Keynote: Computational modeling of protein degradation in tumors
X. Shirley Liu, PhD (Dana-Farber Cancer Institute)
2:00 PM - 2:55 PM EDT on Thursday, 30 July
Welcome, I'm very pleased to introduce Shirley Lou. She's a professor professor, in the department of data Sciences at Dana-Farber Cancer Institute, and professor at Harvard, th Chan School of Public Health. She's also the director of the center of functional concert epigenetics at the Dana-Farber, Cancer Institute and transcription Factor by finding speak and chip chip Coumadin accessibility profiles and Schumer. Munin traction. She's a fellow of the international Society of computational biology or recipient of the Sloan research, fellowship and niacin. Be Anaya,
CD 2020, Innovation award recipient of the 2020 Benjamin Franklin award for open signs in the open-access in life and I'm devices to introduce her. Yeah, thank you agent for that. Kind introduction. So here's my disclosure slides at once. Actually discuss anything right now with it on system, is basically the greatest amount of the proteins in a cell and usually sequence, which is usually in the end of protein and a UPS complex complex with good knife and sequins and then bring the heat you to add
ubiquitin until the end of protein. And then ubiquitinated from, well be targeted for going to the new at this really shaped like a trash can Rated R movie. Over the years, there have been many drugs that are developed, some charges produce all, which makes the protein more stable, either Target, ubiquitination enzyme making the protein more towards that relation. That's the most exciting work in. Recent years is something caused protag or proteolysis targeting quimera. I'm basically on the left side,
what you see is this big E3 E3, there's a scaffold and here's that you chew and they recognize them use a small molecules, bring the two together one and you can buy at Target. The other end of the small molecule can really Target this E3, so you can bring the E3 UPS system to a pro. Do you want to be bread and Wednesday are closed that you too well, add that you could come down to the kindness and in very often in 60 minutes, time to sell what we defeated off. The protein that exciting in 2019, there's a March that there's a major news and feature
article showing that targets the protein to the Target protein for a degradation. You can see here to produce a trash can is really seriously Protein. I just want Mommy to really have to uniquely binds to the Target. Proteins acid attract activation that were as a magic pocket by the way. So we can just read the whole protein. So I'll ask my mom. If you can uniquely buy into the target protein, they don't really have to charge it as soon as I'm out of pocket. And so the really exciting possibility is that because many transcription
factors are really, he's graduating cancer. And so because they don't really have a Target. And so I'm over the years be in the work that you thought was interesting is whenever we reach our Target a new direction we want to make sure that is the direction that we can leverage our existing expertise, then we can like what's a new hose. I Cannot Lie by the time and she works with Juicy. J at pinecastle analysis for all the beings that are frequent and the very bottom are the most commonly
protein. Plenty of time, is it, and they're also things like us, and then you see the chromatin, you know, he's somebody vacation, but you can see transcription factors and protein hasn't been good. I'm so this is our general computacional approach so this is how I met working here and we look at it, all the T. C J. And cancer types are of all the tumors and there are two things. We look at one, is the protein that responsible for degrading meeting food fish and he
truly 3 days. And also that when they have, this is looking at the beauty shop UPS in traps, you know, on the substrate of those which are usually nasty and terminal or c-terminal end of the proteins and sequences changes, the recognition side from the UPS protein switch, Ansel. How would we try to see whether mutations are the UPS protein in Target? I mean, has a pnas paper that he developed in collaboration with gene expression, a mutation pattern as a probability of being
This weekend, also moved to ask you who are restricted to in this case. Just looking after your music lace significance in the accounting for 60% of all the cancer driver genes, which is amazing. And so come shirts, devious analysis from other studies as well as the previously, not reported driving mutations in the UPS halfway. we look at the presence of the majority of our relationship which is responsible and 17% are related to which Rewards Next we look at what are the known that rocks that are documented in the database. So we look at her as a
witch I know where you was just a small-town. Basically I don't need protein for each position on the protein off the protein. No. We see what features are important for that prediction. Accuracy is only one perfect and you can see the most recent and then he's flexibility and then exposure to Regions that are also facing the outside of the protein that are half of solvent. I'm so once we have a big list of this, and one example of a cancer driver Gene is cyclin D1, you probably know that.
And if we look at the cycling, beautiful has an underground, as you can see, are good thing. Is that a protein? Has wild-type expression, protein level versus those that have actually it useless. If you can see, that happens to protein more stable and a castle raid the cancer cell for alliteration. This is another example of a diagonal on. This is related to Ciara. Abl fusion, fusion fuse to the second half for the later, half of the radiology and interesting in this case
is specific height and the width is Fusion you can have higher expression off the second version actually happens. Right after that. That's responsible for And look at the CML patients. Only received over a regular TV set. You were so even though we can have some for Dixie power of, you know, that just based on Evolution, slice ability and solve an exposure because the date of Face Off, 2018, South paper published the first it used to really synthesized, amino acid sequence,
and the basic place. They have a master of the end of every protein. For, for every protein sequence and they fall into an expression Baxter. And so we didn't hear you first, you see this, a very strong and its first Express a red, fluorescent protein, and then there is another green. Fluorescent, protein, different from the rest protein. Serves, as a console Express by, they can be strong. Be greater He was at the end table by Zac Brown and Autumn hear the rest protein signal are very strong. But the
houses from here, We only have seven layers in here to predict whether this is a degradation high or low acid sequence of every human protein and we can actually very well predict that you pssa. And also when we really look at a specific that we are the only look at a time you know, as it's even just looking at the overall amino acid mayhap, you could make some guesses. What's a person asked me to ask you to be more likely to be the greatest but we are more interested in a longer sequence. I don't know if I
just a bag of words of a prediction of the correct comparative, I guess random Forest do Works reasonably well. I was like legit question or just you know I just I mean worse. Ansel from this approach. We identify song backgrounds that were previously announced no more Degrassi places, including some that are flanked by the middle in the middle. But still I wish they had a second. If it's from the original original sequence with the background, that's when we change that. I mean no acid sequence.
Where is the novel that runs that will apply to all the stores will have a diagnostic process which will make it for a few more or less stable. We also use a background model, which we just randomly know how often do you change the background color of transmutation? That's really changing the background. And also again and the most significant mutation is Terminal and got a free protein in both breast cancer and also pain cancer. And the other is the first. Look at it, God or 3, if you look at it.
And it also interesting Lee. I got a three also have a protein, protein walking down. The street is still there and the friendship we make the protein, much more stable. We also specifically, Is it? The wild-type? And this is a transmutation, is basically, if the proteins previously asked him here now, you know? So, even in the point mutations, we should see the protein. Next, we do the gypsies because like, I have three is a transcription Factor when you have a more stable transcription Factor proteins,
using the wild high protein and energy to hear, no more stable protein and protein that got stronger to the promising and we use this over lack of about 100700 in a, where are they near the ocean? At the pathways. That are you reaching you? These things that are related to the stronger as signaling pathway and cancer relationship Pathways, there's a really stable which in turn ask you this. A lot of estrogen receptor Agonist. In addition, which is the second
most frequent location in breast cancer. Another example, we saw is this Kiki and one denotation, this is a negative regulator p53 and you are to be married in the c-terminal. End is here to change the size from a seat with a blue or 6604 from a Visa or two. And then we also play this on 450 and so you can see a huge case this, by the way, this is a more stable compared to the wild-type and increasingly when we have these mutations, you can see even though in the south Cross different
conditions are the Same by the way, 1453 only 15 is when its most active, but actually he's realizing I will make sure you 53 the function of a stable in the cancers. I'm so this is our approach looking at vacations, on background in terms of ability. And from when you have a transcription factor, that is a substrate of, either you three, or do you be personalized and Zayn. And so, you know, maybe first of August, this transcription Factor needs to be DNA and regulating expression. Just based on age. In expression data, we will not really be able to tell that the protein
one table or a table at the protein level. Because if we have to use the phone screen Target, gene expression versus wall, type on the ubiquitin ligase. Where the, where the transcription factor expression break a faster or slower? We actually see the difference. Which factors are factors for decoration. For this event has already seen normalized for gin expression, Target. But in this case, we are looking at all of the TVs in the changes in the downstream, an expression. Using this approach, we were able to
predict that are being targeted. Being significant. Whites are all drivers are no XBox 7 is known to charge admission from him at the ability and the keep one. that regulates our ass, and also I'm so they are some no one's like this. For example, I keep 1303 is the UPS CC GA when we see a cheap wants me to ask you to choose not have expression expression changes by Interesting way when we see the mutations on the scaffold protein together, and when we see the meat
and the PRT, for something Target Field Station we Collide. And you can see basically, Digesting bad? The first part of the summary is that the cars and no me information about UPS regulation. He sees is limited unbiased, no makeup roach which is a global protein Civility and also the eighth together. Are potential targets for Dr. Section used for computation of work. We have in our lab organically because at the same time calling was also help with a relationship and
basically every week Another difference, crispr knockout a different Sheen and then implanted into the mouth tumor or cancer, South Rome, in Union County and this is Union County, the mice that we also before. And after that, you were a grown for a couple weeks, we take out the tumor, isolate the prefer in speech fell and the magic I told you to look at the tumor grows, you can see here in this case where the tumor is growing very quickly that has wild type. In life is slower when we have some
control in here, And when we look at each other very tall is comp one. Basically knock him out. The tumor is growing slower in the adjusting. This is a cancer driver until we know how the couple and even the cancer cells lie and we had a lot of jeans that are down regulated. We are related to Microsoft HP. Nortrax, and macrophage activation. Idolcam protein or a route to ask, whether the cancer cells can see create a different level of final guys. And there are not so many opera
knockout speak up. When we see a lot of cytokines that are not regulated. Guys are done regulated and he's an expression in PGA tour's, we have previously Icee machines in Lagos and you can see here, that's many, many cancers expression is positively correlated with macrophage, You might have a mom applied for and zero macrophage but which is more for a recognizing Adelanto macrophages, really for who is healing is actually pretty bad at your house. More
expression is positively correlated with the one in the mouse. In the tumor that macrophage level insufficient. To see what is the potential Downstream Target is or The Regulators that are related to, what are the transcription factors? Regulate movies, have any differentially expressed use that? We usually run about $200. I spent a while so we don't have to ask what the average United profiles. Such as HTC, 27 or DNA. Basic feature selection profiles that represent
finding a gypsy data or analysis of regulated also 281 family. So this is on the level. We try to use the house and based on the different Shore, Taxi cheese. We can also use another system function to see what's really have finding that overlap with this before. Why do you say if you want a family, Weather protein level where there some backers are different and this is supposed to be here. We see a little bit of a If you want but they are not asking you because I'll ask family meals, happy meals
at we don't actually see as family to be relationship so it seems like maybe the influence to ask ability and ask why you don't seem to have any evidence. It has to be an unfortunately we don't see that that wrong. There's not an on-call pondera on it. So how can talk directly recognize that there's a paper, suggesting that a little kindness. It can be an adapter to link to TV. And then I was like the gather and a simple and easy braided. And so whether these three really quiet, 152 and see if they can
really call each other face-to-face. One dog house. We don't see that it does not even be a little bit more interesting to see how much longer to go to protein stability, and also stronger, and is using another database at where we have 76. A macrophage. What are the jeans that are correlated with wisdom? I can see there's a very, very strong negative correlation. We also see a little bit of false and we suspect that actually in the system in a public domain at. You can see with staffline and Route 80. This
is part of us. And in this case, it's right after the Also the promoter and I'm pencil. You can see them. When we try to knock out a couple I individually and just look at its exact on the tour grossed. The most have not happened in your system faster than mice. You can see that one can really see a fact. I'm using you as bait, knock out in expression. Signature signature doesn't seem to be significant for Anytime is always high in the macrophages and then the patient will respond actually
better to cry. And so if I knew you knew modulator off tumor microenvironment and antitrust immunity, basically, how long can Target be be able to adopt her and can't get rid of these proteins? And I can actually activate the side of production and macrophages your patient. And so, are you sorry for you have a higher, then worse with a lot of macrophage into a new house to work for 2003. Dish Network have presented, you wanted most of the experimental work and he's going to post off with miles. From we have many, many other
members helping and we also want to thank I reach her teens who helped us with global infusion and also we're currently collaborating with two. I'm being supported by the name Andrea. So I think that's all for today. At we also have Between analysis and that this is a very much. Surely, there are a couple questions in the polls. I think we only have time for maybe one or two. I guess, the first one, brca1 was reported as a UPS with transcription Factor esr1. How does that Impact? Drug targets and our understanding of breast cancer?
So far easier to face because amount or transcription factors that yard is more stable. So, it will drive kind of wrap. This case you can use a axis and the amount of all the transcription factors for other transcription factors. That's normally I really hard. Are 28. K protein is generated from a single us, a Popeye's in one order. You just send it to us or I see terminal and of all the proteins in the human genome and then you just close friends of ours, be
back to South Sea Terminus, that's one paper. That Terminus is another paper, would build models for both and I recently, they are actually getting even the internal protein. Sequence in the human genome. So we might be able to find more. In your talk, you show a lot of wet lab results. Did your lab do these or can you give career advice to Junior competition, or research? How to establish collaboration to validate, computational? Find a way to hear the GPS.
When we told them, we found out. And so I think he's able. Also, if you want you can see they are I'm so sometimes, you know, we do you some work? So how far experimental collaborators? But then, they also overtime help us with our star build over time and so did then gradually, you know, you helped you talk to. And I think those makes us stronger compared to a case where it's always been unconditional group, providing health or sometimes Human Service. Maximilian Charlotte. This has been a fantastic talk and so many different Technologies and I think it's really kind of the future where we do have
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