Understanding therapeutic resistance mechanisms in pancreatic cancer

Prof Jen Morton & Dr Andy Campbell

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Labs: Precision-Panc Preclinical Lab and Colorectal Cancer and Wnt Signalling
Duration: 4 years, starting Oct 2023
Closing Date: 6th January 2023

Project Description

Pancreatic cancer, or pancreatic ductal adenocarcinoma (PDAC), kills over 430,000 people every year. It is one of the deadliest epithelial malignancies, and both incidence and mortality are rising. In the UK alone, there are around 10,500 new cases every year, and less than 8% of those patients will survive their disease for five years. Thus, improvements in our understanding of the disease are vital to identify novel targets for therapy.

PDAC is notable for its extensive stroma of fibroblasts, immune cells, and extracellular matrix proteins such as collagen and fibronectin. Evidence shows that this stroma play an important role in tumour progression, able to influence tumour growth, invasion, immunosuppression, and, importantly, therapeutic resistance. The advent of mutant Kras inhibitors has the potential to be game changing in this disease, particularly now that inhibitors are in development for the most mutated form in pancreatic cancer. However, results in other tumour types suggest that resistance can develop quickly. In pancreatic cancer, the stroma can drive drug resistance, and we have evidence already that drugs targeting RAS signalling can cause microenvironmental changes associated with acquired resistance. For example, we find that inhibition of signalling downstream of Kras can have efficacy in tumour-bearing mice. However, most tumours relapse quickly, display elevated fibrosis, and intriguingly, a re-wiring of signalling in the microenvironment. The aim of this project is to identify the best strategies to overcome resistance.

It is essential to investigate these aspects of tumour biology in vivo, in spontaneous tumours with a physiological microenvironment. Using genetically engineered mouse models of PDAC that fully recapitulate human tumours in terms of genetic alterations and microenvironment, the student will investigate the microenvironment changes associated with therapeutic resistance and interrogate the signalling pathways involved. State-of-the-art molecular & digital pathology technologies will be used to spatially link molecular changes to therapeutic responses, and thus increase our understanding of the relationships between signalling pathways, tumour cells and the tumour microenvironment following therapeutic intervention. The student will also use a variety of ex vivo techniques including immunohistochemistry and multiplex immunofluorescence, tissue culture and co-culture systems, genetic manipulation, flow cytometry, as well as routine molecular biology techniques to identify the key targets of these signals and thus, identify new therapeutic options.

For informal enquiries or further details on the project, please contact Prof Jen Morton (jennifer.morton@glasgow.ac.uk)

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Publications

Hallin et al. (2022) Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor. Nature Medicine. 28, 32171-2182. PMID: 36216931

Waters AM & Der CJ (2018) KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb Perspect Med. 8:a031435. PMID: 29229669

Neesse A, Bauer CA, Öhlund D, Lauth M, Buchholz M, Michl P, Tuveson DA & Gress TM (2019) Stromal biology and therapy in pancreatic cancer: ready for clinical translation? Gut 68:159-171. PMID: 30177543

Coffelt SB & Morton JP. (2022) LOXL2 in pancreatic tumourigenesis: the complexity of tumour-stromal crosstalk exemplified. Gut. 2022-327430. PMID: 35428658

Steele CW, Karim SA, Leach JDG, Bailey P, Upstill-Goddard R, Rishi L, Foth M, Bryson S, McDaid K, Wilson Z, Eberlein C, Candido JB, Clarke M, Nixon C, Connelly J, Jamieson N, Carter CR, Balkwill F, Chang DK, Evans TRJ, Strathdee D, Biankin AV, Nibbs RJB, Barry ST, Sansom OJ & Morton JP. (2016) CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma. Cancer Cell 29:832-845. PMID: 27265504

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