MBG MOLEC. GEN DZ PART 2 TRANSCRIPT PDF

Okay, it's one o'clock. Let's go ahead and get started. How are we doing? Good, happy Monday. Thanks for coming. If you are watching this later, what we've done is sort of create a mixed lecture that's just cancer to start. So when we come back, I will have prerecorded the rest of the cancer biology...

Okay, it's one o'clock. Let's go ahead and get started. How are we doing? Good, happy Monday. Thanks for coming. If you are watching this later, what we've done is sort of create a mixed lecture that's just cancer to start. So when we come back, I will have prerecorded the rest of the cancer biology and cancer genetics content, but for this section, it's pretty much we're gonna introduce the basics of cancer. So when we use the term neoplasm or hyperplasia, dysplasia, all of these things related to cancer growth, we are really talking about taking cells and making them abnormal and unhealthy. Unhealthy from the perspective of the organism, many times they are incredibly fit and incredibly good at growing because they have lost all of the pieces that would regulate their growth and help stop them. So for the overwhelming number of cases that you will talk about or see or hear about, the cancer is in fact what we call sporadic. Sporadic cancers are essentially acquired mutations and changes in development over the span of a lifetime that results in cells that don't grow the way that they should. What does it mean to grow the way you should? What is proper growth? It's regulated, excellent answer. I swear to the recording land, there are people in this room right now, I promise. I'm not just pretending to talk to myself. So it's regulated. That means that what happens to make us grow and divide? Signaling, what happens to stop us from dying? What happens to make us die? Signaling, we have absolute regulation where we are told what to do, when and how. Cancer is eliminating that. It is eliminating the regulation. It is eliminating the restrictions. It is eliminating the need for certain things. When it comes to understanding the molecular behavior of cancer, you are literally talking about all the ways in which cells' normal conversations get distorted. A normal conversation is I am in early development and I am supposed to divide this number of times and then stop and become this tissue, right? I migrate in this way, I end up in this position, I tell all these things by me to make a tissue and here we go, this is my job now, right? It's a process of maturation, specialization. All sorts of complicated signals go into putting a cell in the right place with the right programming, right? Cancer can subvert all of that. Every aspect of that can be altered. So because it is so important that we understand cancer from a broader picture, we're gonna start from the place of the hallmarks. This probably isn't new to you, but it was revolutionary when it came out. Historically, treating cancer has been a lesson in individual cancers. You have a breast cancer, here's the path for breast cancer. You have a colon cancer, here's the information on colon cancer. Therapeutics, genetics, there was no in- between until thoughts like this came about. The Hannahan and Weinberg approach of hallmarks of cancer revolutionized how we thought about cancer. It took cancer from this isolated individual disease that we lumped under this Brumbrella term and really honed into these are the things that make cancer, cancer. It gave us the ability to compartmentalize and understand cancer behavior, allowing us to pull back from breast cancer as breast cancer as breast cancer and it's different than colon cancer to how do these things actually look the same and how are they different? How can we target both and versus what's gonna be most effective against one versus the other? And that is absolutely revolutionary. We have the first part of this started out giving us six main hallmarks. Without looking at the slide that's now a giant slide in front of you, what does it sound like would be a major hallmark of a cell losing regulation? What's the first thing when you think cancer, what do you picture? Proliferation, right? Growth, literally the hallmark associated with growth is in self-sufficiency in growth factors, the ability to grow without being told. I can grow because I wanna. I don't need you to tell me to grow. I don't need your system to tell me to grow. I don't need any signaling, I'm just gonna grow. Growth isn't just about being told to grow though, is it? What is also happening that you have to overcome? Being told to die or being told not to grow. Those are two different hallmarks. Being told not to grow is insensitivity to anti-growth factors, insensitivity to things that tell me to stop growing. I'm just not gonna listen to them. Avoiding death is evading apoptosis. So I can have all the signals around me as a cell telling me to die and I just go, hmm, no. Pretty significant hallmark of cancer. What else, besides proliferation? To make a solid tumor, what do I need? If I wanna, what do I need in anything? I wanna build a tissue. I've got a pile of cells. See my pile? Pile of cells. I want this to become a tissue. What has to happen? I have to have a signal, I have to organize it, right? Piles, stacks, nicely. But this part of the stack and this part of the stack need to have the same stuff, don't they? They need to have the same access to oxygen, to nutrients to stay healthy, right? Otherwise, part of the stack's gonna die. So how do we do that? We create a blood supply, right? Cancer has the ability to create its own blood supply. Sustained angiogenesis. I need to create the vasculature to feed these hyperplastic, heavily growing cells. To be truly defined as cancer, as malignant, you must have the ability to invade and damage the basement membrane and other tissues. That's invasion of metastasis. And so then there's that last piece. What tells your cells to stop growing that isn't an external signal? That isn't signaling. But rather about a very important component of your cell. Talamre is gonna be playing a role in this. But what is it that's telling your cell it's time to stop? Teal and mere length. So our limitless replicative potential is overcoming the internal limitations that our genetic material presents. We need to overcome the signals that say it's time to stop because your telomeres are too short. So these are our main hallmarks. Most of them are about growing when you're not supposed to. After that initial paper by Hannah Hannon Weinberg, they came back and they looked again and they said, okay, those are the basics. That's a lot of growth. That's a lot of specific stuff. And they went, there's something else going on here. We're seeing a little bit more. And they defined what they called emerging and enabling characteristics. So they sort of had this, these two are really hallmarks. These two are really features. But they kind of get lumped together now as being, yeah, no, those are all hallmarks. So our next four really do delve into the DNA a little bit more. And so we have genomic instability and further mutation. What does genomic instability sound like? DNA falling apart, DNA having issues, right? DNA breaking, all of the above are true. Not only that, but you can have problems with segregation. You can have further rearrangement. You can have drastically different chromosome complements within a tumor. All of these can be perpetuated with each subsequent cellular division where you can get massive genetic changes that further make more genetic changes. So it is not just a one-off, it's actually a progressive and continual problem throughout the life of a neoplasm. You have another class you're taking this semester that I keep saying there's overlap with. Do you think your tumor is isolated from that other class? Your immune system is intended to do what? Protect you. Sometimes it involves deleting your own cells, doesn't it? Tumors can be very immunogenic. They can actually trigger immune responses. When it is a pro-tumor immune response, they literally create a microenvironment or a small area that enables the tumor to grow by blocking immune function. So we call that tumor- promoting inflammation. In the same sense of that, you actually evade or avoid the immune destruction. So not only do we call in things that let us create this microenvironment, but then as a consequence of that, we can avoid immune cells hurting us. Not all tumors are immunogenic, but many can be triggered to be immunogenic with some therapies. There's a really interesting gene therapy out there that targets turning on the immune system to attack the cancer. And that involves overcoming this feature. And then the last thing, what is the one major determinant for all biochemical and biological activity? It's the one thing when absent, you cannot go. When present to an excessive degree could lead to misfiring. We make a pool of it. We have specific organelles for this purpose. Energy. Can you function without energy? I mean, it's a Monday. How you doing? Energy is critical to a cancer. They are gonna dysregulate energy. What does the cancer need? More or less energy? More, right? What is the number one user of energy in your system? From a cellular perspective or an organismal one? Reproduction. Making more of self, whether that's organismally or on an individual cellular. Cellular division costs a tremendous amount of energy. So you have to have the energy to achieve those proliferative levels. But because this paper is actually really, really old at this point, like not me old, but old, we had some followups that linked a lot of this together. Let's put this into context. We've got the followups that come up. Let's put this into context. Why does this matter? Why does this approach of hallmarks and emerging characteristics matter? Because it identified targets for therapeutics. If all cells, regardless of whether they're breast or lung or liver or running out of tissues to think of off the top of my head, but any of the above, if they all exhibit the same genetic change, when they become cancerous, what you have identified is a universal target to help treat cancer. Does that seem really plausible given what you know about cancers and how different they can be? No, probably not a single bullet for all cancers, but single bullets against specific hallmarks, totally achievable. We have been able to identify specific pathogenic variations that correlate with each of these activities that we can then target. And by using this principle, we've been able to move away from, I tested this in breast cancer and it's restricted to breast cancer therapeutics, to I tested this against this molecular change and now I can use it anytime I observe that molecular change. That is the modern era of cancer therapeutics. We are not picking a drug just because it's applicable to breast cancer and you have breast cancer. We are picking the drug because the changes in your breast cancer are specific to this. And we wanna target that activity, that behavior, to better and more effectively treat the cancer. That is personalized medicine. But you can only do that for each of those cancers if you take away the restriction of this drug must be tested in this cancer before it can be applied to the patient. And so many of our clinical trials are about genetic changes now than just the specific cancer of interest. And so you'll see multiple groups working with multiple cancer types addressing a specific genetic change, molecular behavioral change. Does that make sense? So this one gives you an example for each of these targeted mutations. And it gives you an example of, oh, I'm sorry, it's blocked. It gives you an example of inhibitors you can use for each of these hallmarks. So of course, we had to update this. Just because you're seminal and you've provided an incredible amount of information to a topic doesn't mean you stop reinvestigating. Doesn't mean you stop trying to improve the theory. And so this is where one of my favorite pieces of cancer behavior because it makes sense comes into play. We talked about, oh, so long ago, the idea that becoming specialized gave you a job. And when you're good at a job, you just do that job, right? It's literally why you're spending years of training because y'all wanna be specific career paths, right? And then from there, you're gonna specialize further. But that doesn't mean you lose the programming that came before you specialized, does it? Hopefully you don't forget all the basic science just because you're now gonna be doctors, right? Hopefully we still remember some biochemical pathways, some signaling, think fondly of your time in this classroom kind of thing. Hopefully that stays true because it's certainly true for yourselves. Your cells have not forgotten their programming because it's the same programming, no matter what cell you're in, because that's your DNA. Cancer cells take their programming and flip it back. They hit the reset button. They unequip their gained knowledge and they go back to a state when they were more capable of growing, more capable of dividing. That regression is actually a hallmark of very specific cancers and their behavior. That loss of specialization causes a cell to not fit the rules anymore, to not stay in the tissue. It's referred to as de-differentiation. We are literally reversing that specialization, that job we gave them and saying, you have potential again. And now that potential is completely unregulated. The flip side to that is never being able to differentiate in the first place. And a blocking of differentiation, getting to a certain place and you just can't become more specialized. That too can come with a neoplastic potential. Plasticity is a word that I'm going to talk about a lot because we're gonna talk about hyperplasticity, dysplasticity or dysplasia and anaplasticity. And essentially this is behaviors and potential. It's your ability to grow, move, relate to your environment. When you become cancerous, you are not following the rules. And the major rules of that involve, I'm supposed to be in this location. I'm gonna behave this way. I'm gonna stay and only divide this many times because that's what my DNA says I can do. And we're gonna circumvent all of that. But another update is, do you exist in a vacuum? No, what are two additional factors that we have to pay attention to for every cancer? Not just genetics, but environment and lifestyle. One of the key environment and lifestyle pieces is our micro environment, right? The gut microbiome has a huge impact on the behavior of the gut. And so there is an interaction between microorganisms, infection and cancer. We can't ignore that piece. Especially not for something like colon cancer where material will stay within that environment that could be potentially carcinogenic material for extended periods of time. And thus our risk for our upper GI tract versus our lower GI tract is actually different. Even just the colon itself, the first parts of the colon have a lower risk or lower rate of poly formation than the latter parts. Simply because of exposures. And then of course we have our lovely last piece we've already talked about which is epigenetics. What did they do to our organisms, to our offspring? They had significant potential impacts. And so of course they're gonna have potential impacts in gene expression and transcriptomes of tumors. And some of those changes can be heritable. Most of the somatic mutations we talk about of course are not. Where does the mutation have to occur for it to be heritable? Germline, oocytes, spermatocytes, there. So we can see now our more complete picture adding in those features. This is the first time where we really get to have a more philosophical discussion about cancer. There are really two concepts around the idea of cancer development. The somatic mutation theory and the tissue organizational field theory. I will start this off by saying both are true and neither is true. Because I don't think they can happen isolated from each other. The real answer for cancer cannot just be DNA kept getting mutated. And that was it. Because you don't exist in a vacuum. And so development, conversations between tissues, conversations with the immune system are going to play a role in cancer development. So the reality behind cancer progression and development lies somewhere in the middle. Is somatic mutation probable? Absolutely, what's the number one source of mutation? Replication. What are cells that are growing and proliferating doing a lot of? Replication. But those cells are still part of a what? Still part of a tissue, part of an organ, part of a system. And that system is having a conversation with the other systems, the other tissues, the other organs, with the environment. Excessive growth of the skin, especially the topmost dermal layers, you're in constant exposure with the environment, right? With the lining of the gut, constant exposure to antigens with every meal. Those things impact the behavior of these cells and their growth. So it's not just am I exposing or being exposed or acquiring mutation, but also how is the conversation around me taking place and what role am I having in that conversation? Being able to migrate, being able to move and metastasize, requires very specific signaling. We're gonna talk about that process. I am a breast cell. I can't just get up and decide to be a cell someplace else. That environment has to be created for me. I have to change, but I also have to have a place to land. Cancers metastasize in very specific and predictable ways. They weren't always predictable. We had to do studies to see what the most likely metastases would be, and then we identified microenvironments correlated with those metastases. But we had to create those microenvironments, those niches. So yes, there are two competing theories, but most people argue it's really a necessity of both. Cancer is not just somatic mutation, and it is not just abnormal development. It is a conversation that has gone awry through a combination of factors. Does that make sense? No one mutation gives you cancer. It requires more than that. Even when it's a gain of function oncogenic mutation. So change equals potential. Each of these hallmarks that we talked about, each of the ones that we listed, can be a starting point for neoplastic growth. We don't have to have this and then this and then that. Any of them can be the first hit. But you are unlikely to develop a true malignant neoplastic growth from just one. You need more than one. It's not hallmark of cancer, it's hallmarks. You have to have changes in multiple areas. Even if you can grow without being told, you're able to keep dividing like crazy. That's not necessarily gonna give you the potential to move away from that tissue. So let's think about the skin, because it's the most clear and obvious one we can do right now. I could have excessive growth on the uppermost layers of my skin, right? Just lots of epithelial growth here. That's gonna stay localized if all it is is growth. I mean, I could develop a massive problem, but without being able to bring in vasculature, it's not gonna be able to grow that big. If I can bring in vasculature and I can continue that growth and I can deal with waste and I don't end up necrotic in anywhere and I'm able to properly process them, yeah, maybe I could get incredibly large, but that doesn't mean it's gonna affect the basement membrane in terms of cells actually going through it and disrupting it. Now, bear in mind, benign does not mean problem-free. I am not trying to imply that. We're gonna talk about that in a little bit. But that is different than having the potential to grow here and here or another organ. Does that make sense? When it comes to how we actually promote neoplastic growth, it doesn't just have to be a single gene. We can have chromosomal level changes that influence this. Extra chromosomes, loss of chromosomes, these can contribute to the potential for neoplasms. Makes sense? So genomic instability plays a huge role in this. So let's actually answer it. How might additional copies of a chromosome contribute to cancer? Increased signaling, increased product. Trisomy 21 comes with a substantial increase in risk for leukemias because of that increased signaling. What about too few copies? We already know that that's catastrophic on an organismal level, but within a tumor, we could be losing key regulators. Losing genes that are associated with blocking growth. Gesundheit.