University of Cambridge
Unravelling the epigenetic landscape of pancreatic cancer: The role of cancer-associated fibroblasts in transcription factor regulation
Abstract
dc:description.abstractPancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, with limited treatment options and poor survival rates. It is characterised by strong driver mutations, extensive epigenetic reprogramming, and a dense tumour microenvironment (TME). A defining feature of the PDAC TME is its fibrotic stroma, which is largely composed of cancer-associated fibroblasts (CAFs). Distinct populations of CAFs, including inflammatory CAFs (iCAFs) and myofibroblastic CAFs (myCAFs), have been identified and implicated in PDAC progression. However, the mechanisms that govern their crosstalk with the cancer cells are poorly understood. This thesis aims to investigate how iCAFs and myCAFs differentially shape the epigenetic landscape of PDAC. To this end, I established a co-culture model consisting of epithelial cells and genetically locked myCAFs or iCAFs to study the link between the TME and the gene regulatory machinery in PDAC through genomic and proteomic approaches. This work identified STAT1 as a mediator of iCAF-induced transcriptional reprogramming. STAT1 was found to associate with accessible chromatin regions and to co-occupy a subset of sites with FOXA1/FOXA2, promoting expression of interferon (IFN)-α/γ response genes. Inhibition of IFN-β was sufficient to attenuate iCAF-derived paracrine signalling and suppress STAT1 phosphorylation. In contrast, myCAFs promoted SOX2 upregulation in cancer cells through direct cell-cell contact. SOX2 was recruited to enhancer elements and mediated expression of genes associated with epithelial-mesenchymal transition and hypoxia. In an orthotopic in vivo model, co-injection of cancer cells with either iCAFs or myCAFs reduced survival compared to injection of cancer cells alone. In summary, this thesis provides a comprehensive analysis on how CAF heterogeneity contributes to epigenetic reprogramming in PDAC. By uncovering previously unrecognised roles for STAT1 and SOX2 in stromal-epithelial interactions, it provides novel insights into the complex biology of PDAC. These findings reveal distinct, non-overlapping mechanisms by which CAF subtypes modulate tumour behaviour and underscore the potential of exploring tumour-fibroblast crosstalk to identify more effective therapeutic targets.
Degree
thesis:*- Name dc:type.qualificationname
- Doctor of Philosophy (PhD)
- Level dc:type.qualificationlevel
- Doctoral
- Grantor dc:publisher.institution
- University of Cambridge
- Year dc:date.issued
- 2025
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Pelicano Da Cunha Branco Da Costa, Catarina
- Advisor dc:contributor.advisor
-
- Carroll, Jason S
Subjects
dc:subject × 4Rights
dc:rightsIdentifiers
dc:identifier.*- DOI dc:identifier.doi
- https://doi.org/10.17863/CAM.121992
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/390441