Targeting Osteosarcoma with Canine B7-H3 CAR T Cells and Impact of CXCR2 Co-Expression on Functional Activity
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ABSTRACT:
PROVIDER: PRJNA1037149 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26729600_1.fastq.gz | Fastqsanger.gz | |||
| SRR26729600_2.fastq.gz | Fastqsanger.gz | |||
| SRR26729592_1.fastq.gz | Fastqsanger.gz | |||
| SRR26729592_2.fastq.gz | Fastqsanger.gz | |||
| SRR26729593_1.fastq.gz | Fastqsanger.gz |
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Project description:Abstract. The use of large animal spontaneous models of solid cancers, such as dogs with osteosarcoma (OS), can help develop new cancer immunotherapy approaches, including chimeric antigen receptor (CAR) T cells. Therefore, the goal of the present study was to generate canine CAR T cells targeting the B7-H3 (CD276) co-stimulatory molecule overexpressed by several solid cancers, including OS and glioma in both humans and dogs, and to assess their ability to recognize B7-H3 expressed by canine OS cell lines or by canine tumors in xenograft models. A second objective was to determine whether a novel dual CAR that expressed a chemokine receptor together with the B7-H3 CAR improved the activity of the canine CAR T cells. Therefore, in the studies reported here we examined B7-H3 expression by canine OS tumors, evaluated target engagement by canine B7-H3 CAR T cells in vitro, and compared the relative effectiveness of B7-H3 CAR T cells versus B7-H3-CXCR2 dual CAR T cells in canine xenograft models. We found that most canine OS tumors expressed high levels of B7-H3, whereas levels were undetectable on normal dog tissues. In vitro, both B7-H3 CAR T cells demonstrated activation and OS-specific target killing in vitro, but there was significantly greater cytokine production by B7-H3-CXCR2 CAR T cells. In canine OS xenograft models, little antitumor activity was generated by B7-H3 CAR T cells, whereas B7-H3-CXCR2 CAR T cells significantly inhibited tumor growth, inducing complete tumor elimination in most treated mice. These findings indicated therefore that addition of a chemokine receptor could significantly improve the anti-tumor activity of canine B7-H3 CAR T cells, and that evaluation of this new dual CAR construct in dogs with primary or metastatic OS is warranted since such studies could provide a critical and realistic validation of the chemokine receptor concept.
2024-04-03 | GSE247355 | GEO
Project description:Osteosarcoma is the most common primary bone tumours of dogs. Canine osteosarcoma contains a sub-population of cancer stem cells. Here we used canine-specific microarrays to compare the global gene expression profiles of osteosarcoma stem cells to adherent cancer cells and canine mesenchymal stem cells.
2013-11-05 | GSE52063 | GEO
Project description:RNA-Seq of canine osteosarcoma tumor samples obtained from Canine Comparative Oncology and Genomics Consortium
2023-08-07 | GSE239948 | GEO
Project description:B7-H3 has emerged as a promising target for cancer therapy due to its high expression in various types of cancer cells. It not only regulates the activity of immune cells but also modulates the signal transduction and metabolism of cancer cells. However, the specific interaction partners of B7-H3 still remain ambiguous, limiting a comprehensive understanding of the precise role of B7-H3 in cancer progression. In this study, we reported that B7-H3 can bind to resting Raji cells, stimulated THP-1 cells, and even PC3 prostate cancer cells through its IgV domain alone. Furthermore, to identify the potential interaction partners of B7-H3 on these cells, we adopted an APEX2-based proximity labeling strategy, which unveiled about 10 key potential interaction partners. Interestingly, our results suggested that CD45 could be a putative receptor for B7-H3 on Raji cells, while EGFR could closely interact with B7-H3 on PC3 cells. Based on further computational structure modeling studies, we showed that B7-H3 can bind to the EGF binding pocket of EGFR, surprisingly stronger than EGF itself. Overall, our study provides an effective approach to identifying B7-H3 interaction partners in both immune and cancer cell lines.
2024-12-23 | PXD059197 |
Project description:B7-H3, an immune checkpoint molecule, is overexpressed in various solid cancers, correlating with negative prognosis and poor clinical outcomes. However, its regulatory mechanisms in aggressive cancers and cancer stem cells (CSCs), which contribute to cancer formation, progression, chemoresistance, and recurrence, remain unclear. To elucidate the mechanisms regulating B7-H3 expression in breast CSCs, we employed DNA affinity purification-mass spectrometry (DAP-MS) with presumptive promoter regions of B7-H3 and identified several proteins binding to that promoter regions in CSC specific manner. Subsequent validation studies identified several potential transcription factors, including DNA damage-binding protein 1 (DDB1), XRCC5, PARP1, RPA1, and RPA3, for their significant impact on B7-H3 expression. In vitro inhibition of DDB1 with its known inhibitor, nitazoxanide, resulted in a marked decrease in B7-H3 expression, suppressing tumor sphere formation and cell migration in breast CSCs. Our findings reveal a transcription factor-mediated regulatory mechanism for B7-H3 in CSCs through proteomic analysis and highlight the critical role of these transcription factors in regulating B7-H3 expression. These results may elucidate underlying mechanisms, paving the way for the development of new immunotherapeutic strategies against breast cancer.
2025-05-07 | PXD054584 | Pride
Project description:Osteosarcoma is the most common primary bone tumours of dogs. Canine osteosarcoma contains a sub-population of cancer stem cells. Here we used canine-specific microarrays to compare the global gene expression profiles of osteosarcoma stem cells to adherent cancer cells and canine mesenchymal stem cells. Canine osteosarcoma spheres were isolated by their ability to form tumourspheres. Spheres, adherent cells and mesenchymal stem cells were harvested and used for RNA extraction and hybridisation on Affymetrix microarrays (Canine 2.0). Four biological replicates of each sample were included.
2013-11-05 | E-GEOD-52063 | biostudies-arrayexpress
Project description:Pulmonary metastasis continues to be the most common cause of death in osteosarcoma. Indeed, the 5-year survival for newly diagnosed osteosarcoma patients has not significantly changed in over 20 years. Further understanding of the mechanisms of metastasis and resistance for this aggressive pediatric cancer is necessary. Pet dogs naturally develop osteosarcoma providing a novel opportunity to model metastasis development and progression. Given the accelerated biology of canine osteosarcoma, we hypothesized that a direct comparison of canine and pediatric osteosarcoma expression profiles may help identify novel metastasis-associated tumor targets that have been missed through the study of the human cancer alone. Collectively, these data support the strong similarities between human and canine osteosarcoma and underline the opportunities provided by a comparative oncology approach as a means to improve our understanding of cancer biology and therapy.
2009-11-04 | GSE16087 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE16087: Gene expression profiles of canine osteosarcoma GSE16088: Gene expression profiles of human osteosarcoma GSE16091: Gene expression profiles of human osteosarcoma, set2 Pulmonary metastasis continues to be the most common cause of death in osteosarcoma. Indeed, the 5-year survival for newly diagnosed osteosarcoma patients has not significantly changed in over 20 years. Further understanding of the mechanisms of metastasis and resistance for this aggressive pediatric cancer is necessary. Pet dogs naturally develop osteosarcoma providing a novel opportunity to model metastasis development and progression. Given the accelerated biology of canine osteosarcoma, we hypothesized that a direct comparison of canine and pediatric osteosarcoma expression profiles may help identify novel metastasis-associated tumor targets that have been missed through the study of the human cancer alone. Collectively, these data support the strong similarities between human and canine osteosarcoma and underline the opportunities provided by a comparative oncology approach as a means to improve our understanding of cancer biology and therapy. Two datasets consisting of canine osteosarcoma tumors, canine osteosarcoma cell lines, and three normal tissues and an analogous human dataset were used to define the similarity between human and canine osteosarcoma. A third dataset, human osteosarcoma with outcome data, was then used to suggest that some of the differences between the canine and human osteosarcoma were, perhaps, related to survival.
2009-11-03 | E-GEOD-16102 | biostudies-arrayexpress
Project description:Pulmonary metastasis continues to be the most common cause of death in osteosarcoma. Indeed, the 5-year survival for newly diagnosed osteosarcoma patients has not significantly changed in over 20 years. Further understanding of the mechanisms of metastasis and resistance for this aggressive pediatric cancer is necessary. Pet dogs naturally develop osteosarcoma providing a novel opportunity to model metastasis development and progression. Given the accelerated biology of canine osteosarcoma, we hypothesized that a direct comparison of canine and pediatric osteosarcoma expression profiles may help identify novel metastasis-associated tumor targets that have been missed through the study of the human cancer alone. Collectively, these data support the strong similarities between human and canine osteosarcoma and underline the opportunities provided by a comparative oncology approach as a means to improve our understanding of cancer biology and therapy. Profiles of dog osteosarcoma and several normal tissues, single channel design, tumor versus normal
2010-05-08 | E-GEOD-16087 | biostudies-arrayexpress
Project description:Pulmonary metastasis continues to be the most common cause of death in osteosarcoma. Indeed, the 5-year survival for newly diagnosed osteosarcoma patients has not significantly changed in over 20 years. Further understanding of the mechanisms of metastasis and resistance for this aggressive pediatric cancer is necessary. Pet dogs naturally develop osteosarcoma providing a novel opportunity to model metastasis development and progression. Given the accelerated biology of canine osteosarcoma, we hypothesized that a direct comparison of canine and pediatric osteosarcoma expression profiles may help identify novel metastasis-associated tumor targets that have been missed through the study of the human cancer alone. Collectively, these data support the strong similarities between human and canine osteosarcoma and underline the opportunities provided by a comparative oncology approach as a means to improve our understanding of cancer biology and therapy. This SuperSeries is composed of the SubSeries listed below.
2009-11-04 | GSE16102 | GEO