Fran Supek

bric.ku.dk

candidate.hr-manager.net/ApplicationI...

📣 Attention postdocs in the life sciences! Are you ready to take the big leap?

Start your lab at the Biotech Research and Innovation Centre in Copenhagen! 🇩🇰 @bric-ucph.bsky.social

Collegial atmosphere, cutting-edge science, core funding.

(+the weather is wonderful, relative to Siberia😁)

Apply!👇

Congrats to colleagues from IRB!

Variable efficiency of nonsense-mediated mRNA decay across human tissues, tumors and individuals - Genome Biology Background Nonsense-mediated mRNA decay (NMD) is a quality-control pathway that degrades mRNA bearing premature termination codons (PTCs) resulting from mutation or mis-splicing, and that additionally participates in gene regulation of unmutated transcripts. While NMD activity is known to differ between examples of PTCs, it is less well studied if human tissues differ in NMD activity, or if individuals differ. Results We analyzed exomes and matched transcriptomes from Human tumors and healthy tissues to quantify individual-level NMD efficiency, and assess its variability between tissues, tumors, and individuals. This was done by monitoring mRNA levels of endogenous NMD target transcripts, and additionally supported by allele-specific expression of germline PTCs. Nervous system and reproductive system tissues have lower NMD efficiency than other tissues, such as the digestive tract. Next, there is systematic inter-individual variability in NMD efficiency, and we identify two underlying mechanisms. First, somatic copy number alterations can robustly associate with NMD efficiency, prominently the commonly-occurring gain at chromosome 1q that encompasses two core NMD genes: SMG5 and SMG7 and additional functionally interacting genes such as PMF1 and GON4L. Second, deleterious germline variants in genes such as the KDM6B chromatin modifier can associate with higher or lower NMD efficiency in individuals. Variable NMD efficiency modulates positive selection upon somatic nonsense mutations in tumor suppressor genes, and is associated with cancer patient survival and immunotherapy responses. Conclusions NMD efficiency is variable across human tissues, and it is additionally variable across individuals and tumors thereof due to germline and somatic genetic alterations.

Check out the full story here:

"Variable efficiency of nonsense-mediated mRNA decay across human tissues, tumors and individuals"

genomebiology.biomedcentral.com/articles/10....

👏👏to Guille for marvelous work!

To NMD or Not To NMD: Nonsense-Mediated mRNA Decay in Cancer and Other Genetic Diseases The nonsense-mediated mRNA decay (NMD) pathway degrades some but not all mRNAs bearing premature termination codons (PTCs). Decades of work have elucidated the molecular mechanisms of NMD. More recent...

Why care? Our prior work (Lindeboom et al., reviewed in www.cell.com/trends/genet... ) + Guille paper supports that NMD

🛑modulates selection on somatic nonsense "driver" mutations
🛑associates w/cancer (immuno)therapy💊response (neoantigens!)
🛑linked w/ severity of inherited genetic disease

👇

A key genetic safeguard works differently across tissues and individuals A puzzling question in molecular biology has been why our bodies do not uniformly eliminate faulty genetic information—especially that which could lead to disease. A key mechanism responsible for this...

Interestingly, genetic variants can change global NMD efficiency in an individual🤔

🧬 inherited variants - SNVs in KDM6B chromatin modifier gene
🧬 somatic variants - copy number alterations at chromosome 1q (SMG5, SMG7...)

Nice IRB writeup here 👇
www.irbbarcelona.org/en/news/scie...

🛑Guille's @guillepalou.bsky.social no-nonsense 😉 paper is out in @springernature.com Genome Biology!

We report variable activity of the NMD pathway (mRNA QC) across tissues & individuals:

🧠less active in the nervous system & in reproductive tissues
🩸more active in digestive tract, muscle, blood

Full dataset here
👇
elsevier.digitalcommonsdata.com/datasets/btc...

Fantastic to be in such great company!🤩

👏Congrats to 19 colleagues from my institutions (🇩🇰BRIC @UCPH_health and 🇪🇸@IRBBarcelona) in this year's Elsevier/Stanford top 2% most cited researchers list

Thanks to organizers for inviting!

🧬New approach to decoding mutational signatures improves prediction of prognosis in #OvarianCancer.

📰 #GenomeMedicine ✍️ Patricia Ferrer-T Iván Galván-F & @fransupek.bsky.social

➡️ bit.ly/4nA579b 📌DOI: 10.1186/s13073-025-01497-7

@genomedatalab.bsky.social @bric-ucph.bsky.social

🧪

Congrats to our CRISPy fresh doctor 👏👏 Marcel McCullough for successfully defending his PhD thesis:

🧬✂️"Combinatorial Gene Editing in Human Cells to Model Deficiencies of DNA Repair in Cancer"

Thx to committee members Julian Ceron, Laura Valle and David Szuts for a great discussion!

Join us at BRIC/FinsenLab -- start your group at the University of Copenhagen!

DiffInvex reveals how cancers rewire driver genes to beat chemotherapy Just as species adapt over generations, our body’s cells accumulate DNA changes throughout life. Most are harmless, yet a few “driver” mutations give a cell a competitive edge and can spark cancer. Ch...

Why care? This gives:
-new resistance biomarkers (eg MAP2K4 in breast)
-framework to compare pre/post-treatment genomes
-warning about "driver genes" that are evol. relics
Huge thanks to funders & bravo to our Ahmed K.!👏

➡️Nice @irbbarcelona.org write-up: www.irbbarcelona.org/en/news/scie...

Bonus analysis: "cancer drivers" that are under selection in healthy tissues🧬.

NOTCH1 (known) and ARID1A mutations promote clonal expansions w/o cancer transformation.

Challenges assumptions about what makes a true driver - maybe some mutations are just along for the ride 4/5

Found 11 genes under therapy-associated selection - some expected (ESR1, EGFR) but surprises too:

💊PIK3CA selected in antiestrogen-treated
💊SMAD4 under pressure in 5-FU-treated
💊STK11 mutations with methotrexate

Resistance often piggybacks onto existing oncogenic programs 3/5

DiffInvex identifies evolutionary shifts in driver gene repertoires during tumorigenesis and chemotherapy - Nature Communications Identifying mutations in cancer that are causal for resistance to chemotherapy remains challenging. Here, the authors develop DiffInvex, a computational framework to identify conditional selection on ...

Chemo changes mutation rates *and* selection pressures - a confounding mess.🔥 DiffInvex cuts through this by using non-coding DNA as evolutionary baseline, separating signal (driver mutations) from noise (therapy-induced mutagenesis) in ~30 cancer types:

🔗 doi.org/10.1038/s414...
2/5

AI-generated illustration of DNA with mutations, cancer cells, and drugs applied to them

🧵 Ahmed’s @genomedatalab.bsky.social paper on evolution of chemotherapy resistance is out @natcomms.nature.com!

We developed DiffInvex - a method tracking how #cancer driver genes change under therapy using ~10k whole-genomes. Key insight: drug resistance often emerges through existing pathways 1/5

Fri forskning styrkes med 52 banebrydende projekter 52 talentfulde forskere skal med deres nyskabende og excellente forskningsprojekter løfte dansk forskning til nye højder. Danmarks Frie Forskningsfond har netop uddelt 318 millioner kroner til forskni...

Grateful for the award of this collaborative project with Claus Sørensen group also at BRIC @bric-ucph.bsky.social; they will apply their #CRISPR-Select method (Niu et al 2022 Nature Genetics) to introduce heterozygous edits into human cells.

Read more at DFF ➡️ dff.dk/om-fonden/ny...

Copy number losses of oncogenes and gains of tumor suppressor genes generate common driver mutations - Nature Communications Inferring the emergence and selection of cancer drivers remains a daunting task. Here, the authors develop MutMatch, a statistical method to analyse somatic mutation rates and estimate conditional sel...

🧬 We aim to identify TSG #mutations that could be #targets for therapeutic inhibition - an idea supported by our recent finding that tumor suppressor #genes, paradoxically, can get copy number gains that drive cancer (Besedina & Supek 2024 Nature Comms nature.com/articles/s41...)

Great news – we received funding from the Independent Research Fund Denmark (DFF)!

🧬We will study #cancer driver mutations in tumor suppressor genes. In particular, we will focus on so-called "dominant negative" mutations, by combining #genomics, #AI & CRISPR gene editing.