Comparative Transcriptome Analysis Quantifies Immune Cell Transcript Levels, Metastatic Progression, and Survival in Osteosarcoma

Abstract

Overall survival of patients with osteosarcoma (OS) has improved little in the past three decades and better models for study are needed. OS is common in large dog breeds and is genetically inducible in mice, making the disease ideal for comparative genomic analyses across species. Understanding the level of conservation of inter-tumor transcriptional variation across species and how it is associated with progression to metastasis will enable us to more efficiently develop effective strategies to manage OS and improve therapy. In this study, transcriptional profiles of OS tumors and cell lines derived from humans (n=49), mice (n=103) and dogs (n=34) were generated using RNA-sequencing. Conserved inter- tumor transcriptional variation was present in tumor sets from all three species and comprised gene clusters associated with cell cycle and mitosis and with the presence or absence of immune cells. Further, we developed a novel Gene Cluster Expression Summary Score (GCESS) to quantify inter-tumor transcriptional variation and demonstrated that these GCESS values associated with patient outcome. Human OS tumors with GCESS values suggesting decreased immune cell presence were associated with metastasis and poor survival. We validated these results in an independent human OS tumor cohort and in 15 different tumor data sets obtained from The Cancer Genome Atlas (TCGA). Our results suggest that quantification of immune cell absence and tumor cell proliferation may better inform therapeutic decisions and improve overall survival for OS patients.

Metastasis‑associated gene MAPK15 promotes the migration and invasion of osteosarcoma cells via the c‑Jun/MMPs pathway

“…nih.gov/geo/), and subsequently used to perform WGCNA and DEG analysis. The GSE87624 dataset, comprising 44 human patient OS samples and 3 normal bone samples, was first published by Scott et al (22).…”

Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

“…Many are monospecific antibodies in which both binding sites are directed against the same target; others are bispecific antibodies where the binding sites are directed to different targets, allowing engagement of immune cells, inhibition of signalling pathways, or delivery of cytotoxic molecules . Studies have suggested a correlation between prognosis and the presence of tumour infiltrating lymphocytes as well as with specific patterns of infiltration within the tumour microenvironment . A better understanding of the sarcoma microenvironment of different sarcoma subtypes will be critical to the development of new therapeutic strategies focused on targeting and manipulating the microenvironment to overcome immune evasion .…”

“…113,114 Studies have suggested a correlation between prognosis and the presence of tumour infiltrating lymphocytes as well as with specific patterns of infiltration within the tumour microenvironment. [115][116][117][118][119][120] A better understanding of the sarcoma microenvironment of different sarcoma subtypes will be critical to the development of new therapeutic strategies focused on targeting and manipulating the microenvironment to overcome immune evasion. 121 A plausible approach is to link mAbs to recombinant toxins to generate ligand-directed "immunotoxins," or to radioisotopes, to enable energy release from the radioisotope into a solid tumour to kill both tumour and surrounding stromal cells.…”

Molecular Mechanisms of Canine Cancers

“…Approximately 20% of dogs will survive more than two years [9][10][11]. The prognosis for osteosarcoma is similarly poor: Unless early and intense treatment is started upon detection, the average survival time is 3 months without treatment [12][13][14]. Canines with malignant melanoma have a median survival time ranging from three to 18 months, depending on the stage at diagnosis [15].…”

“…The most effective management of canine appendicular osteosarcoma involves the incorporation of multimodal therapy to address the primary tumor and metastatic disease [14,18]. Palliative and curative-intent treatments are used for the bilateral synchronous appendicular bone tumors [19].…”