Lu Group

Research Summary

Normally, we store our genetic information in 23 pairs of chromosomes. However, cancer cells seldom conform to this number. Rather, cancer cells undergo whole genome doubling to duplicate all their 23 pairs of chromosomes to 46 pairs in one fell swoop. Following this, mutations and chromosomal rearrangements occur repeatedly in cancer cells, resulting in a population of highly variable chromosomal numbers. These events correlate with worse clinical outcomes, drug resistance and cancer metastasis.

Using existing population genomic and clinical data, our lab aims to functionally characterise the events that contribute to whole genome doubling and chromosomal instability. We are interested in FAT protocadherins,  a class of proteins which are often mutated in lung, breast, skin and oesophageal cancers. By understanding the role played by the FAT proteins, we aim to find novel treatment strategies

DPhil project available

Deciphering the Role of Chromosomal Instability and Tumour Microenvironment in Cancer Evolution

Project Overview

The Chromosomal Instability lab is interested in the mechanisms by which cancers karyotype mutates and evolves to become resistant to therapy. By understanding the underlying mechanism driving cancer evolution, we aim to overcome therapy resistance and identify novel therapeutic opportunities. Recently, we have identified that FAT1 alterations, which frequently occur in lung and oesophageal cancers, can lead to whole-genome doubling (WGD) through the dysregulation of the Hippo signalling, and elevated chromosomal instability (CIN) through an elevated rate of micronuclei formation (Lu et al., Nature Cell Biology 2025). WGD creates a tetraploid genome, which can buffer the effects of deleterious mutations and provide a platform for further chromosomal alterations. It has been shown that the combination of WGD and CIN can lead to dismal clinical outcomes. Beyond intrinsic genetic changes, CIN also influence how cancer cells interact with the microenvironment. Through the activation of autocrine signalling, such as IL-6, cancer cells with high CIN can interact with the tumour environment and create a chemo-resistant niche (Gilbert and Hemann, Cell 2010; Hong et al., Nature 2022). Furthermore, this might also increase the possibility of horizontal transfer of genetic material among cancer cells (Xu et al., Cell Discovery 2022). Both phenomena are key contributors to drug resistance in cancer therapy. To visualise the interplay between CIN and microenvironmental changes, this project will generate oesophageal and lung cancer cell line co-culture systems expressing neonGreen-H2B and mCherry-H2B, respectively. Micronuclei formation and transfer rate, cGAS-STING activation rate will be monitored in co-culture experiments using microscopy. The contribution of the tumour microenvironment towards drug resistance rate, particularly the resistance against targeted therapy, will be investigated. The project will improve our knowledge of how microenvironment factors can contribute to cancer evolution trajectory, with the long-term aim to reveal new avenues to overcome drug resistance in highly genomic unstable cancers.

Collaborators

Prof. Eileen Parkes, University of Oxford, UK

Prof. Nnennaya Kanu, University College London, UK

Prof. Fabrice André, Institut Gustave Roussy, France (SCANDARE cohort)

Prof.  Christophe Le Tourneau, Institut Curie, France (SCANDARE cohort)

Dr. Monica Arnedos, Bordeaux Institute of Oncology, France (SCANDARE cohort)

Prof. Sherene Loi, Peter MacCallum Cancer Centre,  Australia (kConFab cohort)

Dr Heather Thorne, Peter MacCallum Cancer Centre, Australia (kConFab cohort)