Addressing vascular and immunological features in a model of pancreatic ductal adenocarcinoma lung metastasis

De Donatis, Marco (2023) Addressing vascular and immunological features in a model of pancreatic ductal adenocarcinoma lung metastasis. PhD thesis, University of Glasgow.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is known for its high aggressiveness. The overall 5-year survival rate is 11%, but when stratified by stage at diagnosis, it plummets to 2.9% for those diagnosed with distant metastasis. This highlights the need to better understand how to restrain PDAC metastasis. The lung, frequently affected by PDAC spread, is characterized by a rich vascular network and a finely tuned immune system. Here, the immune defence against external threats must co-exist with the need to minimise inflammation to maintain efficient gas exchange. It is now evident that PDAC can affect the lung environment even prior to its arrival in the lungs, however the effect of established metastasis has not been fully investigated so far. Therefore, the aim of this thesis is to study vascular and immunological features of a model of established PDAC lung metastasis, and the possible interplay between the two.
We initially scored archived specimens of lungs and liver metastasis of KrasG12D/+; Trp53R172H/+; Pdx1-Cre (KPC) mice and found that tumour cells grow by co-opting pre-existing lung capillaries, rather than inducing angiogenesis. We then recapitulated this observation in a more tractable transplant model, in order to study established lung metastasis though the intravenous injection of KPC cells. Resultant lung tumours were studied using flow cytometry and spectral multiplexed 3D confocal imaging to explore the vasculature morphology, as well as the immunological infiltrate and its localisation. We found that co-opted endothelial cells become permeable, lose CD31 expression while upregulating intercellular adhesion molecule 1 (ICAM1). Immune landscaping revealed a ten-fold increase in CD103+CD11b+ dendritic cells (DCs), which are not normally abundant in the lungs but restricted to the small intestine. Phenotypic characterization revealed that this subset is activated and immunosuppressive. We observed that tumour-bearing mice that lack the transcription factor interferon regulatory factor 4 (IRF4) have reduced CD103+CD11b+ DCs. Injection of OTI and OTII cells in these mice resulted in higher proliferation compared to their wild type counterparts, indicating that the absence of CD103+CD11b+ DCs is immune promoting. Finally, we showed that the presence of these DCs is dependent on TGFβR signalling as well as ICAM1/2, the latter suggesting a role for vessel co-option in the infiltration of CD103+CD11b+ DCs in KPC lung metastasis.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: R Medicine > RC Internal medicine; R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Supervisor's Name: Carlin, Dr. Leo
• Date of Award: 2023
• Depositing User: Theses Team
• Unique ID: glathesis:2023-83956
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 16 Nov 2023 10:56
• Last Modified: 28 Nov 2025 11:07
• Thesis DOI: 10.5525/gla.thesis.83956
• URI: https://theses.gla.ac.uk/id/eprint/83956