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Prikvačeni tweet
First
#preprint for 2020! This has been a really cool study looking at response and resistance to#WNT inhibition in#CRC. It was a monumental effort, done almost single-handedly by Teng Han - not on Twitter - but looking for postdocs
. A thread
/1https://www.biorxiv.org/content/10.1101/2020.01.22.914689v1 …Prikaži ovu nitHvala. Twitter će to iskoristiti za poboljšanje vaše vremenske crte. PoništiPoništi -
Knowing how to use public transport ticket machines in a different city is so oddly satisfying.
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“We’re not in Kansas anymore, Toto” *checks notes* “Umm, actually, let me get back to you”
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How can “He did it... but we don’t care” be the conclusion to months of “He didn’t do it, this is a hoax”?? I just can’t with this BS anymore.
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Anyone want to guess at a *rough* estimate of how much has been spent on sequencing cancer genomes? Spoiler: I have NO idea...
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And after 5 years
@TengHan5 is on Twitter! Congrats, Teng!Prikaži ovu nitHvala. Twitter će to iskoristiti za poboljšanje vaše vremenske crte. PoništiPoništi -
Dow Lab proslijedio/la je Tweet
Seminal work from Luke Dow’s lab!https://twitter.com/dow_lab/status/1220341966405357570 …
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Dow Lab proslijedio/la je Tweet
Great work from the
@dow_lab !TGFbeta primes for Wnt independency in cancer
https://twitter.com/dow_lab/status/1220341966405357570 …Hvala. Twitter će to iskoristiti za poboljšanje vaše vremenske crte. PoništiPoništi -
Dow Lab proslijedio/la je TweetHvala. Twitter će to iskoristiti za poboljšanje vaše vremenske crte. PoništiPoništi
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That's it for now! Thanks to everyone in the lab, and all who contributed along the way!
@ElementoLab@Yess_Indeed@ekta_khurana@FanyingTang. Right, now I gotta go finish a grant! /Outpic.twitter.com/NOqeZkI4dXPrikaži ovu nitHvala. Twitter će to iskoristiti za poboljšanje vaše vremenske crte. PoništiPoništi -
Finally, though they are WNT independent the lineage reverted cells become entirely reliant on YAP/TAZ activity for survival -> treatment with either Verteporfin or genetic depletion completely shuts down proliferation, while WNT dependent cells are barely affected. /11pic.twitter.com/LIYobrQQWK
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In fact, in the absence of a SMAD4 mutation or TGFb priming, activated YAP (or TAZ) is sufficient to induce drug resistance. /10pic.twitter.com/paWapKm9SI
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Turns out that TGFb priming engages YAP to rewire transcriptional programs and induce what we call ‘lineage reversion’, where the cells adopt a fetal-like state. Similar occurs during injury repair, as described by Stefano Piccolo and
@kim_bak_jensen@JensenLab_UCPH /9pic.twitter.com/lRBqvFB4FN
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This was not an organoid culture artifact, as engraftment of TGFb-naïve cells led to escape from WNT suppression in vivo. However, like the in vitro cultures, those with disrupted TGFb receptor remained WNT dependent. /8pic.twitter.com/Q92bYDfe8J
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To cut a very long story short, Teng figured out that not only was the genotype important, but to become resistant the cells had to be (transiently) exposed to TGFb. We dubbed this 'TGFb priming’. Cells with a dysfunctional TGFb receptor ('KRPT') never became resistant. /7pic.twitter.com/iu7G16ObqR
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About 25% of cases had downstream WNT reactivation, in some instances, by mutations or amplification of b-catenin... Not surprising. But the majority (75%) had no evidence of this. /6
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This is a relatively common genotype in CRC, so we needed to understand what was going on. What do you do when you don’t know what to do...? OMICS! All the omics! /5pic.twitter.com/U3rAycpw6b
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In most cases, these cells remained hyper-responsive to WNT974 (PORCN inhibitor), except for one genotype... those carrying KRAS (or BRAF), p53, and SMAD4 mutations. Unbelievably (to me at least
), the same genotype could escape APC restoration! /4pic.twitter.com/omirSkCW0F
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Taking a leaf out of the
@HansClevers / Toshi Sato book, Teng engineered many, many primary organoid cultures to mimic the combination of oncogenic lesions seen in human RSPO fusion CRCs. /3pic.twitter.com/fYzWUMZmU2
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A few years back, Teng built in vivo CRISPR-based models of RSPO fusions. He showed they were tumor-initiating events and extremely sensitive to PORCN inhibitors (that block WNT ligand secretion). Great! But these are not truly cancers... /2 https://www.nature.com/articles/ncomms15945 …pic.twitter.com/Y2VMiE0WZc
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