Modeling brain cancer with CRISPR

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We are proud to announce that our latest manuscript: “Somatic chromosomal engineering identifies BCAN-NTRK1 as a potent glioma driver and therapeutic target”, has been just published in Nature Communications. This work was the result of a truly collaborative effort  between our lab and the lab ot our neighbors at MSKCC: Robert Benezra and Maurizio Scaltriti. A follow-up to Danilo Maddalo’s work, this project used CRISPR-based somatic genome editing to model a set of rare genomic rearrangements responsible for  brain cancer-associated gene fusions. Peter J. Cook, is the lead author of this paper and is a joint postdoctoral fellow between the Ventura and the Benezra lab, and the project was funded by the Pershing Square Sohn Cancer Foundation and by the Brain Tumor Center at MSKCC.

BCAN_NTRK1_IMAGE.001Peter’s initial goal was to use CRISPR-Cas9 to model a set of uncharacterized, potentially oncogenic chromosomal rearrangements in the brain. Four gene fusions identified from human glioma patient RNA-Seq data were selected and the chromosomal inversions, deletions, and duplications underlying these fusions were modeled in mouse adult neural stem cell primary cultures and directly in the brain using adenovirus-mediated in vivo genome editing. He found that a chromosomal deletion resulting in the fusion between the secreted proteoglycan Bcan and the receptor tyrosine kinase Ntrk1 was capable of  transforming p53-null neuronal stem cells cells, resulting in high grade gliomas by either in-vitro orthotopic stem cell implantation or by direct in-vivo viral induction. Interestingly, we also found that these tumors were  sensitive to a small molecule kinase inhibitor specific to Ntrk1.

figure_3_cook.jpgWe are excited about this work not only because it resulted in a new a clinically relevant genetically-engineered mouse model for human glioma, but also because it provides an experimental pipeline that can be readily adapted to interrogate a wide range of brain cancer associated  mutations of unknown functional significance.

 

A goodbye and a welcome

Last Friday was Stephanie Cervino’s last day in our lab. Our fearless admin assistant/lab manager/organizer is going back to school. Needless to say, Stephanie will be missed by us all, but we are comforted by the hope that she will not forget us, and by the certainty that she will do great things! Good luck, Stephanie!

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If Friday was a bitter-sweet day, Monday was simply sweet, as Sandra Casseus started her first official day in the lab. In truth, Sandra has been shadowing Stephanie for the past couple of weeks, learning all the tricks to manage our crazy lab, so we already got to know and appreciate her. Welcome, Sandra!

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Introducing GuideScan

Screen Shot 2017-05-26 at 4.00.30 PMThe Ventura lab, in collaboration with the Leslie lab, is proud to introduce GuideScan, a new open source software and a companion website that we hope will greatly simplify and improve the design of CRISPR libraries.

The GuideScan website allows users to design gRNAs for SpCas9 or for Cpf1 for the most common model organisms, while the command line tool is fully customizable and allows the more experienced users to generate gRNA database for any genome of interest and for any RNA-programmable endonucleases.

The algorithm GuideScan uses to identify gRNAs is different from most other currently available online tools, and guarantees that the gRNAs returned  will have no perfect or near perfect off target sites elsewhere in the genome. It also return the total number and the location of potential off target sites with 2 or 3 mismatches.

Another advantage of GuideScan is that it allows to generate paired gRNAs libraries with a simple mouse click. Simply input a list of genomic coordinates in any of the supported formats (or upload a file), choose whether you want single gRNAs cutting within the each genomic region, or pair of gRNAs flanking it, and then click the ‘Guide Me’ button. For more details, please checkout our Nature Biotechnology paper.

Kudos to Alex, Yuri, and Joana for leading this project and bringing it to completion in record time!

 

Ad majora, Ciro!

5Today is the last (official) day in the lab for Ciro Bonetti (aka Ciruzzo), one of our senior postdocs. Ciro is leaving to begin a new and exciting adventure at Regeneron. To say that Ciro will be missed is a big understatement and while we are happy for him, he leaves a hole that will be very difficult to fill.

Ciro begun his scientific career in the beautiful city of Naples and, as many Italian aspiring scientists do, came to the US for his postdoctoral training. We have been incredibly lucky to have him in the lab;  during the past six years Ciro contributed to many exciting projects. He was the first to work on lncRNAs in our lab, and thanks to his results we were able to obtain NIH funding. As part of this work he generated four different genetically engineered mouse strains, whose characterization will keep us busy for  years to come.
Together with Joana (another postdoc that soon will start her independent career), Ciro also lead  an exciting project on improving CRISPR-based gene replacement efficiency. This work is nearing completion and hopefully you will hear more about it in the not so distant future on this blog!

In addition to his remarkable scientific accomplishments, Ciro has been a generous and friendly lab member, an outstanding volleyball player, an assiduous concert goer, and a truly nice guy. The sadness of seeing him leave is attenuated by the fact that Ciro will remain in NYC, and we are sure he will not forget his friends and colleagues here at MSKCC.
Ad majora, Ciruzzo!

The beginning

By Andrea Ventura

Today we are launching our new website. Our goal is to give you a sense of what we do in the lab and out of the lab. Here you will find our latest research news, topics that we find interesting, papers for our weekly journal club, and much more…

I want to start with a few pictures I took on the first week of my career as a lab head, back in late 2008. I had done my postdoctoral training in Boston, in the amazing lab of Tyler Jacks at the MIT Center for Cancer Research (now Koch Institute), and the excitement of starting a new adventure was mixed with the fear of having to begin from scratch: hiring my collaborators, unpacking the tools and reagents, and starting an hopefully successful research program. For the first time I realized that I was really on my own!

The next eight years since that initial day have been an amazing adventure. I have been blessed by the trust of so many collaborators who decided to believe in this project and joined what at the time was an empty lab space and a very risky bet. This site is also a way to thank all of them, hoping that the next eight years will be equally exciting and fruitful.