Gabriele Picco

COLO-REACH UK = the new name for the EOCRC Research Consortium (REsearch in Early Age Colorectal cancer Hub) supporting collaboration between UK clinical academics and patients in research of bowel cancer in people below age 50 years @bowelcanceruk.bsky.social

Thanks, Ryan, for highlighting this very interesting study. Am I missing the other three, excluding Fielden et al. and this one?

Huge thanks to colleagues at the Wellcome Sanger Institute, and to collaborators at GSK, IDEAYA, the Candiolo Cancer Institute IRCCS, the Babraham Institute, and all partners who make this work possible. @mgarnett.bsky.social @mattcoelho.bsky.social @houseleylab.bsky.social @emanuelvgo.bsky.social

On-target mutations confer resistance to WRN helicase inhibitors in Microsatellite Unstable Cancer Cells. Werner helicase inhibitors (WRNi) are in clinical development for microsatellite-unstable (MSI) tumors with defective DNA mismatch repair. Here, we investigate how cancer cell evolution shapes respons...

This and much more in our new preprint!

www.biorxiv.org/content/10.6...

Resistance is not uniform.
Some hotspot mutations remain sensitive to distinct WRN inhibitors → sequential targeting possible.

Recurrent WRN hotspots in ctDNA could detect emerging resistance and guide therapy adaptation.

To some extent, WRN inhibitors used upfront alone or with chemotherapy can delay or prevent the emergence of resistance in MSI models.

Intronic alterations that truncate exon 13 are associated with WRN inhibitor resistance while preserving enough function for MSI cell survival.

These would be missed by panel sequencing → WGS matters for tracking resistance routes.

Semi-saturation mutagenesis of WRN identifies recurrent hotspot mutations that preserve WRN function while reducing inhibitor activity.

These same variants emerge during prolonged WRN inhibitor treatment in preclinical MSI models, including in vivo in patient-derived xenografts.

WRN loss is lethal in MSI tumours.
No gene knockout enables sustained survival without WRN.

Some DNA repair factors, including SMARCAL1 and ATM, are associated with variation in WRN inhibitor sensitivity, but the fundamental dependency remains.

WRN inhibitors are being tested in patients with MSI cancers. How do tumours adapt to WRN inhibition, and can therapy stay ahead of resistance?

Our latest preprint investigates how MSI tumours evolve under pressure from WRN inhibition. Highlights below.

We had the 3rd meeting of the UK EOCRC Research Consortium in beautiful Edinburgh yesterday supported by British Society of Gastroenterology (BSG) and @bowelcanceruk.bsky.social attended by over 50 UK academics - celebrating our first project funding success only 1 year after foundation

Very cool story and especially useful mathematical models for everyone to use! Check it out!!!

Epigenetically driven and early immune evasion in colorectal cancer evolution - Nature Genetics This study nominates immune escape as an early event in colorectal cancer and shows how this can be driven through both genetic and epigenetic changes.

New @natgenet.nature.com paper from the brilliant @eszterlakatos.bsky.social presents evidence that chromatin alterations disrupt antigen presentation & neoantigens in colorectal cancer. Also that immune escape is part of the "Big Bang", at the outset of CRC growth. www.nature.com/articles/s41...

Thanks, Isabelle! I was watching you draw while taking notes on the other speaker — very impressed!

Thanks Isabelle. Wonderful experience presenting our work @mgarnett.bsky.social #genomicsatscale25! Thanks for having me!

Somatic mutation and selection at population scale - Nature A new version of nanorate DNA sequencing, with an error rate lower than five errors per billion base pairs and compatible with whole-exome and targeted capture, enables epidemiological-scale studies of somatic mutation and selection and the generation of high-resolution selection maps across coding and non-coding sites for many genes.

Our latest work is out in Nature today. In this paper, we introduce an improved version of NanoSeq, a duplex sequencing protocol with <5 errors per billion bp in single DNA molecules, and use it to study the somatic mutation landscape of oral epithelium in >1000 people www.nature.com/articles/s41...

DNA mutagenesis driven by transcription factor competition with mismatch repair Competition between transcription factors and mismatch repair machinery drives localized hypermutation at regulatory elements, with implications for cancer and genome evolution.

I'm very pleased to announce the official publication of our lab's paper "DNA mutagenesis driven by transcription factor competition with mismatch repair" in today's issue of Cell! www.cell.com/cell/abstrac...

depmap miner logo

The Garnett Lab is excited to launch DepMap Miner, a new tool to explore cancer dependency data!
Built on the Sanger DepMap, the DepMap Miner brings together multi-omic and functional datasets for over 1300 cancer cell models.

Start mining data now: dataminer.depmap.sanger.ac.uk

Fluctuating DNA methylation tracks cancer evolution at clinical scale - Nature Cancer evolutionary dynamics are quantitatively inferred using a method, EVOFLUx, applied to fluctuating DNA methylation.

new out in Nature www.nature.com/articles/s41...

Ongoing genome doubling shapes evolvability and immunity in ovarian cancer - Nature A single-cell sequencing study using more than 30,000 tumour genomes from human ovarian cancers shows that whole-genome doubling is an ongoing mutational process that drives tumour evolution and disru...

Goldschmidt's hopeful monsters in cancer: single cell DNAseq shows whole genome doubling (WGD) is an ongoing and frequent mutational process in ovarian cancer. www.nature.com/articles/s41... beautiful work from @sohrabshah.bsky.social and team

Cytidine diphosphate diacylglycerol synthase 2 is a synthetic lethal target in mesenchymal-like cancers - Nature Genetics The paralogs cytidine diphosphate diacylglycerol synthase 1 and 2 form a potentially targetable synthetic lethal relationship in mesenchymal-like cancers that involves disruption of lipid metabolism.

www.nature.com/articles/s41...

Cytidine diphosphate diacylglycerol synthase 2 is a synthetic lethal target in mesenchymal-like cancers

On behalf of InSiGHT, we are delighted to welcome you to the #InSiGHT2026 meeting in Singapore, taking place from 4 – 7 March 2026 #LynchSyndrome #Polyposis @cgaigc.com @stmarksgenomics.bsky.social

insight2026.org

Changes to the 2026 and 2027 Work Programmes With the launch of the competitions for grants under ERC Work Programme 2026 in July of this year, several changes to the submission of applications and the evaluation of proposals will apply. The mai...

Planning to apply for #research #funding from the ERC?

From the next application rounds, expect changes to the:

• proposal structure
• evaluation process
• extra funding you can request
• eligibility for Starting & Consolidator #Grants (from 2027)

More 👇 europa.eu/!RPHWvv

🚨 Excited to share our latest preprint!
@mgarnett.bsky.social @mattcoelho.bsky.social
We introduce BEstimate, a flexible, comprehensive tool for designing and interpreting CRISPR-based editing experiments.
#CRISPR #BEstimate #BaseEditor

How does tumour heterogeneity arise? How can we predict cancer cell plasticity? In 2 new studies, we trace #glioblastoma heterogeneity to a spatial cancer cell trajectory w. multimodal cell atlassing bit.ly/4mkrWgs & predict plasticity w. snRNA/ATAC+deep learning bit.ly/3FbI6Ic 🧵

Great to see WRN featured in the #AACR25 Special Session on 'Bringing Science to the Clinic: Overcoming Hurdles for Therapeutic Translation.' Grateful to Tim Yap for highlighting our past and ongoing work!

Great talk by Yanhua Rao at #AACR2025 on GSK’s new clinical WRN inhibitor. Proud to see our unpublished data spotlighted for revealing new MoA insights. Exciting times ahead! @mgarnett.bsky.social

CRISPR screens in the context of immune selection identify CHD1 and MAP3K7 as mediators of cancer immunotherapy resistance Cancer immunotherapy is only effective in a subset of patients, highlighting the need for effective biomarkers and combination therapies. Here we systematically identify genetic determinants of cancer...

A fantastic collaboration with Emile Voest’s lab at NKI, the new @mattcoelho.bsky.social group. WG CRISPR screens in MSI organoids co-cultured with autologous reactive T cells! Amazing work from Alex Watterson! New preprint here: www.biorxiv.org/content/10.1...
#Organoids #Immunotherapy #CRISPR #MSI

6 years from WRN:MSI discovery to first-in-human trial data — incredible. A fantastic journey. Now, hoping for exciting news at AACR and real impact for patients real soon! #CancerResearch

Just landed in Chicago for #AACR25 — Millennium Park in bloom! Excited for team talks on WRN inhibitors in MSI cancers, with first-in-human data discussed by @mgarnett.bsky.social at the Clinical Trials Plenary. I’ll present new data on WRNi-driven evolution — Poster #420! #MSI #SyntheticLethality