Stromal interactions in pleural mesothelioma
type: CreativeWork
description: Pleural mesothelioma (PM) is a devastating malignancy primarily related to past asbestos exposure. There are no curative options, and 1-year survival stands currently at just 40%. The genomic landscape in mesothelioma is dominated by loss of function of tumour suppressor genes rather than targetable oncogenes. It is a stromal rich malignancy with cancer cell nuclei frequently accounting for less than 25% of all tumour nuclei. The remainder are largely comprised of stromal cells, the roles of which have been relatively neglected by existing studies. Of particular interest are the cancer-associated fibroblasts (CAF) whose interactions with cancer cells modulates the tumour microenvironment. The rarity of mesothelioma is a challenge to studying its biology since fresh tissue is not reliably available for experimentation. In this thesis, I sought to understand the composition of the tumour stroma in PM to identify interactions between the tumour stroma and malignant mesothelial cells. I generated a single cell transcriptomic dataset from both fresh tissue for single-cell RNA-sequencing, and isolated nuclei from frozen samples for single nuclei RNA-sequencing. Following rigorous quality control, I retained 268,089 cells and nuclei across asbestos exposed benign and malignant pleura. I characterised the heterogenous populations of mesothelial cells identifying various states of trans-differentiation, and discovered a previously unexplored malignant mesenchymal cell population within sarcomatoid PM. I identified key gene regulatory networks that govern the identity of these cells and use in situ hybridisation to spatially localise gene biomarkers specific to distinct states of mesothelial cell trans-differentiation. I then explored CAF heterogeneity revealing both universal and pleura-specific fibroblast subtypes, including a population of myofibroblasts unique to sarcomatoid PM that upregulate genes in Hedgehog signalling pathways. This work advances our understanding of …
abstract: Pleural mesothelioma (PM) is a devastating malignancy primarily related to past asbestos exposure. There are no curative options, and 1-year survival stands currently at just 40%. The genomic landscape in mesothelioma is dominated by loss of function of tumour suppressor genes rather than targetable oncogenes. It is a stromal rich malignancy with cancer cell nuclei frequently accounting for less than 25% of all tumour nuclei. The remainder are largely comprised of stromal cells, the roles of which have been relatively neglected by existing studies. Of particular interest are the cancer-associated fibroblasts (CAF) whose interactions with cancer cells modulates the tumour microenvironment. The rarity of mesothelioma is a challenge to studying its biology since fresh tissue is not reliably available for experimentation. In this thesis, I sought to understand the composition of the tumour stroma in PM to identify interactions between the tumour stroma and malignant mesothelial cells. I generated a single cell transcriptomic dataset from both fresh tissue for single-cell RNA-sequencing, and isolated nuclei from frozen samples for single nuclei RNA-sequencing. Following rigorous quality control, I retained 268,089 cells and nuclei across asbestos exposed benign and malignant pleura. I characterised the heterogenous populations of mesothelial cells identifying various states of trans-differentiation, and discovered a previously unexplored malignant mesenchymal cell population within sarcomatoid PM. I identified key gene regulatory networks that govern the identity of these cells and use in situ hybridisation to spatially localise gene biomarkers specific to distinct states of mesothelial cell trans-differentiation. I then explored CAF heterogeneity revealing both universal and pleura-specific fibroblast subtypes, including a population of myofibroblasts unique to sarcomatoid PM that upregulate genes in Hedgehog signalling pathways. This work advances our understanding of …
author: Veale, Niki
language: eng
keywords: Mesothelioma, Pleural biology, Asbestos, Single-cell transcriptomics
license: https://www.repository.cam.ac.uk/bitstreams/c33bac73-62c7-457c-9ab5-b5b06e97ca7c/download
license: http://purl.org/NET/rdflicense/allrightsreserved
date published: 2025-03-17
date modified: 2026-07-22T22:24:28Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.123097