Wei-Ting Lu

Image shows cell types which correlate with increasing chromosomal instability (myeloid populations dominate) and representative images of inflamed, CINhigh tumor and a CINlow tumor

Using snRNA-sequencing (Izar lab @columbiauniversity.bsky.social) with matched multiplex immunophenotypic profiling (@jleslie1.bsky.social) we found tumor cell-intrinsic innate immune activation and intratumoral myeloid infiltration as phenotypic consequences of ongoing micronucleation in EAC. 7/11

Wei-ting Lu presents data from the TRACERx lung cancer study on FAT1 alterations and chromosomal instability.

#AACR2025 | @weitinglu.bsky.social | @crick.ac.uk

The homologous recombination factors BRCA2 and PALB2 interplay with mismatch repair pathways to maintain centromere stability and cell viability Graham et al. demonstrate that BRCA2 and PALB2 protect centromere integrity in non-cancerous cells through distinct mechanisms, partly counteracting the mismatch repair factor MLH1. In cancer cells, B...

We are delighted to share our latest work, characterising the role of BRCA2 and its binding partner PALB2 at centromeres, just out in the latest issue of Cell Reports. ⬇️

www.cell.com/cell-reports...

I got an idea to make you feel *worse* 🙃🙃-- read Michael Lewis's the fifth risk.

We are fortunate to get a trial of the NL5+ confocal system from confocal.nl which is a total gamechanger. @crick.ac.uk @calm-stp.bsky.social just got a NL5+ system after the trial -- can't wait to have more fun with it♥️!! 4/4

The biggest nemesis of live microscopy is light toxicity. The success rate for mitotic imaging is painfully low because one has to balance resolution vs cell death – either you have a blurry movie or a high-resolution movie showing a dead cell. 3/4

The cover is designed by Jeroen at Phsopho Animation,
who converted a mitotis time-lapse movie into some awesome cover art. One can see that chromosomes (white) align and then pulled apart by tubulin (red) as the cell divides, showing lagging chromosomes and chromosomal bridges. 2/4

We’re thrilled to see our research has been highlighted as the cover of NCB this month 🎉 🎉. We are honoured to share this issue with thought-provoking articles investigating multiple aspects of chromosomal instability and mitosis @dfachinetti.bsky.social
@thecesarelab.bsky.social 🧵 1/4

TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling - Nature Cell Biology Lu et al. perform systematic functional analyses using data from the TRACERx cohort of patients with non-small-cell lung cancer and delineate how FAT1 regulates homologous recombination repair, chromo...

We hope this is useful for the field. Our paper can be found here:
www.nature.com/articles/s41...
Or the readcube link below:
rdcu.be/d5gAe
Finally we wish everyone a happy new year!!! 14/end

Finally, a huge thank you to all our funders without which our work would not be possible @crick.ac.uk, Genomics England, @cancerresearchuk.org, @uclh.bsky.social @bcrfcure.bsky.social, Danish Cancer Society, UCL Cancer Institute and @cruk-cityoflondon.bsky.social. 13/14

We thank all our collaborators @mcclellandlab.bsky.social @taponlab.bsky.social @kfugger.bsky.social @nicky Mcgranahan, Nicholas Birbak, Kevin Litchfield and Mariam Jamal-Hanjani. Thank you to the patients and their families, without which we would not be able to start this project. 12/14

This would not be possible w/o the bioinformatics input of @jrmblack.bsky.social @oriolpich.bsky.social Chris Bailey @ruizc.bsky.social, Paco Gimeno-Valiente, Ieva Usaite, Kerstin Thol, Maise Al Bakir & Dhruva Biswas who are dedicated to integrating real-life data with experimental results. 11/14

This work is co-led by @weitinglu.bsky.social and @nnennayakanu.bsky.social lab, with significant input from our long-term collaborator Jiri Bartek . @panoszalmas.bsky.social and high throughput screening core @crick.ac.uk were instrumental in starting this project. 10/14

Now, which of the FAT1 KO phenotypes are due to YAP1 localization? By depleting YAP1 in FAT1 KO cells, we could fully rescue the cytokinesis failure in FAT1 KO. cells, suggesting this is YAP1 dependent. However, the ⏫mitotic error rate was not dependent on YAP1 dysregulation 9/14

How does FAT1 loss lead to its phenotype? We noticed that similar to another key member of the Hippo🦛 pathway LATS1, FAT1 depletion enhances YAP1 nuclear signal. Perhaps LATS1/2 loss contribute to the DDR defects and the phenotypes might be somehow dependent on YAP1? 8/14

How does FAT1 loss cause WGD? Using the FUCCI system in RPE1 cells (thanks to John Diffley lab @crick.ac.uk ) we could track the fidelity of cell division in real-time. The cell without FAT1 failed cytokinesis, could not finish mitosis and remained as 1 daughter cell with 2x the genome content 7/14

We also used live cell imaging to quantify mitotic errors. 6/14

Focusing on CIN, FAT1 loss increased micronuclei formation. FAT1mutant tumours exhibited a higher mutational burden. FAT1 depletion increased ⏫ chromosome number and ⏫radial chromosome structures (blue arrows) and we also observed an⏫ rate of mitotic defects. 5/14

Experimentally, FAT1 depletion reduced ⏬end-resection at DNA double-strand breaks, ⏬HR repair and alternative end-joining, but did not affect cNHEJ. Using TCGA and TRACERx data, we confirmed that FAT1mutant tumours exhibited hallmarks of HR deficiencies like TAI and LST. 4/14

We devised 2 screens to identify drivers that might contribute to both deficiencies in the DNA damage response (DDR) and cause CIN. We focused on a gene called FAT1 (4q35.2), which is extensively mutated/lost in NSCLC before WGD, but we knew little about its function. 3/14

This journey started 7 years ago when we explored the cancer evolution data from TRACERx100, and observed that clonal diversification cooccurs with whole genome doubling (WGD) & extensive chromosomal instability (CIN). Might this be triggered by specific cancer driver events? 2/14

I am happy to see that our paper is out just before the new year!!! We have a lab tweetorial out for anyone interested! Got to say it was an exciting journey working with CharlesSwanton, the wider TRACERx and PEACE team, and @nnennayakanu.bsky.social Jiri Bartek labs. 🧵1/14

Congratulations Simone and team!! Great work!! 🎉🎉🎉

Oh no! Sorry to hear - my condolences.

You probably need to revive your famed cat thread here...😀