Browsing by Subject "Osteosarcoma (OS)"

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    The Crucial p53-Dependent Oncogenic Role of JAB1 in Osteosarcoma in vivo
    (Nature, 2020-06) Samsa, William E.; Mamidi, Murali K.; Bashur, Lindsay A.; Elliott, Robin; Miron, Alexander; Chen, Yuqing; Lee, Brendan; Greenfield, Edward M.; Chan, Ricky; Danielpour, David; Zhou, Guang; Orthopaedic Surgery, School of Medicine
    Osteosarcoma (OS) is the most common primary bone cancer and ranks amongst the leading causes of cancer mortality in young adults. Jun activation domain binding protein 1 (JAB1) is overexpressed in many cancers and has recently emerged as a novel target for cancer treatment. However, the role of JAB1 in osteosarcoma was virtually unknown. In this study, we demonstrate that JAB1-knockdown in malignant osteosarcoma cell lines significantly reduced their oncogenic properties, including proliferation, colony formation, and motility. We also performed RNA-sequencing analysis in JAB1-knockdown OS cells and identified 4110 genes that are significantly differentially expressed. This demonstrated for the first time that JAB1 regulates a large and specific transcriptome in cancer. We also found that JAB1 is overexpressed in human OS and correlates with a poor prognosis. Moreover, we generated a novel mouse model that overexpresses Jab1 specifically in osteoblasts upon a TP53 heterozygous sensitizing background. Interestingly, by 13 months of age, a significant proportion of these mice spontaneously developed conventional OS. Finally, we demonstrate that a novel, highly specific small molecule inhibitor of JAB1, CSN5i-3, reduces osteosarcoma cell viability and has specific effects on the ubiquitin-proteasome system in OS. Thus, we show for the first time that the overexpression of JAB1 in vivo can result in accelerated spontaneous tumor formation in a p53-dependent manner. In summary, JAB1 might be a unique target for the treatment of osteosarcoma and other cancers.
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    ELEVATED LEVELS OF PLATELETS AND MDM2 EXPRESSION ARE CONTRIB-UTING FACTORS TO FACILITATING THE METASTASIS OF OSTEOSARCOMA
    (Office of the Vice Chancellor for Research, 2012-04-13) Lipking, Kelsey; Kacena, Melissa A.; Konopka, Jeff A.; Mayo, Lindsey D.; Sandusky, George E.
    Osteosarcoma (OS) is the most common form of primary bone cancer and the 6th leading cause of cancer in pediatric patients. A chart review of OS patients treated at this institution suggests that a high platelet count at di-agnosis is significantly (p=0.023) and inversely associated with the first year of survival. As the effects of platelet interaction with OS have been exten-sively researched and suggest that platelets may facilitate tumor metastasis, and the most important prognostic factor for OS patient survival is metasta-sis to the lungs, we hypothesized that platelets increase metastasis to the lungs and reduce survival. Therefore, we sought to determine whether in-creasing platelet numbers in a well characterized OS mouse model would de-crease survival and/or increase metastasis to the lungs. We found that thrombopoietin (TPO) treated mice, had increased platelet numbers, died earlier than placebo treated controls, and that lungs from TPO treated mice contained a small number of large tumor cells (most metastatic lesions were 2-4 cells), whereas lungs from placebo treated controls showed no signs of metastases. Next, an OS tissue microarray (TMA) was built from OS patients seen at our institution over the past 10 years. Mdm2, p53, TPO, and c-mpl expression were evaluated by immunohistochemical (IHC) staining followed by quantitation using the Aperio Imaging system and analysis software. C-mpl (TPO receptor) expression was higher in the metastatic than the primary tumors, suggesting that platelets may contribute to the metastasis of OS. Elevated levels of Mdm2 correlated with metastasis and lower levels of p53, as detected by IHC. In conclusion, both the mouse model and the human OS data were similar, suggesting that both platelets and Mdm2 promote metas-tases in OS.
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    Integrative Multi-OMICs Identifies Therapeutic Response Biomarkers and Confirms Fidelity of Clinically Annotated, Serially Passaged Patient-Derived Xenografts Established from Primary and Metastatic Pediatric and AYA Solid Tumors
    (MDPI, 2022-12-30) Pandya, Pankita H.; Jannu, Asha Jacob; Bijangi-Vishehsaraei, Khadijeh; Dobrota, Erika; Bailey, Barbara J.; Barghi, Farinaz; Shannon, Harlan E.; Riyahi, Niknam; Damayanti, Nur P.; Young, Courtney; Malko, Rada; Justice, Ryli; Albright, Eric; Sandusky, George E.; Wurtz, L. Daniel; Collier, Christopher D.; Marshall, Mark S.; Gallagher, Rosa I.; Wulfkuhle, Julia D.; Petricoin, Emanuel F.; Coy, Kathy; Trowbridge, Melissa; Sinn, Anthony L.; Renbarger, Jamie L.; Ferguson, Michael J.; Huang, Kun; Zhang, Jie; Saadatzadeh, M. Reza; Pollok, Karen E.; Pediatrics, School of Medicine
    Establishment of clinically annotated, molecularly characterized, patient-derived xenografts (PDXs) from treatment-naïve and pretreated patients provides a platform to test precision genomics-guided therapies. An integrated multi-OMICS pipeline was developed to identify cancer-associated pathways and evaluate stability of molecular signatures in a panel of pediatric and AYA PDXs following serial passaging in mice. Original solid tumor samples and their corresponding PDXs were evaluated by whole-genome sequencing, RNA-seq, immunoblotting, pathway enrichment analyses, and the drug−gene interaction database to identify as well as cross-validate actionable targets in patients with sarcomas or Wilms tumors. While some divergence between original tumor and the respective PDX was evident, majority of alterations were not functionally impactful, and oncogenic pathway activation was maintained following serial passaging. CDK4/6 and BETs were prioritized as biomarkers of therapeutic response in osteosarcoma PDXs with pertinent molecular signatures. Inhibition of CDK4/6 or BETs decreased osteosarcoma PDX growth (two-way ANOVA, p < 0.05) confirming mechanistic involvement in growth. Linking patient treatment history with molecular and efficacy data in PDX will provide a strong rationale for targeted therapy and improve our understanding of which therapy is most beneficial in patients at diagnosis and in those already exposed to therapy.