Targeted Deletion of Cxcl1 in MSCs Promotes Osteogenesis and Suppresses Bone Metastatic Prostate Cancer.

Abstract

Bone metastasis continues to be the greatest challenge in treating prostate cancer (PCa) patients, despite ongoing research. In bone, PCa tumors hijack normal bone remodeling processes to drive cancer progression. However, it is unclear how these interactions drive BM-PCa growth in the bone environment. To understand the mechanisms associated with BM-PCa regulation of MSCs, we previously identified that BM-PCa induces MSC expression of the pro-inflammatory chemokine CXCL8 and its mouse functional homolog Cxcl1. To date, there has been little to no information as to the role of CXCL1/8 in MSC biology and its impact in the tumor-bone environment. Using genetic deletion of Cxcl1, we discovered a novel role for Cxcl1/8 in regulating MSC osteoblast differentiation, such that targeted deletion of Cxcl1 enhanced MSC osteoblastogenesis. Despite the osteogenic nature of PCa, co-injection of Cxcl1 knockout (KO) MSCs with BM-PCa in bone significantly suppressed tumor growth compared to co-injection with Scrambled Control (non-targeting) MSCs, even in the presence of 3 times more prostate cancer to MSCs. Further, bulk RNAseq revealed immune response pathways, both in Cxcl1 KO MSCs and BM-PCa tumors containing Cxcl1 KO MSCs. In support of this, Cxcl1 KO MSCs reduced immature neutrophils in the bone environment, while increasing monocytes. These findings demonstrate the importance of MSC-derived Cxcl1 in the bone microenvironment and highlight the importance of Cxcl1 for in BM-PCa progression. Implications: MSC-derived CXCL1 regulates PCa progression in bone.