, or from a particular pancreatic lineage. However, in the Pdx1-Cre; LSL-KrasG12D; LSLTp53R172H mouse model of pancreatic cancer, all pancreatic lineages are susceptible to express mutant KRas and p53. Hence, such mouse model implies a scenario of maximal heterogeneity of cancer cell origins. On this basis, I isolated seven subclones of heterogeneous mouse pancreatic cancer cells from a single tumour; each of them had a distinct morphology and gene expression profile. Notably, they possessed different intrinsic phospho-SMADs downstream of the TGFβ receptor (phospho-SMAD2/3) or the BMP receptor (Phospho-SMAD1/5/8). I discovered that SMAD4, a co-SMAD which is frequently found to be lost in pancreatic caner tissues, upregulated HNF4α via the classical BMP-SMAD1 pathway, when cells were experiencing metabolic stress upon deprivation of serum, or in the presence of excess thymidine. Under serum starvation at a hypoglycemic-like glucose concentration, the HNF4α-expressing sub-clones appeared to be more able to sustain an unstressed morphology than other non-HNF4α-expressing sub-clones. Immunohistochemical staining on pancreatic cancer sections revealed nuclear co-localization of SMAD4 and HNF4α in human (half of the cases) and in mouse samples. As a secondary project conducted during characterization of cells, I also found that three of the subclones more robustly proliferated under anchorage independent conditions, and they relied on the MEK-ERK pathway and the canonical Wnt pathway, to a different degree. Both studies demonstrate for the first time in primary cell culture that pancreatic cancer cells within a tumour could be highly heterogeneous in terms of both morphology and signaling pathways.
Supervisor: Hastie, Nicholas ; Frame, Margaret ; Brunton, Valerie Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: pancreatic cancer ; mouse model ; BMP ; SMAD4 ; HNF4a ; stress ; heterogeneity