Leung, S. G. | Search bioRxiv

bioRxiv2025

STING activation reshapes the tumor microenvironment leading to tumor regression in osteosarcoma

Osteosarcomas are characterized by a high degree of aneuploidy, chromothripsis and micronuclei, yet these tumors typically have an immunosuppressive, macrophage-rich, T-cell depleted tumor microenvironment. cGAS-STING dysregulation is a possible mechanism by which immune activation in response to tumor genomic instability could be repressed. We identified almost universal repression of cGAS or STING in human osteosarcomas. However, a STING-activation gene signature was predictive of survival in osteosarcoma patients suggesting potential for activation of this pathway in the osteosarcoma tumor microenvironment. Indeed, in immunocompetent osteosarcoma models, systemic STING agonism led to complete regression and induced lasting immunologic memory. Host STING activation is sufficient to promote this anti-tumor immunity even in the absence of tumor STING. These results nominate the cGAS-STING pathway as an important therapeutic target in osteosarcoma, a disease in which no new curative therapies have been developed in the last 40 years. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/684275v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@15b1e5corg.highwire.dtl.DTLVardef@12650aaorg.highwire.dtl.DTLVardef@79ef71org.highwire.dtl.DTLVardef@15704c9_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Development and characterization of new patient-derived xenograft (PDX) models of osteosarcoma with distinct metastatic capacities

Models to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology, especially for highly aggressive cancers with a propensity for metastatic spread. Osteosarcoma is a rare cancer with a complex genomic landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, a large panel of models is needed to fully elucidate key aspects of disease biology and to recapitulate clinically-relevant phenotypes. We describe the development and characterization of osteosarcoma patient-derived xenografts (PDXs) and a panel of PDX-derived cell lines. Matched patient samples, PDXs, and PDX-derived cell lines were comprehensively evaluated using whole genome sequencing and RNA sequencing. PDXs and PDX-derived cell lines largely maintained the expression profiles of the patient from which they were derived despite the emergence of whole-genome duplication (WGD) in a subset of cell lines. These cell line models were heterogeneous in their metastatic capacity and their tissue tropism as observed in both intravenous and orthotopic models. As proof-of-concept study, we used one of these models to test the preclinical effectiveness of a CDK inhibitor on the growth of metastatic tumors in an orthotopic amputation model. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden in this model. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=74 SRC="FIGDIR/small/524562v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@17ea2a8org.highwire.dtl.DTLVardef@e8fcc7org.highwire.dtl.DTLVardef@2b9f8corg.highwire.dtl.DTLVardef@1f7b802_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗