| First Author | Kansara M | Year | 2019 |
| Journal | Cancer Discov | Volume | 9 |
| Issue | 11 | Pages | 1511-1519 |
| PubMed ID | 31527131 | Mgi Jnum | J:280883 |
| Mgi Id | MGI:6370051 | Doi | 10.1158/2159-8290.CD-19-0154 |
| Citation | Kansara M, et al. (2019) Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23. Cancer Discov 9(11):1511-1519 |
| abstractText | The glutamate metabotropic receptor 4 (GRM4) locus is linked to susceptibility to human osteosarcoma, through unknown mechanisms. We show that Grm4(-/-) gene-targeted mice demonstrate accelerated radiation-induced tumor development to an extent comparable with Rb1(+/-) mice. GRM4 is expressed in myeloid cells, selectively regulating expression of IL23 and the related cytokine IL12. Osteosarcoma-conditioned media induce myeloid cell Il23 expression in a GRM4-dependent fashion, while suppressing the related cytokine Il12. Both human and mouse osteosarcomas express an increased IL23:IL12 ratio, whereas higher IL23 expression is associated with worse survival in humans. Consistent with an oncogenic role, Il23 (-/-) mice are strikingly resistant to osteosarcoma development. Agonists of GRM4 or a neutralizing antibody to IL23 suppressed osteosarcoma growth in mice. These findings identify a novel, druggable myeloid suppressor pathway linking GRM4 to the proinflammatory IL23/IL12 axis. SIGNIFICANCE: Few novel systemic therapies targeting osteosarcoma have emerged in the last four decades. Using insights gained from a genome-wide association study and mouse modeling, we show that GRM4 plays a role in driving osteosarcoma via a non-cell-autonomous mechanism regulating IL23, opening new avenues for therapeutic intervention.See related commentary by Jones, p. 1484.This article is highlighted in the In This Issue feature, p. 1469. |
