Deciphering the tumor microenvironment in metastatic osteosarcoma for therapeutic benefit
Mentor Name: Riaz Gillani
Osteosarcoma is the most prevalent malignant bone tumor among children and adolescents. Despite significant improvements in pediatric cancer treatment more generally over the last several decades, treatments for osteosarcoma have seen little progress. This is particularly true for metastatic osteosarcoma, where the 5-year overall survival is approximately 25% with current standard-of-care approaches involving chemotherapy and surgery. A better understanding of the unique biology driving metastatic osteosarcoma is needed to inform more rational and effective treatment strategies for this aggressive disease. The Gillani Lab has found that a gene expression program of dedifferentiated malignant cells is seen in metastatic disease in osteosarcoma. We hypothesize that the immune microenvironment in metastatic osteosarcoma plays an important role in mediating this unique biology and may represent a novel axis of therapeutic intervention. We will investigate the role of macrophages and other immune cells by applying computational methods to large-scale patient tumor sample derived single-cell transcriptomic sequencing data. By elucidating the specific roles and mechanisms of heterogenous macrophages within the tumor microenvironment, we aim to identify novel targets for immunomodulatory interventions that could enhance treatment efficacy and improve patient outcomes in osteosarcoma. We plan to expand the data processing methods provided as part of the Alex’s Lemonade Stand Foundation’s single-cell Pediatric Cancer Atlas (scPCA) to generate a large-scale, uniformly processed osteosarcoma patient tumor single-cell RNA-seq dataset. We will leverage commonly utilized computational approaches, such as clustering algorithms, marker gene expression, pathway gene analysis, and matrix decomposition, to identify and annotate heterogenous cell types present within the tumor microenvironment. In order to more comprehensively identify potential immunosuppressive mechanisms within the tumor microenvironment, we will use cell-cell communication inference methods to elucidate the relationship between malignant and immune cells. By unraveling the interactions between macrophages, dendritic, and other immune cells with the malignant tumor cells, we hope to uncover insights into the mechanisms driving metastatic disease development in osteosarcoma. Our findings have the potential to inform novel therapeutic interventions for this aggressive pediatric cancer.
