Bailey Roberts, MD - Best of the Best in Pediatric Surgery 2024

All right, so one heat down, a few more left to go until we get to see who the true best of the best of 2024 is. And so we'll move on to the second heat of the day. First, we have the International Society of Pediatric Surgical Oncology and CAPS, the Canadian Association of Pediatric Surgeons, uh, to represent. So we'll watch all four, and then we'll vote. Awesome. So first, we have Doctor Bailey Roberts. She's a pediatric surgeon from Cohen Children's Medical Center and Feinstein Institute of Molecular Medicine at Northwell Health. She's representing IPSO with extracellular vesicles from metastasic osteosarcoma contribute to creation of a pre-metastasic niche. So let's hear it. Hello, my name is Bailey Roberts. Thank you for the opportunity to share the work I presented at the International Society of Pediatric Oncology. My work is entitled Extracellular Vesicles for Metastatic Osteosarcoma Contribute to Creation of a Pre-metastatic niche. I have no disclosures. Osteosarcoma is a malignant pediatric tumor of the bone. It most commonly affects adolescents and young adults. Gross metastasis at the time of diagnosis is present about 20% of the time, and the most common site of metastasis is in the lung. Overall survival worsens from 80% to about 20% for metastatic disease. Recurrence is also very common in osteosarcoma, and the most common site of recurrence is in the lungs. Extracellular vesicles or EVs are small nanoparticles released from all cells. They're carriers of amino acids, proteins, mRNA or other forms of cellular communication. The EV content is unique and specific to the cells that released it, and therefore can be traced back to the cell type. EVs are involved in the metastatic cascade and implicated as potential markers for disease diagnosis and staging. They're involved in influencing immune cells or other cells at distant sites from the primary tumor. For example, they've been shown to change fibroblasts, inhibit T cell activity, and importantly, are involved in establishing a pre-metastatic niche. The aim of our study was to determine if extracellular vesicles from osteosarcoma can establish a pre-metastatic niche and increase pulmonary metastasis in a mirroring model of osteosarcoma. For these experiments, we use two similar cell lines with varying metastatic potential. K12 is a spontaneous osteosarcoma with low metastatic capability. Conversely, K7M2 is a highly metastatic osteosarcoma. It is derived from a spontaneous osteosarcoma like K12, that then went through two reiterations of harvesting spontaneous lung metastases and reimplanting them into the mouse to create a highly metastatic tumor cell line, thus giving it the name K7M2. This survival curve shows evidence that this K7M2 cell line is more aggressive and causes death at a much higher rate than K12. In these experiments, EVs were collected from both the K7M2 or the K12 cell lines. Equal numbers of EVs or empty liposomes as control, were injected into the tail veins of mice a total of 10 times over 3 weeks in a process referred to as EV education. After education, either K7M2 or K12 tumors were implanted into the tibia of the mice and allowed to grow and metastasize for five weeks. After this duration, lungs were collected and examined for metastatic burden. Here we're looking at the mice with K7M2 tumors. As you can see here, pulmonary metastasis is common with K7M2 tumors and some smaller metastatic fosci. Education with liposomes and K-12 EVs did not dramatically change the metastatic burden. Strikingly, pre-education with K7M2 EVs drastically increases the metastatic burden in the lungs of mice. You can see the large metastatic fossci and distortion of normal lung architecture due to the tumor in the mice pre-educated with K7M2 EVs. Additionally, the pre-education with K7M2 EVs increased the overall mortality during the five-week study period, as shown by this survival curve noted in the red line. Here, we're looking at the mice given K12 tumors. Almost no metastasis is seen in the controls with no pre-education, with liposome pre-education, and very little metastasis in mice given pre-education with K12 EVs. However, K7M2 EV education led to increased metastatic burden. The representative images depict the very small micrometastases from educating with K12 EVs and the larger micrometastases from educating with K7M2 EVs. Thus, pre-education with a highly metastatic cell line EVs increases the metastasis seen in a normally low metastatic tumor. No mice with K12 tumors died in the study period. In conclusion, extracellular vesicles delivered prior to tumor implantation from highly metastatic K7M2 increase the metastatic burden of K7M2 tumors. This increased metastatic burden from the extracellular vesicles decrease the overall survival. These same extracellular vesicles from the highly metastatic K7M2 also increase the metastatic burden of less metastatic K12 tumors. Extracellular vesicles can cause metastatic spread and therefore be a therapeutic target for osteosarcoma metastasis. Thank you very much. Awesome. Um, we love your presentation. Thank you, Doctor Roberts. Um, I have a question. Um, will, it's a complex question. So, will future immunotherapy targeting this high metastasic EVs help to prevent the formation of metastasis or just treat them? Um, that's a very interesting question. Thank you. Um, I think that, um, learning the, um, methods of metastasis kind of gives us new, uh, places to target. Um, unfortunately, all cells in the body release EVs, so we can't just generally target EVs and hope to decrease the establishment of a pre-metastatic niche. Um, other work that my lab is doing is actually trying to parse out what inside those EVs make them more likely to cause a pre-metastatic niche versus, uh, the less metastatic, uh, tumor cells that also release EVs. Um, Uh, uh, one of the things that we're looking at is actually a molecule called IRF 5. So we could then, um, have immunotherapy targets towards um something like that. Um, so that's something that we're exploring. Awesome. Um, and you think this will also help to treat the primary tumor or only the metastasis? Um, I, I don't think that it could treat the primary tumor as well as surgically removing it, which is, um, the current standard of care. And just to make sure I understand, targeting the EVs is, there's, there's not expressed proteins on the, on the, on the membrane that would allow you to target specific EVs. Is that what you're saying? Yeah, so there are certain membrane EV markers, um, but they're shared by all types of EVs. The, the differences in EVs by cell type have more to do with the contents inside of them than the targets on them, which makes them difficult to target as far as treatment. Uh, it's better more for a prognostic, um, evaluation. Um, there's even studies in dogs where they're able to take serum of the dogs with osteosarcoma and determine, um, their likelihood of metastasis, um, just based on the EVs. So that's more of a direction I think it could go, um, unless there's a specific, uh, molecule in the EVs that you could target. Yeah, wow, incredible. Yeah, yeah, um, we have, uh, one question that was put in the chat. Uh, we have, unfortunately, uh, to go to the next presentation, but if you could reply that, Doctor Roberts, it will be awesome. Andrew Davidoff asked a question, so you may wanna go, go look at that. Thanks, Andy, for the question. All right, thank you.