Dissecting the impact of SMAD4 loss and KRAS mutations in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival rate of ~10% that is set to make this disease the second leading cause of cancer-related deaths by 2040. Poor survival rates for PDAC are a consequence of late-stage diagnosis due to non-specific early-stage symptoms, and largely ineffective treatment options. Treatments are ineffectual particularly for advanced disease and partially due to a limited understanding of the dense stroma that comprises most of the tumour microenvironment. Cancer-associated fibroblasts (CAFs) are the most abundant cells within the stroma and are a heterogeneous population with functional diversity, including myofibroblastic myCAFs that deposit collagen, and inflammatory iCAFs that secrete cytokines. PDAC malignant cells harbour combinations of mutations in four key genes: KRAS, TP53, CDKN2A and SMAD4; which have been shown to shape stromal composition. Lack of representation of complex genetic profiles in pre-clinical models of PDAC, which focus on Kras G12D and Trp53 mutations, alongside limited consideration of CAF heterogeneity, have potentially contributed to largely inefficient treatment options for this disease. In this work, I use Trp53-mutant mouse models driven by Kras G12D or Kras G12V mutations with or without Smad4 to investigate the impact of SMAD4 loss on malignant cell to CAF crosstalk. Smad4 deletion accelerated the progression of PDAC tumours and reduced the proportion of myCAFs. In Kras G12D Smad4 deficient tumours there was a marked increase in iCAFs and enhanced JAK/STAT signalling in malignant cells. Targeting of the JAK/STAT pathway by JAK inhibitors selectively reduced growth of Kras G12D Smad4-deficient PDAC compared to Smad4-proficient controls. In contrast, malignant cells with Kras G12V mutations in combination with Smad4 loss did not have a dependency on JAK/STAT signalling. Taken together, my work exemplifies how PDAC mutational profiles instruct stromal composition and could inform the design of precision therapeutics for specific groups of PDAC.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Lloyd, Eloise

Advisor dc:contributor.advisor

• Biffi, Giulia

• pancreatic cancer
• cancer associated fibroblast
• tumour microenvironment

Licence

• https://www.repository.cam.ac.uk/bitstreams/d0712a00-25be-4cf7-86c1-bbb82f088201/download
• http://purl.org/NET/rdflicense/allrightsreserved

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.114592

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/377936