The Chromosomal Instability Lab
Meet the Team
Dr Audrey Lumeau
Postdoctoral Researcher
Pancreatic Cancer UK
Tracking genome evolution in pancreatic cancer Pancreatic cancer is a very aggressive cancer with poor prognosis and still too few therapeutic options for patients. My work aims to track genome evolution of pancreatic cancer primary cells and patient-derived organoids to study intra-population heterogeneity, ongoing chromosome instability and their relationship with chemoresistance. The project is based on a method to generate clones from single cells of a parental population and monitor single-cell clone growth over time, study their copy number alteration profile via single-cell DNA sequencing, their segregation error rate via imaging and their sensitivity to chemotherapies. These experiments are also performed under the pressure of chemotherapies, relevant for pancreatic cancer patients, to induce selection and/or adaptation and identify patterns of copy number alterations in the emerging clones, potentially predictive of chemoresistance. The end goal of this project is to better understand pancreatic cancer biology and help guide therapeutic strategies to counteract chemoresistance in pancreatic cancer.
Dissecting how different modalities of radiotherapy impact CNA patterns My previous projects have included determining how inducing either mitotic defects or DNA replication stress in stable diploid cells can generate reproducible patterns of aneuploidy. This may partially explain why we see such patterns in cancer genomes. I also examined the mechanisms driving chromosomal instability (CIN) in high grade serous ovarian cancer and how they relate to therapy resistance. My current project focuses on how radiotherapy affects both normal and cancerous breast cells. I am studying how different modalities of radiotherapy can induce DNA damage, triggering different DNA repair mechanisms, and then how that is related to formation of copy number alterations (CNAs) in the genome at the single-cell level. I hope to establish “repair profiles” of normal and cancerous cells which could be exploited to help us sensitise cancer cells to lower doses of radiotherapy and thus spare healthy tissue from side effects of therapy.
Dr Nadeem Shaikh
Staff Scientist
Cancer Research UK
Dissecting how different modalities of radiotherapy impact CNA patterns My previous projects have included determining how inducing either mitotic defects or DNA replication stress in stable diploid cells can generate reproducible patterns of aneuploidy. This may partially explain why we see such patterns in cancer genomes. I also examined the mechanisms driving chromosomal instability (CIN) in high grade serous ovarian cancer and how they relate to therapy resistance. My current project focuses on how radiotherapy affects both normal and cancerous breast cells. I am studying how different modalities of radiotherapy can induce DNA damage, triggering different DNA repair mechanisms, and then how that is related to formation of copy number alterations (CNAs) in the genome at the single-cell level. I hope to establish “repair profiles” of normal and cancerous cells which could be exploited to help us sensitise cancer cells to lower doses of radiotherapy and thus spare healthy tissue from side effects of therapy.
Dr Sarah Johnson
Postdoctoral Researcher
BBSRC
The role of ZFP64 in centromere function and chromosomal instability in cancer In my previous project, we addressed the lack of model systems for exploring the impact of specific chromosomal alterations on cell biology by developing a method to induce such alterations in cells. Now in my current project I am investigating drivers of chromosomal instability. Although we understand several processes that become dysfunctional in cancer and fuel instability, many of the specific molecular drivers that underlie this remain unclear. My project focuses on the potential contribution of one such gene; ZFP64. We have found ZFP64 to be frequently overexpressed in chromosomally-unstable cancers. Through our investigation of ZFP64 function, we have uncovered fundamental roles for ZFP64 in maintaining accurate chromosome segregation and at the centromere. Our work on this project is now focussed on unravelling how ZFP64 activity is regulating centromere function, and whether it could promote centromere dysfunction in colorectal cancer.
Dissecting how different modalities of radiotherapy impact CNA patterns My previous projects have included determining how inducing either mitotic defects or DNA replication stress in stable diploid cells can generate reproducible patterns of aneuploidy. This may partially explain why we see such patterns in cancer genomes. I also examined the mechanisms driving chromosomal instability (CIN) in high grade serous ovarian cancer and how they relate to therapy resistance. My current project focuses on how radiotherapy affects both normal and cancerous breast cells. I am studying how different modalities of radiotherapy can induce DNA damage, triggering different DNA repair mechanisms, and then how that is related to formation of copy number alterations (CNAs) in the genome at the single-cell level. I hope to establish “repair profiles” of normal and cancerous cells which could be exploited to help us sensitise cancer cells to lower doses of radiotherapy and thus spare healthy tissue from side effects of therapy.
Dr Molly Guscott
Postdoctoral Researcher
Cancer Research UK
Evaluating the impact chromosomal instability has on genomic evolution The research for my PhD is about understanding how chromosome instability impacts ongoing genomic evolution, including differences dependent on the mechanisms of CIN, as well as how these impact the response to therapy. I use High Grade Serous Ovarian Cancer, a cancer that has a extremely high occurrence of chemotherapy resistance and is a highly chromosomally unstable cancer type, as a model to investigate these questions. This includes using in vitro cell biology, syngeneic in vivo models and computational methods to interrogate genomic changes in different CIN environments.
Dr James Scarth
Postdoctoral Researcher
MRC
Tracking genomic instability from HPV infection to cancer initiation My project focusses on understanding the contribution of oncogene-induced replication stress (Oi-RS) to chromosomal instability (CIN) during cervical cancer initiation. Oncogenic HPV infection is known to induce replication stress and genomic instability in the host cell, but a mechanistic understanding of how this contributes to carcinogenesis is currently lacking. Working with collaborators at the University of Birmingham and the University of Cambridge, I am using primary human keratinocyte-based models of HPV infection and disease to address this question. We are using a combination of in vitro cell biology assays, long read sequencing and single cell sequencing to reveal the interplay between Oi-RS, mitotic dysfunction and genomic instability during the progression from initial HPV infection to cervical cancer.
Dissecting how different modalities of radiotherapy impact CNA patterns My previous projects have included determining how inducing either mitotic defects or DNA replication stress in stable diploid cells can generate reproducible patterns of aneuploidy. This may partially explain why we see such patterns in cancer genomes. I also examined the mechanisms driving chromosomal instability (CIN) in high grade serous ovarian cancer and how they relate to therapy resistance. My current project focuses on how radiotherapy affects both normal and cancerous breast cells. I am studying how different modalities of radiotherapy can induce DNA damage, triggering different DNA repair mechanisms, and then how that is related to formation of copy number alterations (CNAs) in the genome at the single-cell level. I hope to establish “repair profiles” of normal and cancerous cells which could be exploited to help us sensitise cancer cells to lower doses of radiotherapy and thus spare healthy tissue from side effects of therapy.
