It is part of a very productive, long-term collaboration of my lab with the lab of Monte Winslow (http://winslowlab.stanford.edu ). This paper also started a collaboration with @ccurtis and her lab. Very happy about this! 2/n
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We use lentiviruses to initiate a large number of genetically defined tumors in the mouse lung. Each tumor is uniquely barcoded at initiation and tumor sizes are measured by sequencing barcodes. Tumor barcoding (Tuba-seq) was described previously: http://petrov.stanford.edu/pdfs/0136.pdf 3/n
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Here we use a combination of Tuba-seq with CRISPR/Cas9 to quantify the growth of tumors initiated with 31 different combinations of common drivers. This is more than the whole field has done in the past 15 years! And Monte's lab did it with ~20 mice. 4/n
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Key takeaways: 1) Most genes show strong context-dependence, showing growth advantage in some but not all contexts. 2) The magnitude of the effect also varied depending on the context. 5/n
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3) Genetic interactions we define are reflected in the human cancer data. E.g, we found that Rb1 and P53 synergize with each other and indeed tend to be found together; Lkb1 and Setd2 appear to be redundant and indeed tend not to occur together in the human data. 6/n
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Note that these interactions in the human data could only be detected because we had very clear prior expectations. Otherwise, the very large number of possible genotypes kills statistical power with multiple testing. 7/n
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4) Assessment of the effects of the drivers must take the genetic background into account. For instance, rare drivers can be very important when present. Indeed, they might be rare not bc they are weak but because they require very specific and thus rare contexts. 8/n
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5) The large number of known drivers and the importance of genetic interactions means that much remains to be done. The good news is that our method can assay ~500 moderately strong interactions with ~100 mice. 9/n
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Kudos to Zoe Rogers and Chris McFarland and all the coauthors! Check out the paper and tell us what you think. n/n
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And here is a write up by Stanford News:https://news.stanford.edu/2018/04/03/stanford-scientists-track-cancer-growth-crispr/ …
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And a lovely, through, and very thoughtful News and Views by James Kim (http://profiles.utsouthwestern.edu/profile/124974/james-kim.html …) and John Minna (http://profiles.utsouthwestern.edu/profile/14991/john-minna.html …) - http://petrov.stanford.edu/pdfs/RogersetalKimandMinnaN&V.pdf …
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