Josh Neman-Ebrahim, PhD, an assistant professor of neurological surgery and physiology and neuroscience at the Keck School of Medicine of USC, discusses the basic biology of cancer metastasis, including how systemic cancers travel to the brain and information about his research projects.
Mm, Mhm and yeah, yeah, yeah. Mm. Hi, everyone. My name is Dr Josh Neiman, and I'm an assistant professor of neurological surgery, physiology and neuroscience. I'm also a member of the Brain Tumor Center here and the member of the Neurons Comprehensive Cancer Center here at the Keck School of Medicine. Today. What I'd like to speak to you about is brain metastasis from perspective of cancer neuroscience That is the focus of my laboratory on our translational research studies. And I'd like to convey to you what we are doing in this journey into making breakthroughs for brain tumor patients. You may ask, What is cancer neuroscience? Well, as a card carrying neuroscientist, the goal of my laboratory is to look at the look at perspective of brain tumors from the perspective of the brain. How does the brain allow these tumors to enter from the body? That's what metastases. And I'll go through it and allow it to grow. So with that, let's move forward. Like I mentioned you, I'm the director of the Cancer Neuroscience Laboratory here, and what my lab focuses on is brain metastases. So number one tumors that spread from the body up to the brain. These can include breast cancers, melanoma, lung cancers to, say a couple. The other aspect of my research, which I will not get into today and hopefully we can discuss in the future is pediatric brain tumors, a specific one, and one of the most aggressive is modular blocks. Toma. What we look at is how these cancers spread down the spine and other parts of the brain in these childhood brain tumors. So to really understand brain metastases, we have to go to the beginning. How does cancer start and spread, and why does it spread from the body up to the brain? So sort of going as in back to the future, going back to the basics. So I'd like to start to speak to you about just the basics of cancer biology and the propensity of these tumor cells to want to get up and leave and go to the brain. So let's start from the beginning. Cancer. What does that really charmed mean? So the origin of cancer came from basically, uh, for 300 b. C, where Hippocrates Hippocrates was, the Greek physician and the father of modern day medicine coined the term, the word cancer means crab crab like structures. And, as you can see, when he looked under his type of microscope that he had back, uh, in the fourth century BC, he saw these cells that are basically crawling around and looking like crabs. So really thinking about cancer and these crab like structures. We always had the notion or the thought that cancer was just cells dividing uncontrollably. So if you look at the panel from left to right, you have normal cells, and then something happens, and then they start dividing. And it's just uncontrollable division. That is somewhat of a true statement. But cancer is more complex than that. It is not just uncontrollable cell division. Cancer has multiple facets to it. The basics of cancer biology is that cancer cells, although they start dividing very fast. They basically set up an environment, a city, and they recruit other cells of our body to come in to help them so it becomes an infrastructure and that term is called the tumor micro environment. So as you can see from this from this dense illustration, the tumor cells are actually in red, but the remaining cells are actually normal cells in the body of our own body that had been hijacked by the tumor cells. And in order for the tumor cells to allow, uh, for them to be, you know, allow them to to grow. So what happens is that is that the tumor cells hijack our normal cells, and they built an infrastructure of cells and a city and an environment that is conducive to their growth. This sort of much looks like what happens in a in a dense freeway system city where the freeways are the cells coming in the highways of Selves, leaving and getting up and going somewhere. And you have multiple cell types that are controlling the infrastructure of the city. So with that said, why are we at the point where we can't find and cure this infrastructure, this city? How does that work? So really, to understand why current treatments fail is to understand the heterogeneity or the or the differences within those tumor cells themselves. So imagine in this illustration you have tumor cells. It could be breast cancer. It could be lung melanoma, any type of cancer, but just their different marbles. Okay, so if it's a breast cancer tumor. They are just different marbles of breast cancer cells. Current treatments basically hit the initial tumor, and they'll basically take out the Purple Marbles. But they'll leave a small what we call a population a residual number of cells that are remaining in that in that city. And what ends up happening is that it is those seeds that re grow and cause recurrence to happen and eventually metastases or spread. So what is metastases again? So the word literally means removal or change or spread. As you can see from this scan of a patient, all of the black dots are basically tumor cells that have left their original site, and now they're throughout the body. Now this is a very complicated process, and visually it's very complicated where it's not understood so well. Metastases. What does that really mean when cells pick up and get up and go? So I like to illustrate it, show you through an animation and an illustration. So let's take, for example, breast cancer. In this illustration, you have the breast cancer tumors or the cells sitting in green. What I want you to understand and appreciate is that a woman, or sometimes a man will never die of the breast cancer here within the breast. It is when the tumor gets up and it floats through the pipeline of the body and travels to other distant organs. So, for example, breast cancer can go through our blood vessels. It can go through our lymph notes, and it can go into the liver into the bone, into the lung and into the brain. So when a breast cancer is now in the brain, it is actually breast cancer tissue that is growing in the brain. So when my neurosurgical colleagues go in and they want to take out a breast to brain metastases, it is actually breast tissue that they are taking out within the context of the brain. It's not like the brain has now become cancerous. It's still that origin of that tissue that is now in a distant and a separate place, and this holds true for other types of cancers, including colon and pancreatic cancers. So this year we lost two integral and Seminole people to both colon and pancreatic cancer, So so so Chadwick Boseman and Ruth Bader Ginsburg. They both passed away and died of metastatic cancer. And that means that in case he had colon cancer was metastatic colon cancer. So it was when colon cancer cells so cells in the colon got up and they went to the other parts of the body. Unfortunately, and the same is true for pancreatic cancer. So what ends up happening is that we get within society. We get a lot of misnomers and misrepresentations of what metastatic cancer is, and I want to talk to you about something that was I took from the headlines of this year, and that is Taylor Swift's mom. She was. She currently was diagnosed with breast cancer, but then she potentially had a brain metastases. But the news agencies they consider, and this is something that happens all the time. And I want to dismiss this. This this, uh, notion of what metastatic cancer is is that is that? They said that she had now a brain tumor on top of her potential metastatic breast cancer, but that in reality it's still breast cancer. But it's in the brain. So I hope through that illustration, you've understood what a brain metastases now is. It's not a separate thing It's actually that when that cancer gets up and goes and that brings us brings me to the topic of brain metastases now going into brain metastasis. It's a type of a brain tumor, and now we understood. And I hope I've conveyed to you that metastases is different than a tumor that is already originated in the brain. But I want to go back to this topic. So the cancers that begin in the brain these include glioblastoma. So the types that unfortunately Senator McCain and Senator Kennedy, Elizabeth Taylor succumb to Those were cells that started in the brain and they became bad. They became cancerous. We have about 23,000 of those patients that have those incidents of those types of cancers that begin in the brain. But as you could see tumors that spread to the brain, including breast cancer, long melanoma, prostate, sometimes in colon they outnumber the primary brain tumors by 20 to 1. So it is a real necessity for us to understand why that is happening. Why are these tumor cells going into their brain, and how are they growing? Like I mentioned to you, the incidence of brain metastases now by primary tumor origin. I hope you understand. You understand the meaning of that now, is, is that the top three or four cancers that go to the brain are lung brust and melanoma. Now, unfortunately, if patients do have a brain metastasis, they have a dismal probability of 20% chance or less of surviving for more than a year. And so this is why we need to do the research that we are doing to understand why this is happening or how are how are you are sold entering the brain. So with respect to that, this is the cellular pathway of brain metastases on the right, You have primary the primary tumor site, so let's say breast again. These tumors, you can see are not just the green tumors, but they have many other tumors, uh, many, many other cells that they that they are friends with at the primary site within the breast. They enter the blood vessel, so that's where it becomes a circulating tumor cells. Or, if you've heard of the term liquid biopsy. So these are cells within the blood vessels. They travel through the highways of the body, and they basically come to the brains gateway, the blood brain barrier. Now you can think of the barrier of this barrier as being the T s. A. When you go to the airport, they are the secure. It's a security system that the brain has set up and the tumor cells have to bypass this, and then they enter the brain. But when they do enter so that when they pass the t s a and they enter the brain, they don't grow right away. Some of them become, they go into hibernation and they go into hibernation for months or even years. And that's why sometimes primary cancer patients, like breast cancer patients, they don't see brain metastases for years out from their diagnosis. It's because these tumors, once they've gone to the brain, they go into hiding, hiding. And we are learning. And we are studying. Why does this happen? And if we can basically understand this biology, then we can come up with better therapies and basically kill these hibernating cells. The other perspective is, well, these tumor cells start growing right away, and they use that environment of the brain to grow. And this is where we come into the term of cancer neuroscience. So we're looking at the contribution of the city, the brains environment to allowing the tumors to grow. Normally, we think of tumor cells as being wildfire. Wherever they land, they start growing, they start growing out. But we're finding out more and more that this hijacking concept is that where tumor cells are actually communicating with our own brain cells and they're telling our brain cells, Hey, come help me. I'm I'm in desperate need. I need nutrients. I need certain molecules to survive, So therefore the brain starts helping the tumor cells, and it's this cross communication which ends up happening, this molecules going back and forth So normally you know cells can take molecules and basically automatically turn themselves on. That's on the top where you see us as auto Quran signaling. But in the case of the micro environment or the environment, other cells come to help. So whether it be a neuron, a the bona fide brain cell or the support of cells of the brain, they help the tumor cells grow. And this is exactly what what this slide is showing. This is an image from one of our studies that we're doing in our laboratory in my laboratory right now, where you see the tumor cells in red and you see the brain cells in green, and what you can see is those. Remember what I talked to you about the original with the word cancer means the crab like shape of the tumor cells and red and their crab like claws are sitting peacefully on the brain cells. So you would think that these tumor cells were just once they land, that they were just ravaged environment. But that's not true. They sit there nicely, talking with these neurons and these brain cells, and they do it through these basically molecules, how they interact with each other and my laboratory were studying what these cross communication molecules are so that we can come in and intercept them and prevent the tumor cells from talking with our brain cells. And if we do that, we can basically isolate the tumor cells from its environment and potentially starve them to death without affecting our brains. And that is one of the goals of of of, of our laboratory studies. Now you might ask, Well, that's great, but it comes to another aspect of this is as a neuroscientist, I don't look at the brain as a whole as one organ. The brain actually has multiple neighborhood. It has multiple regions okay, and going back to that communication of how tumor cells talk with brain cells well within every region of the brain. There are different types of brain cells that can communicate with different through different molecules, and so this gives us what's called the topography of the brain. As you can see on the right, the front of the brain has different types of neurons, and they use different types of molecules to talk with each other versus the side of the brain that's in has different molecules. And so we are studying to see well, how are these neighborhoods causing? How do these neighborhoods allow the tumor cells to grow? So this is an example of the four neighborhoods within the brain, and you can see the four different color paths of neurons a neuronal pathways, so the highways of the brain and you can see that they're different, and they're different because the molecules that they use to communicate with each other during those along those highways are different. So we said, if the molecules are different, then potentially are different tumors attracted to different parts of the brain because of those different molecules. So we actually did a study with patients here at USC, where we looked at almost 20 years worth of patients who have had brain metastases. And we said, Do certain tumors that are different from origin? Do they like to go to different parts of the brain? So we looked at five top tumors that go to the brain. We started with melanoma, which is skin cancer, breast cancer, lung, colon and renal cancer. And we used imaging studies that we've had here for the past 20 years in almost 1000 patients. And we said, Well, do these tumors like to go to different parts of the brain? And certainly what we see is that these four or five different humors do you have a propensity or they like to go to different parts of the brain. So, for example, breast cancer likes to go to the back of the brain to the cerebellum versus melanoma, or skin cancer likes to go to the front right of the brain versus lung likes to generally go to the back area here. Colon cancer. It just goes anywhere in the brain so it doesn't have any proclivity or any, uh, special place that I'd like to go just like to spread everywhere. So then connecting this with the highways and the different neurons in the brain, we ask, Well, what happens, You know, why is it that certain cancers like to go to certain parts of the brain? Can we can we use our neuroscience knowledge of the different molecules within each part of the brain to study how these tumor cells communicate? And can we stop that communication and potentially come up with with with therapies for our brain metastases patients here so that we could extend their lives? That is the ultimate goal of this. And so what I want you to take away from my lecture and our discussion today is that these tumor cells, when they go to other parts of the body when they metastasize, they act like the wolf in sheep's clothing. They pretend that they are the sheep, and they are the friends and the friends of of that region. But in actuality, they are the photos they put on their masks. The sheep masks so that they can communicate with our brain cells, okay? Or with lung, when they go to lung cancer, you know, lung metastases or liver metastases. They use, you know, common commonalities of that organ specifically within the brain to communicate. And then they take over, and then they unmask themselves. And that's where you see the wolf come out. So I want to thank you for listening to my, uh, presentation today and our research on brain metastases. I hope I hope that you've, uh, gained some insights into this devastating disease that we're trying to find cures for. And, Lassie, I would like to thank my team because it is never a one man person. It is a adventure of a multidisciplinary team here, especially at USC and our brain tumor center and neurosurgery. I'd like to thank all of the patients who have been integral to our studies, and I hope to see you soon and have more discussions. Thank you. Mm. Yeah,