A novel cell line panel reveals non-genetic mediators of platinum resistance and phenotypic diversity in high grade serous ovarian cancer
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Objectives: Resistance to cancer therapy is an enduring challenge and accurate and reliable preclinical models are lacking. We interrogated this unmet need using high grade serous ovarian cancer (HGSC) as a disease model. Methods: We created five in vitro and two in vivo platinum-resistant HGSC models and characterised the entire cell panel via whole genome sequencing, RNASeq and creation of intraperitoneal models. Results: Mutational signature analysis indicated that platinum-resistant cell lines evolved from a pre existing ancestral clone but a unifying mutational cause for drug resistance was not identified. However, cisplatin-resistant and carboplatin-resistant cells evolved recurrent changes in gene expression that significantly overlapped with independent samples obtained from multiple patients with relapsed HGSC. Gene Ontology Biological Pathways (GOBP) related to the tumour microenvironment, particularly the extracellular matrix, were repeatedly enriched in cisplatin50 resistant cells, carboplatin-resistant cells and also in human resistant/refractory samples. The majority of significantly over-represented GOBP however, evolved uniquely in either cisplatin- or carboplatin52 resistant cell lines resulting in diverse intraperitoneal behaviours that reflect different clinical manifestations of relapsed human HGSC. Conclusions: Our clinically relevant and usable models reveal a key role for non-genetic factors in the
evolution of chemotherapy resistance. Biological pathways relevant to the extracellular matrix were repeatedly expressed by resistant cancer cells in multiple settings. This suggests that recurrent gene expression changes provide a fitness advantage during platinum therapy and also that cancer cell intrinsic mechanisms influence the tumour microenvironment during the evolution of drug resistance. Candidate genes and pathways identified here could reveal therapeutic opportunities in platinum60 resistant HGSC.
evolution of chemotherapy resistance. Biological pathways relevant to the extracellular matrix were repeatedly expressed by resistant cancer cells in multiple settings. This suggests that recurrent gene expression changes provide a fitness advantage during platinum therapy and also that cancer cell intrinsic mechanisms influence the tumour microenvironment during the evolution of drug resistance. Candidate genes and pathways identified here could reveal therapeutic opportunities in platinum60 resistant HGSC.
Date Issued
2022-10-01
Date Acceptance
2022-07-23
Citation
Gynecologic Oncology, 2022, 167 (1), pp.96-106
ISSN
0090-8258
Publisher
Elsevier
Start Page
96
End Page
106
Journal / Book Title
Gynecologic Oncology
Volume
167
Issue
1
Copyright Statement
© 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
License URL
Sponsor
Imperial College Healthcare NHS Trust- BRC Funding
Ovarian Cancer Action
National Institute for Health Research
Grant Number
RDB01
n/a
NIHR202372
Subjects
Chemotherapy
Drug resistance
Evolution
Extracellular matrix
Gene expression
High grade serous ovarian cancer
Non-genetic
Platinum
Transcription
Oncology & Carcinogenesis
1112 Oncology and Carcinogenesis
1114 Paediatrics and Reproductive Medicine
Publication Status
Published
Date Publish Online
2022-07-30