 Welcome to the OnFoTarget YouTube channel. This week I'll be introducing you to Dr. Herbie. She worked with the division of medical oncology department of medicine, Washington University School of Medicine, St. Louis, Missouri. Please enjoy. My name is Angie Herbie and I am a new assistant professor on faculty at Washington University in St. Louis associated with the Stightman Cancer Center and the Neurofibromatosis Clinic. I'm going to discuss a paper that I worked on during my postdoctoral years when I worked under the mentorship of Dr. David Gottman, who is head of the NF Center here. And the title of our work is Spatially and Temporally Controlled Postnatal P53 Knockdown. Cooperates with embryonic Schwann cell precursor NF1 gene loss to promote malignant peripheral nerve tumor formation. It's a mouthful. So I am a physician scientist and my clinical and research efforts are really aligned. So I treat sarcoma patients in the clinic and that is what I focus in my laboratory. And so one of our major goals is to gain a better understanding of the biology behind malignant peripheral nerve-shaped tumors. And one way that we can do that would be to study the genetics of these tumors. And the goal with that is to learn about what genes and pathways are important for the generation of these tumors and to try to identify different biomarkers that we can use to help in diagnosis and treatment. And so when we're talking about trying to identify new treatment options, it's really important to have some kind of preclinical model that we can use to assess treatment response before you would bring these therapies into the clinic to test in patients. And there are a number of mouse models for malignant peripheral nerve tumors that do exist. And I talk about some of these in the manuscript. But some of the major issues and the challenges with dealing with many of the models that exist are that they often require complicated crosses of mice. And so they take long periods of time for you to actually get tumors to study. Another issue is that you don't know where in the mouse body these tumors are going to show up, nor do you know exactly when they're going to show up. And so one of the things that I wanted to do when I was still in David's lab to have, you know, with me as I begin my new laboratory, were to have, to generate some kind of model where we would have control over when and where these tumors form. And so, you know, when looking in the literature, we decided to take advantage of the conditional knockout NF1 mouse that exists. And then, you know, add another common technique that people use, and that's the use of lentivirals, lentiviral system in order to, you know, knock down or overexpress other genes. And so we decided we'll just kind of start with the basics. We know, obviously, NF1 is important for MPNST pathogenesis. And so with the NF1 conditional knockout mouse, we know that that mouse will get the benign precursor lesions to MPNSTs, but they won't actually go on to form the cancers. So we wanted to see if we introduced some other genetic change that we know is important in MPNST biology, could we get these aggressive tumors to form. And so, you know, we know that P53 loss or P53 mutation is a major factor in a number of cancers, including MPNSTs. So about 30 to 50 percent of MPNSTs will have a mutation in P53. So we worked with some of our collaborators in Dr. Verma's lab and took one of their lentiviruses that would allow us to knock down P53. And then I perfected a surgical procedure in the lab where we could actually isolate the sciatic nerve from a mouse, from a NF1 conditional knockout mouse, and then use that lentivirus to knock down P53 in that specific nerve. And so by doing this, you know, we've generated a model where we do have control over where and when tumors can form. And, you know, as we discussed in the paper, we can get these tumors fairly quickly. So within about three months from the time that we introduced the lentivirus. And so this model is really a foundation that I can build on in my lab going forward. You know, we sort of showed proof of principle this works. You lose NF1, you lose P53, and you get a mulligant peripheral nerve sheet tumor. But as I said, you know, my lab is interested in understanding kind of all of the factors that that may be important in MPNST formation. And so future work in my lab is continuing in the line of genomic studies to try to identify new genes that are involved in MPNST pathogenesis. And then we can use this system to assess the importance of those genes that we find in our sequencing efforts. So for example, if we find a gene that is knocked down in a number of tumors, we can then engineer lentivirus to make a hairpin to this particular gene so that we can knock it down in our mouse model and see if, you know, that affects MPNST tumor formation. Or if we think that we find a gene that's overexpressed in our sequencing studies, and this may be something that is contributing to MPNST pathogenesis, we can generate a lentivirus that will lead to overexpression of that gene and then see how that affects the tumors that form in this mouse model. So, you know, I'm very hopeful that this will serve as a platform for us to identify and verify the importance of other genes in MPNST pathogenesis. And then eventually, we can even use this tool as a way to test drugs that may be beneficial in treating these tumors. By clicking the link below, you can learn more about the research discussed in the interview from the cover of Paper of Value 7, Issue 7. Thank you for watching.