Meet Dr Wei-Ting Lu: Exploring Genome Instability in Cancer

Meet our group leaders! Dr Wei-Ting Lu joined the Department of Oncology in September 2025, establishing a research group focused on chromosomal instability and whole genome doubling in cancer. Originally from Taiwan, Dr Lu spent most of his childhood in the Malaysian island of Borneo. He did his undergraduate and PhD studies at the University of Sheffield, focusing on genome instability. Dr Lu’s postdoctoral researcher further developed his expertise in genome integrity, as well as working with large-scale, real-world datasets.

In this blog, Dr Lu shares insights into his lab’s research and the discoveries, both his own and those of others, that sparked his interest in the field.

What are the big questions your new research group is trying to answer?

Darwin's famous Tree of Life sketch, 1837

I think there are two very important concepts that have emerged in cancer research over the past decades. Firstly, technological advances in sequencing have provided strong evidence to flesh out the cancer evolution theory first proposed by the late Peter Nowell back in 1975. We are increasingly thinking about cancer through a Darwinian lens and view it as an ever-changing evolutionary process – the more branches there are, the more heterogeneous the cancer is likely to be, and potentially harder to treat.

Secondly, thanks to the work of Inigo Marticorena, Phil Jones, and many others, we know that normal cells can be littered with cancer driver mutations as we age. Yet most of these cells never become cancerous.  A major unresolved question is  why these normal cells get the same TP53 driver mutations but don’t transform to cancer! 

Peter Nowell’s clonal evolution theory, Science 1975.

Taken together, these findings encourage the field to re-examine our current understanding of tumour initiation.  The advent of the Cancer Genome Atlas and longitudinal patient cohorts enable us to annotate of the cancer evolutionary process in much greater detail (the x-axis/time element of Peter Nowell’s tree). Multiple findings show that the branching points of the cancer evolutionary tree coincide with whole-genome doubling and chromosomal instability.

These are two processes that reinforce each other. Chromosomal instability alters the number of chromosomes in a cell, and therefore the number of copies of the genes they carry, which generates genetic diversity on which selection can act, driving cancer cells to diversify, adapt and colonise. However, losing genetic material can be detrimental in the long run, because once a gene is lost, one can never gain it back. One way cancer cells may buffer the detrimental effects of chromosomal instability, such as the loss of essential genes and the resulting reduction in cellular fitness, is whole-genome doubling, where the cell duplicates its entire chromosome set and is associated with poor clinical prognosis.

Here at Oxford, we are trying to understand which mutations can trigger whole-genome doubling and chromosomal instability in one fell swoop, creating new branchers in the cancer evolutionary tree. Initially, we are going to focus on investigating the roles of FAT protocadherin genes. I believe by working closely with our medical colleagues, we can identify more of these genes that lead to both whole-genome doubling and chromosomal instability.

What prior work led you to establish a research group focused on chromosomal instability in cancer? 

I have always been fascinated by how different cell types maintain their genomes, given that every chromosome comes in pairs (except sex chromosomes). Imagine you have 2 sets of everything in your home with a very busy lifestyle; sometimes one might get lazy in maintenance and let some things to fall into disrepair!

My first postdoctoral position after my PhD was a detour into RNA biology with Prof. Martin Bushell, where I investigated how cells orchestrate RNA transcriptional and translational outputs, particularly when their DNA is damaged. This work lead to some high-impact papers, but I had always want to work more closely with real-life datasets. My second postdoctoral position was with Prof. Charles Swanton at the Francis Crick Institute, where I had the opportunity to connect what I had learnt about genomic instability with a longitudinal cancer patient cohort. With a longitudinal cohort, researchers can track the cancer’s mutational history with an evolutionary lens, creating an unique opportunity to functionally dissect how one mutational event can lead to the next step of the cancer evolutionary process.

We spent a lot of time with our medical colleagues trying to identify genes that contribute to both whole-genome doubling and chromosomal instability. We identified one such gene, FAT1, which is frequently mutated in lung cancer and oesophageal cancer. We went on to prove that its loss can lead to the dysregulation of a signalling pathway called the Hippo pathway, a signalling pathway often disrupted in cancer. We still do not know how exactly FAT1 loss leads to chromosomal instability, although our evidence suggests that it may reduce the accuracy of DNA repair. We are now developing more molecular tools to further study FAT1 and proteins related to FAT proteocadherins.

Why is this area of research important right now?

We are entering a golden era of cancer research, where a lot of things that were unthinkable previously are suddenly becoming reality. After decades of research, mutant RAS became druggable; researchers are exploring clinical trials to vaccinate against cancer, or even utilising CRISPR technologies to directly target cancer cells (Zeng et al, Nature 2026)!!

Understanding whole-genome doubling and cancer evolution, particularly in early cancer, is therefore increasingly important. For the first time in decades, we have a growing set of powerful tools to detect, intercept and treat cancer. Understanding the evolution roadmap of cancer will allow us to better identify the what sort of character the tumour is going to shapeshift into during disease progression and allow us to intervene one step earlier.

What are you enjoying/looking forward to exploring in Oxford?

My partner has been working in Oxford since 2018, so our commute was always quite a chore – I took the train to London, and she spent a lot of time getting stuck on the A418. I am actually enjoying my 15-minute commute by bike now, which has given us back 2-3 hours of each day!

In a new era of cancer research driven by unprecedented technological advances and data availability, Dr Lu aims to better understand the events that contribute to whole genome doubling and chromosomal instability. Thought to play an important role in how tumours adapt and progress, identifying novel genetic drivers may uncover new opportunities for cancer treatment. If you are interested in genomic and chromosomal instability and want to find out more about opportunities to join the Lu lab, you can reach out to Dr Wei Ting Lu.