Benjamin D. Greenbaum

Thank you @mskcancercenter.bsky.social for highlighting our work on #viralmimicry in our genome, its evolution, the selective forces on it, and its potential role in cancer.

A great years long collaborative effort with @petrsulc.bsky.social, @daniel-decarvalho.bsky.social, & many great colleagues!

I would usually write a summary but I will defer to the text this time and just express thanks for the interactions and experiences this work generated. Its been a gateway into a lot of fun science that we are still unpacking...

It also required an amazing set of deep collaborations: particularly @daniel-decarvalho.bsky.social
(whose work motivated a lot of our thinking) and John Lacava who went all in for this work with their great labs and colleagues.

Trying to answer these questions required a theoretical framework at the intersection of physics, machine learning and evolutionary dynamics that our lab most enjoys - led by Petr Šulc, long-time collaborators at Ecole Normale in Paris, and our amazing lab at @mskcancercenter.bsky.social

* How, exactly, do we quantify viral mimicry: the expression of features associated with "nonself "viruses by our own "self" cells?
* Why do we see mimicry in so many disease settings such as cancer?
* How broad a phenomena is this?
* How do we think about selection in this evolutionary context?

Sharing a paper below in Cell Genomics @cellpress.bsky.social
that took us literally 10 years+ (!) to write on the topics of:

Repeats mimic pathogen-associated patterns across a vast evolutionary landscape An emerging hallmark of disease is transcription of pathogen-associated molecular patterns from within the genome–known as viral mimicry. We propose a statistical physics framework to measure “selecti...

Excited to have this paper out today!

Repeats mimic pathogen-associated patterns across a vast evolutionary landscape."

It was a fun and productive collaboration with Benjamin Greenbaum John LaCava, Simona Cocco, Petr Šulc and many others!

www.cell.com/cell-genomic...

Repeats mimic pathogen-associated patterns across a vast evolutionary landscape An emerging hallmark of disease is transcription of pathogen-associated molecular patterns from within the genome–known as viral mimicry. We propose a statistical physics framework to measure “selecti...

Nice to see this story out! The idea that viral mimicry is an intrinsic feedback mechanism for sensing cellular dysregulation is fascinating and this paper explores this idea really well.

It was inspiring to be part of this collaborative work. Thanks to @bengrbm.bsky.social and the rest!

Early registration rates end this coming Monday for #mDNASRC. Join your colleagues in beautiful Porto alongside organizers like @bengrbm.bsky.social. Save your space: buff.ly/P6hZjQz

MSK is pleased to announce @time.com has named two MSK physician-scientists, Dr. Andrea Cercek and Dr. Vinod Balachandran, to the 2025 TIME100 Health, a list of the most influential individuals in health and medicine who have made significant contributions to industry.

Learn more: bit.ly/3GGblTR

Call for abstracts! #mDNASRC is in beautiful Porto this year! Organizers @bengrbm.bsky.social, John LaCava, Zhao Zhang, and Vera Gorbunova may select you for a poster session or short talk. You can even register now and submit your abstract later. Save your space: buff.ly/PAKp55o

Come out tomorrow at 10 am to learn about transposable elements in cancer - it will be a great session with @chiappinellilab.bsky.social & Ting Wang #AACR25! @theaacr.bsky.social

Could blocking ‘jumping genes’ help fight disease and aging? The first clinical trials are testing inhibitors of transposons, DNA sequences that hop around the genome on their own

Great article in @science.org highlighting our efforts to target the #darkproteome!

Nice to see our colleagues David Ting, Daniel De Carvalho, and Marty Taylor highlighted along with the amazing work of @rometx.bsky.social👇👇👇

www.science.org/content/arti...

#mDNASRC is back and stronger than ever after 30 years! Discover how transposable elements shape our genomes and impact health, featuring keynote speaker @bengrbm.bsky.social, and more! Save your space: buff.ly/QiSc4E6

Thank you @mskcancercenter.bsky.social for highlighting our work and our great collaborators!

Most importantly our work could not have happened without the support of the National Cancer Institute. The ability to receive NIH funding and interact with our colleagues there was critical to the growth of this work and our lab.

Structures, functions and adaptations of the human LINE-1 ORF2 protein - Nature X-ray crystallography, cryo-electron microscopy, structural modelling, biochemistry, cell biology, and evolutionary analysis enable characterization of ORF2p, the reverse transcriptase of the ancient ...

Understanding LINE-1's role in cancer is therefore a fundamental evolutionary problem and offers a potential therapeutic index for immune and other strategies that target its mechanism (such as the RT pathway see below) 👇👇👇

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

National Center for Biotechnology InformationTwitterFacebookLinkedInGitHubNCBI Insights BlogTwitterFacebookYoutube

We found other genes associated with LINE-1 beyond p53.

We also found activity in Li-Fraumeni Syndrome, a pre-disposition syndrome associated with p53 mutations. Finally, we deposited our estimates of germline activity on dbGAP, one of the largest datasets on the topic:

ncbi.nlm.nih.gov/gap/

The main predictor of LINE-1 activity is if p53, the most mutated gene in cancer, is mutated. This is a deep evolutionary relationship. We mathematically modeled the dependence of LINE-1 action on p53 status, finding a mixture of transcriptional and genomic regulation:

We were able to rank tumor types by their "RT burden" - the degree to which new LINE-1 insertions happen in the self genome & also capture locus specific transcriptional heterogeneity:

We were able to quantify lots of interesting events, such as the rate LINE-1 inserts inverted copies, important for the generation of #viralmimicry through creation of "non-self" double-stranded RNA in the self genome.

We recently explored this phenomena in cancer below:

cell.com/immunity/pdf/S

GitHub - Rome-Tx/totalrecall Contribute to Rome-Tx/totalrecall development by creating an account on GitHub.

We quantified the landscape of LINE-1 activity in the now ~5000 whole genomes and transcriptome datasets in the Cancer Genome Atlas. We built our own caller TotalReCall to measure how often LINE-1 copies itself in cancer. TotalReCall is publicly available:

github.com/Rome-Tx/tota...

Our latest work on the #darkgenome is out now in @naturecomms.bsky.social. LINE-1 is the only known autonomous retrotransposon still active in our genome. Co-led by our Alexander Solovyov @MSKCancerCenter - our work was also great collaboration with @rome_tx 👇👇👇

nature.com/articles/s4146

We’re excited to announce a new publication in Nature Communications: the first large-scale, pan-cancer analysis of LINE-1 expression levels and retrotransposition (RT) activity. These data demonstrate the potential for precision LINE-1 RT-targeted therapeutic approaches. rometx.com/press-releas...

RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancer - Nature In a phase 1 trial, patients with pancreatic ductal adenocarcinoma who were treated with surgery and bespoke neoantigen mRNA vaccines combined with anti-PD-L1 and chemotherapy exhibited marked lo...

An new publication in @Nature by SU2C Convergence Team leaders @thevinodlab.bsky.social @bengrbm.bsky.social @mskcancercenter.bsky.social showed an individualized neoantigen mRNA vaccine for #pancreaticcancer led to prolonged survival and effector T cell responses www.nature.com/articles/s41...

(1/2) Results from a phase 1 clinical trial of the #mRNA-based therapeutic cancer vaccine autogene cevumeran for treating #pancreaticcancer is published in @nature.com. bit.ly/4b9ofEZ

Cancer cells restrict immunogenicity of retrotransposon expression via distinct mechanisms Overexpression of transposable elements is a common feature of cancer. Sun, You, et al. show that, in pancreatic ductal adenocarcinoma, tumor cells adapt through different mechanisms to mitigate a spe...

A new study in @cellpress.bsky.social Immunity from the lab of Dr. Benjamin Greenbaum provides insights into how #PancreaticCancer cells accommodate active retrotransposons without triggering the innate immune response. #oncsky #medsky