Symptoms and Causes of Metastatic Cancer and Cell Metastasis and How It Begins in the Body with Engda Hagos

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Sleep science, cancer, stem cells, ketogenic diets, and more. Here come the geniuses. This is the Finding Genius Podcast. The Richard Jacobs. Hello, this is Richard Jacobs with the Finding Genius Podcast, now part of the Finding Genius Foundation. I have Ainda, a baby, Hagels. He is a PhD. He's associate professor of biology at Colgate University. We're going to talk about various topics and cell biology, molecular biology, and perhaps minor country. So, Ainda, thanks for coming. Thank you so much for having your new Richard. I really appreciate it. Your backstory looks very interesting. Would you mind telling people how you got to the university and how you got into this field? Yeah. So I'm originally from Ethiopia, so I came here as an immigrant, as I was actually a refugee in Kenya for a year before I came here. I didn't have much background in biology, but I was very fascinated by the field. So I did my undergrad at the University of Illinois in cell and structural biology, and then moving on, I did my master in molecular biology in Northeastern Illinois, and then did my PhD in inverse of Georgia. So, actually, I did not study cancer during my PhD. My PhD was focused on development biology on understanding how the embryos are up in early development, basically how single cell give rise to an organism. That's amazing, yeah. Yeah, and then I moved on to did my post-docs. So I was extremely amazed by embryo and early on, you know, the question of development, the question of differentiation, how that one cell actually can give rise to many different types of cells, how does the other body produce another body, you know, reproduction is very fascinating. And how does a cells communicate to give you this organ which are specifically located, our eyes are always located on our head, not anywhere else. So then, yeah, actually, I have a quick question about that. Over all time, let's say 100 billion people have ever lived, and why is it that almost all of them have two eyes and not three? Why are they in the same spot? Why is our liver located usually in the same spot in opposition to other organs? Like, where do you think that information resides in cells so that they know not only to create an organism, but the patterning of it? Yeah, so that's a great question. So I think what we think happening in early embryo is the egg is extremely important for many reasons. One is all the organelles are actually coming from the egg and nutrition, but also there are a lot of materials could be deposited from the mother into the egg. That could be specifically determined, for instance, if I study in Zibrafish, and in early on, some of the dorsal ventral anterior postural axis are determined by sort of the all sides. It's already specified there. So that information is retaining there, and then when the sperm is fertilizing the egg, forming that zygote, then the zygotic gene is turned on. So this information to give where the liver is on the right side, the eyes are on the head. You can only get two eyes, not three or one. These informations are due to cell cell communication. So one of the gen I study when I was in grad school is this called cyclop. So cyclop is really important for separation of the eye field. So in the absence of this gen actually, we call it this neuro-octoderm, which is separating the two eye field is not going to be separated. And the fish is actually creating one big eye. It's going to be cyclopic eye rather than having to eye. So I think the information with this powerful genus which are making sure, so what that gen is doing is this mid in the mid between the eye, it's scaling the cell is not to become eye field. Of course, it is determined by many many others. For instance, the sonic H-shock, which is a huge signal in pathways involved in that. But just informations are really very cool. I don't want to go more far that, but if you look at it, you know, fish, they live in a very deep water. They don't have eye. The eye field is actually there, but they don't see. The reason they don't see or they don't really not only see, but they don't have the eye field is because, evolutionary, why do you want to spend time for something you don't need? You know what I mean? So I think these genus are really there to make sure that the cell communication, cells they talk to each other to form the basis of these three germilers from the three germilers, then they're going to talk about where this organ's form and where they should be going in terms of migratory. So when we think about development, we are talking about cell division, differentiation, but also migration where all these cells they need to be migrated. All right, so what would you like to focus on? The cell division component or a cell to cell communication? Or what would you like to speak about? Thank you for me with most. But what's good because I think, you know, one thing I was fascinated about this when I was a grad student, are how do this embryo set up? But also when moving on, you know, if you look at it, cancer is self. We think is happening because of one bad cell is happening in that patient. So both embryos start from one cell and then this cell also in terms of cancer is that mistake happening, either it's mutation or epigenetic change, which is capping the code of life DNA, that change is giving signal continuously to divided without stopping, without shutting off, finally, then the cells divide uncontrollably and then they start migrating somewhere, for instance, the colon can go to the liver and then eventually it kills the very person it burns to it. So I think, you know, we can talk about cell cell signaling, that's what cancer is about or embryo is about, we can talk about cell division either is fine or what are fine. What does cell does cell signaling look like? Is that accomplished through multiple paths? Like, I've heard this membrane transduction, there's tunneling nanotubes, there's extraciliburbesicles, what have you observed in the predominant ways that cells communicate? Yeah, so my main area when I study whether it's embryo or cancer is cell cell signaling, we have this about 90% of cells they communicate through this called para-creen signaling, meaning that one cell is thinking about the cell phone, a cell phone when we call, you know, to that number out of millions of cells, it's going to go only to that person, you know, that person's then going to pick it up that signal, all right? So the same analog in here, some cells are sending signals and the other cells are receiving it, they must have specific receptors from them to receive it, whether to die, you know, by a pothosis, which is a program cell does, or to move or to divide it, you know what I mean? So whatever signal incoming from neighboring cells are determined or influence the behavior of that neighboring cells. So cell cell communications are triggers, whether in embryonic development, or in cancer in cancer development. What aspects of cell does cell signaling, again, appear to be important in cancer? Like what do you think first creates metastasis? What kind of signaling is going on and where to create that, for instance? So in terms of metastasis, it's very interesting. While we know so far, there are many, many, of course influence metastasis, but you know, the very basic thing I can say is, so this cell cell communication is highly governed, you know? If you look at it in embryo, the cells they divided, for instance, if they come, you know, in embryos there are, call this embryonic stem cells, like mesoderm in the and octoderm. For instance, if you think about octoderm, like the octoderm devised to the brain and to the skin, and then they came from one cell type, but they need to really differentiate it, meaning that signaling between them are communicating, well, I become a neuro-hybrid skin, something like that nature is happening in that. So in in in in concerts, if you look at it, in terms of metastasis, one of the big factors, for instance, is angiogenesis, which is wiring of blood vessels, for instance. This wiring of blood vessels is normally happening by signaling, by cell cell signaling. For instance, there is this signaling called VGF, vascular indetular growth factor. It's a ligand that's going to send. So during injury, for instance, or during embryonic development, you know, angiogenesis must wire to heal a wound, or angiogenesis must wire during the menstrual period or something like that. So, but it is highly governed. In concert cells, that kind of rule is out. So what happened is the concert cells are, instead of waiting for signal, they are starting producing themselves. So what they are doing is, these concert cells are originally more from epithelial cell types, like the skin or the gut or anything like that. And then these epithelial cells are sending signal to endotelial cells. Endotelial cells are cells of blood vessels. When they send that signal, the epithelial cells, they have no idea. They're going to say, "Ah, we got signal in, then we have to wire that blood vessels." So not all concerts are doing that, you know, wiring angiogenesis. But concert cells, they do that so that they can feed themselves. They can get rid of some toxic substance from them, but also be able to metastasize from one area to another area. So this is just one, an example, how metastasis can happen by wiring angiogenesis. But in general, a lot of metastasis is happening, not just by this mechanism. You know, what we think happening after tumor development is, it must be additional mutation can happen. For instance, if the cells are keep dividing, they're going to say at some point, if for instance, in a colon, the cells are keep dividing, dividing, dividing, and then they're going to change their behavior from maybe denying tumor to malignant tumor. Once they become the malignant tumor, when the cells are dividing, there is a tendency they're going to make more mutations, more epigenetic changes. The mutations or epigenetic changes could be influenced the behaviors of the cells to break the extracellular matrix, for instance. Breaking the extracellular matrix leads to maybe going from one area to another area. For instance, they're going to be access to the blood stream. So the concerts cells from colon, they're going to get into the blood stream. They're going to be circulating and they're going to end up into the liver. Once they go to the liver, then they're going to keep dividing their air and then they're going to make the liver out of use and that patient is going to die because of the application. So how do you, so I guess we're talking about the epiphalyole, to mesenchymal transition, is that what you're describing? So how do you think that, how do you think that starts? What stressors cause that? Or do you think it's like a random mutation? What do you think causes it? I think so. If you look at it, they did a lot of assay in terms of epithelial cells. And then there are markers for mesenchymal cells. So what they found was there is this transition from epithelial to mesenchymal cells because if it's about it, epithelial cells, they are not capable of migrating. They are not capable of migrating. They are not capable of metastasis. But if you look at it, human cancer, about 90% of human cancers are epithelial origin. So in order for these epithelial cells to migrate, they need to change into mesenchymal cells. The mesenchymal cells are the ones they are able to migrate. So what we to answer your question, could be a random mutation. That random mutation is at some point this epithelial cells, if in order for them to migrate, they need to change or they need to turn it on. Genus is important for mesenchymal cells. There are mesenchymal cells. Genus, they're going to be turned on. Once they turn it on that, then they're going to change from this epithelial to mesenchymal types of cells. But once they change their behavior and they metastasis and go, for instance, from calling to the liver, when they reach out the liver, mesenchymal cells, they are not actively divided. They don't like to divide it. So what happened is that they have to change back to epithelial cells. So we don't really know the mechanism of that. Is it a random mutation happening during that or is the cancer cells already figured out to go back again to epithelial cells so that they're going to keep dividing in that liver so that they're going to take over the entire organ. I've been working too hard and not working out enough. I wanted to get in shape, but I don't have time to get to the gym. Ashelon brings us a gym home to me. So right now for a limited time, podcast listeners get up to $800 off MSRP. To get this exclusive podcast discount, text Genius, G-E-N-I-U-S to 81, 81, 81, to get up to $800 off MSRP. Once again, text Genius to 81, 81, 81, and message and data rates may apply. See terms for details. Well, it seems like for different cancers, metastatic sites are preferred in certain organs. So it seems like certain cancers have a tropism for metastatic sites in certain spots instead of just randomly. What do you think governs that? That's a great question. So I think there are some conditionists, some kind of hypothesis. Why is a specific cancer when to choose a specific organ? So this is not all covering all the entire kind of cancer, why they are metastaticized, where they go, but there are specific kind of indications. Hypothesis, for instance, you know, origin of that cancer. So in embryonic development, the embryo develops into this germ layers called octoderm, messaderm, and indederm. And like I said, earlier, the octoderm, for instance, give rises to skin and the brain. So somehow cells are remembering that. So one of the hypothesis is maybe the cancer cells, which is originated from skin, are preferably to go to the brain. It's a kind of asking, hey, remember, we worked together a long time ago, and then please can I stay here? That kind of analog can happen. So cells are remembering where the originator come from. The other important aspect, if you look at it, for instance, prostate cancer. Prostate cancers often migrate or metastaticize to the bone. And one of the study, many studies indicate why does prostate go to the bone is because they might use similar growth factors. And then the liver is also a lot of organs, a lot of, I mean, cancers they go to the liver. One of the idea is maybe the liver has a lot of growth factors. The other important aspect to think about is blood flow. If you think about the lung, the lung is a site of almost all metastasis, like cancers, because every cells take oxygen in our body. Also, due to cellular respiration, all the cells they need to get rid of CO2, carbon dioxide out. So that means the lung is actually getting all these kinds of things from all the cells. So, cancers are circulating into the blood stream, has a tendency they can stay in the lung. The other important thing along with that well-studied is maybe a kind of liver. If you look at it, colon cancer, usually it goes to the liver. And what the best way to understand this is the food we eat during whatever we put it in our mouths, it needs to go through the liver first. Through this called, you know, hepatic portal vein. It needs to pass through that. So, if you think about these GI drugs, all colon cancers are, since they are going to pass through that, since foods are going to be passing or processing through that, then there is a tendency, these cancers, they're going to go through that and then they might say, "Huh, I can stay there." So, the blood flow, origins of, you know, the embryonic development early on, and then maybe the presence of some specific growth factor may influence where cancer cells they can go. Well, what about some brain cancers that do not seem to metastasize? I think glioblastoma, certain kinds don't, but they don't appear to outside of the brain. So, why, in that case, you think they don't metastasize to the distal organs? Yeah, so that's a good question. So, why are certain cancers they don't metastasize is, I mean, last time I was as deadly as others, you know, I mean, it's really bad cancer to have, but, you know, the easy. answer I don't really know much about it but the Aussie answer maybe I can think about is maybe you know I think cancer takes way many years to develop you know I mean so if you look at it this deadly cancer however maybe the patient is of actually could die before its metastasized because of this complications happening but metastasis does not just happen overnight you know if you look at it you know that's what screening and preventations are really important if you look at it colon cancer in a normal populations it doesn't come until age 4550 the reason is actually your body is trying not to give you cancer but some mutations might accumulate so cancer says they don't want to metastasize unless there is additional accumulation of mutations are happening so I think in this brain cells they don't want to metastasize maybe the cancer does not stay for very long period of time eventually the patient might die because of that complications. What are some of the big issues that you're researching and trying to answer in regards to cancer? So I do basic cancer research so when I was at Emory University we studied this gene called Crouple like factor 4 it's KLA 4 it's a transcription factor it is usually normally expressed in this differential itself so it is anti cell division it's anti-polification so when I got higher at call gate I need to branch it out myself so one foundation idea which is a very unique and important aspect of my research I did when I was at Emory is the study of this gene is usually happening in mice and in a lot of you know cancer types like colorectal cancer types my finding in 2009 what we published is actually in fibroblasts in a normal fibroblast cells if we take away this gene they have this genomic instability DNA damage they show anti-ploidy abnormal numbers of chromosomes they seem to they look like transform so it's really back in all the time what is this really mechanism why is it really happening KLA 4 is a transcription factor it's not a kinase protein how is it really regulating DNA repair mechanisms so when I came here I tried to look into these processes cellular processes like RFHG reactive oxygen species and so on and so on so what we found was in the absence of this gene there are these reactive oxygen species are upregulated and then this are not upregulated there is more the reactive oxygen species are not they are not genes so reactive species is a lot present in the absence of these reactive oxygen species are normally kin damage DNA and then they can cause mutations in the DNA right so the question is how is this reactive oxygen species present when this gene is out how is it regulated so what we found is normally these reactive oxygen species are produced during cellular respiration right these free radicals are coming but there are anti-oxidants in our body there are these antioxidants are they going to scavenge them and then they going to reduce them or get rid of them what we found in our study was these antioxidants are downregulated when this gene is absent so then we kind of looking what if the what about you know we also know that you know the this called my defege or out of the fege out of the fege is a recycling mechanism cells are at a topology yes at a fege yeah at a fege is when you know cells are stressed out or they are starved or when there is old substances or old molecules like proteins or lipid or kind of organelles they need to recycle in time in time in time the fashion so since we are really found these reactive oxygen species are increasing we were really thinking about you know what about the mitochondria so this is a recycling machinery so we thinking about this this is called my defege my defege is a special type of at a fege which is making the cells the mitochondria need to be recycled in time the fashion it need to be degraded in time the fashion because the mitochondria a lot of the cellular respiration which is cellular respiration are happening in the mitochondria then we thinking maybe that could be a problem so while we found which is we published in 2020 with 10 undergraduate students are we found that this my defege is also impaired so when we look at it why my defege is impaired also we found that our specific gene we call this BCl genes you know BCl3 genes are absent in the absence of these genes so by putting together the antioxidant genes are absent in this gene when the gene is not present the KLF or is not present and the my defege genes which are requiring for recycling of mitochondria are absent when we combine together this KLF4 is actually very important for regulating my defege in the cells as a result if that is not KLF or present then high levels of reactive oxygen species could lead to the any damage that the any damage could lead to genetic instability so I don't know do you think the answer will be found in genes or epigenetic change or is there some other regulatory mechanisms in cells or you know communication methods that I don't know or beyond this that could be responsible for a lot of this collectivist behavior yeah that's that's a wonderful question well that's why we are trying to figure it out so one of one of the question is you know when we when we study these transcription factors it's a very huge thing you know is it really KLF4 directly doing this is it really regulating at the at the gene level binding as a transcription factor binding to specific promoter of BCL2 BCL3 or to specific promoter of this antioxidant genes so that it can be turned on to regulate all these cellular processes or is it really KLF4 activates other genes they couldn't do the work is it dependent directly or independent directly is it epigenetically modified these genes are epigenetically maybe the regulatory sequences are somehow you know medillated so that they are their activity is shattered off turned off in these in the absence so in the lab what we are doing right now is we are trying to figure out what is the molecular mechanism how KLF4 is regulating is it at the transcription level whether it's terminal or terminal of these genes or is it an epigenetic modification happening in this genus when the KLF4 is absent so we don't know the answer for that what we know is somehow we have some kind of indication we did some microarray data and then we did some kind of you know transcription acid using RTPCR and it seems like in the absence of this gene their expression is downregulated and then when we put back KLF4 into the cells actually there is rescue there is some kind of recover is happening there but in order to look closely at the promoter at the regulatory sequences we need to do other assets like they call it chip assets so that you know it will tell us whether KLF4 is physically turning of this genus orna so what do you think is it possible research wise in the next five years versus let's say the next 20 like near term any breakthroughs coming or not yet on my research or in general in cancer oh on cancer research yes yeah I mean I think I you know in terms of cancer research I hope you know we can see you know more of this this this is affecting many many people in many many ways and you know it is I think to think about Preventation I think we are we don't talk much about Preventation Preventation can include screening I think Preventation can be a personalized medicine I would say that has its own problem but I think our lifestyle changes I think diet could be a big thing I think you know our lifestyle diet or whether smoking or drinking or maybe exposure to radiation or anything like that I think those are a very important aspect of thinking I'm hoping to see in the next five years so other important aspect to think about is often we tackle problems from the disease perspective we thinking about well there is cancer what is really the cancer doing but if you look at it actually in our body the the normal cells are as good as the cancer cells you know but the normal cells are helping the cancer cells to divide it they are helping the cancer cells perhaps to metastasize so I think I would like to see for researchers to kind of thinking about what kind of target tarab we can think about look. looking in normal cells, what kind of things we can do to normal cells so that they are now going to make them to divided, they are now going to make them to metastasize these cells or maybe targeting this so that they're going to be able to kill them or something like that. So I think targeting therapy is really important in that aspect I would say if you think about a lot of cancer cells are similar about 20,000 gyms in normal cells, the same in cancer cells. So I'm hoping to see if there is a specific gene or specific pathways in cancer cells exist so that we can specifically using targeted therapy for that specific cancer to do that. So these are very powerful, it's very difficult but they are very powerful because often chemotherapy radiation is really, really difficult in terms of cancer treatments, but targeted therapy is really a good way to I'm looking seeing the next 15 years, I think there's three things I mentioned hopefully I mean they are already start there are a lot of immunotherapy for instance we see which is really great for you know liquid tumor like in cancer cells. Like you know look at the cancers like you know leukemia and lymphoma but they are not great in terms of other solid tumors like colon or you know breast cancers so but I think that is particularly how do you going to train your immune cells so that or modify them so that they can tackle or attack cancer cancers I think this kind of targeted therapy are really critical for cancer prevention I would say. It sounds like targeted therapy could be confounded by cell just medication it could either supported or hindering and you know I don't it seems like it would be a danger to stop cell the cell communication because probably a whole host of processes may not work so how do you accomplish targeted therapy. So I think if you think about you know let's say if there is a patient that is diagnosed with breast cancer right so with if the patient is diagnosed with breast cancer often the physician should think about you know how is it caused right so that we have two things there one is is it happening because of hormones because there are specific cancers that are happening by hormone prostate cancer or worrying cancer breast cancer thyroid cancer and others right so if it happened to be happening by having hormone dependent cancer meaning that the estrogen receptor is actually presence there over express a lot there then they need to figure out this is not necessary to do chemotherapy for these patients I think having to stop a stroigen binding to the receptor to stroigen receptor is the key to go and then often a lot of patients actually having hormone dependent are really cured as long as they take that tablet I don't know one said they or one so we call whatever they are cured as long as there is no mutation in other cells. So what you think about it is if there is a patient in that breast cancer patient still it's not hormones so they ruled out the possibility this cancer is not happening by by hormone but it happens by a specific receptor let's say there is a receptor called in you know epithelial growth factor receptor often in breast cancer for instance there is this called human you know they call it human epithelial growth factor receptor which is often over express in this press patients if they found that there is a simple as they can do and then they can look and then by biopsy and then if they feel that that patient is they have that mutation then they can actually give a specific antibody antibody or specific drug again to block that communication you know the ligand that grows factor to prevent from binding to the receptor and there are many drugs many drugs are septin I don't know if you heard about that for instance is a very good yeah very common drug they give it to the patients and a lot of patients are fine the problem with that is assuming that the problem is in the receptor cancer cells often they change you know cancer of cancer cells often they develop these drug resistors what does that mean is what if the mutation is down it's not at the receptor but in the cytoplasm some transcription factors or some genes are involved in cell cycle then if that mutation is happening the patients they take her her septin for instance is not going to work because her septin is responsible only to block the signal in upstream at the beginning but cancer cells can come with a different mechanism they're going to say I'm going to just mechated this and in that case the patient need to take some radiation or chemo therapy treatment so I think I believe this targeted therapies are actually powerful because in a given cells there are many many receptors you know presence there for many many reasons but this target therapy are you are targeting specific kind of receptors so that actually the side effect is extremely minimum as well you know people patients they take her septin have they don't have much side effect as people they take you know chemo therapy already well very good what's the best way for people to find out more about your research where can they find more the papers and everything if they go to call gates that idiot slash the haggles they can find me there I think Google color is a perfect way to look at for my researches there are my publication records or just simply Google and the haggles and then they will get some while we do in the lab very good well and thank you so much for coming it's been a very good call I appreciate it. Thank you so much to share have a great day. Thank you for listening I hope you enjoyed the podcast which has been sponsored by echelon when you're trying to reach your fitness goals it can really help to have world class instructors like Nicole Griffin and Michael Brown choreographing classes with music from your favorite artists like pitbull and you get a community of hundreds of thousands of people who can give you that extra push echelon gives you that echelons certified fitness instructors are supportive engaging and fun they really know how to get you move it and right now for a limited time podcast listeners can get up to eight hundred dollars off MSRP to get this exclusive podcast discount text genius to 81 81 81 to get eight hundred dollars off MSRP once again text genius to eight one eight one eight one message and data rates may apply please see terms for details. You've been listening to the Finding Genius Podcast with Richard Jacobs. 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