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OPG promotes lung metastasis by blocking the RANKL-RANK-CXCL10 axis to drive NK cell paucity (CRISPR)

ABSTRACT: Metastasis is the major cause of cancer-related mortality. In the lung metastasis, monocyte-derived macrophages (Mo-macs) exhibit a complex function. However, tumor cells how to derive lung metastasis through Mo-macs remains unclear. Here we show that a tumor-secreted protein osteoprotegerin (OPG) contributes to the lung metastasis of cancer depends on the Mo-macs by an in vivo screening. OPG binds with RANKL to block the signaling between RANKL-RANK on Mo-macs. RANKL-RANK signals induce Mo-macs to secrete CXCL10, recruiting NK cells to control the lung metastasis. Increased expression of OPG in the metastases is regulated by TGF-β. Consistent with our findings, enrichment of OPG amplifications was observed in metastatic cancer patients, and increased expression of OPG was also shown in the lung metastatic sites compared with the paired primary breast cancer samples. Overall, our findings reveal a mechanism of how tumor cells promote lung metastasis via inhibiting the function of Mo-macs.

ORGANISM(S): Mus musculus

PROVIDER: GSE260469 | GEO | 2024/12/16

REPOSITORIES: GEO

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OPG promotes lung metastasis by blocking the RANKL-RANK-CXCL10 axis to drive NK cell paucity

Project description:Metastasis is the major cause of cancer-related mortality. In the lung metastasis, monocyte-derived macrophages (Mo-macs) exhibit a complex function. However, tumor cells how to derive lung metastasis through Mo-macs remains unclear. Here we show that a tumor-secreted protein osteoprotegerin (OPG) contributes to the lung metastasis of cancer depends on the Mo-macs by an in vivo screening. OPG binds with RANKL to block the signaling between RANKL-RANK on Mo-macs. RANKL-RANK signals induce Mo-macs to secrete CXCL10, recruiting NK cells to control the lung metastasis. Increased expression of OPG in the metastases is regulated by TGF-β. Consistent with our findings, enrichment of OPG amplifications was observed in metastatic cancer patients, and increased expression of OPG was also shown in the lung metastatic sites compared with the paired primary breast cancer samples. Overall, our findings reveal a mechanism of how tumor cells promote lung metastasis via inhibiting the function of Mo-macs.

2024-12-16 | GSE259293 | GEO

Delayed denervation-induced muscle atrophy in Opg knockout mice

Project description:Recent evidence has shown a crucial role for the osteoprotegerin/receptor activator of nuclear factor κ-B ligand/RANK (OPG/RANKL/RANK) signaling axis not only in bone but also in muscle tissue; however, there is still a lack of understanding of its effects on muscle atrophy. Here, we found that denervated Opg knockout mice displayed better functional recovery and delayed muscle atrophy, especially in a specific type IIB fiber. Moreover, OPG deficiency promoted milder activation of the ubiquitin-proteasome pathway, which further verified the protective role of Opg knockout in denervated muscle damage. Furthermore, transcriptome sequencing indicated that Opg knockout upregulated the expression of Inpp5k, Rbm3, and Tet2 and downregulated that of Deptor in denervated muscle. In vitro experiments revealed that satellite cells derived from Opg knockout mice displayed a better differentiation ability than those acquired from wild-type littermates. Higher expression levels of Tet2 were also observed in satellite cells derived from Opg knockout mice, which provided a mechanistic basis for the protective effects of Opg knockout on muscle atrophy. Taken together, our findings uncover the novel role of Opg in muscle atrophy process and extend the current understanding in the OPG/RANKL/RANK signaling axis.

2023-05-01 | GSE220152 | GEO

Amplification of RANK- and c-Met-mediated signaling promotes metastatic colonization

Project description:We found that RANKL, expressed by cancer cells or derived from exogenous sources, consistently induced human prostate, breast, kidney, lung and liver cancer cells to colonize or metastasize to bone in an animal model of cancer bone metastasis. RANK-mediated signaling established a premetastatic niche through a forward feedback loop by inducing RANKL and c-Met expression and downstream signaling via upregulation of master regulator transcription factors regulating EMT (Twist1, Slug, Zeb1, Zeb2), stem cells (Sox2, Myc, Oct3/4 and Nanog), neuroendocrine cells (Sox 9, HIF-1α and FoxA2) and osteomimicry (c-Myc/Max, Sox2, Sox9, HIF1α and Runx2). Abrogating RANK or its downstream signaling network, c-Myc/Max or c-Met, abolished PCa skeletal metastasis in mice. We observed that a small number of RANKL-expressing PCa cells can initiate bone and soft tissue metastases by recruiting non-tumorigenic or bystander PCa or host cells from the circulation or at metastatic sites to co-colonize bone. The recruited bystander PCa cells assume the phenotypes of RANKL-expressing PCa cells by expressing increased c-Met, phosphorylated c-Met and RANKL. RANKL expression at a single cell level in primary PCa tissues predicted disease-specific survival, reflecting the significant role of RANKL-RANK signaling in the development of lethal bone metastasis. Global gene expression analysis perturbed by RANKL in LNRANKL compared to LNNeo cells.

2014-02-06 | E-GEOD-48432 | biostudies-arrayexpress

Amplification of RANK- and c-Met-mediated signaling promotes metastatic colonization

2014-02-06 | GSE48432 | GEO

Recombinant RANKL causes modulation of inflammatory signaling pathways in C2C12 myotubes

Project description:Previous reports indicate that RANKL-RANK signaling participates in regulating muscle mass and strength in denervated animals, while RANKL inhibition by OPG-Fc peptide improves the muscle phenotype in dystrophic mdx mice. RANKL has also been shown to activate STAT3 to regulate osteoclastogenesis, although it is not known whether such interaction also plays a role in skeletal muscle. The objective of this aim is to clarify whether RANKL directly affects skeletal muscle.

2022-03-30 | GSE149606 | GEO

Expression data from cells with siRNA-mediated knockdown of OPG and from HVSMCs incubated with RANKL or TRAIL

Project description:We used microarrays to assess gene expression changes in cells with siRNA-mediated knockdown of OPG compared to normal cells. Furthermore, we used microarrays to assess gene expression in cells treated with either RANKL or TRAIL compared to vehicle-treated cells.

2014-09-22 | GSE29955 | GEO

Expression data from cells with siRNA-mediated knockdown of OPG and from HVSMCs incubated with RANKL or TRAIL

2014-09-22 | E-GEOD-29955 | biostudies-arrayexpress

Project description:Murine lung Mo-macs Transcriptome

| PRJNA1079493 | ENA

Lenalidomide and Pomalidomide inhibit Multiple Myeloma-induced osteoclast formation and RANKL/OPG ratio in myeloma microenvironment targeting the expression of adhesion molecules.

Project description:Multiple myeloma (MM)-induced osteoclast (OC) formation occurs in close contact with MM cell infiltration into the bone marrow (BM) due to the imbalance of the receptor activator of NF-kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio in favor of RANKL in the micorenvironment. Soluble factors including CCL3/MIP-1?, IL7 and IL-3 also contribute to the increased OC formation in MM.The immunomodulatory drugs (IMiD®s) directly inhibit OCs, however their effect on the mechanisms involved in MM-induced OC formation are not known and have been investigated in this study. We found that both Lenalidomide (LEN) and Pomalidomide (POM), at concentration ranging reached in vivo, significantly blunted RANKL up-regulation normalizing the RANKL/OPG ratio in human BM osteoprogenitor cells (PreOBs) co-cultured with MM cells and inhibited CCL3/MIP-1? production by MM cells. The reduction of CD49d expression on MM cells, a molecule critically involved in RANKL up-regulation in the micorenvironment, accompanied this effect. Consistently the pro-osteoclastogenic property of the conditioned medium of MM cells co-cultured with PreOBs was reduced in the presence of both IMiD®s. By microarray analysis we further investigated the effect of POM and LEN on the transcriptional profile of both MM cells and PreOBs. We found a significant down-regulation in MM cells, in addition to CD49d, of genes belonging to the adhesion molecules family such as ITGA8 and ICAM2 (CD102) induced by both IMiD®s compounds. In conclusion our data suggest that POM and LEN inhibits MM-induced OC formation through the inhibition of RANKL/OPG ratio targeting the expression of adhesion molecules by MM cells.

2013-04-13 | GSE37302 | GEO

RANKL regulates testicular cancer growth and Denosumab has tumor suppressive effects in GCNIS and advanced seminoma

Project description:Testicular germ cells tumors (TGCTs) have a high sensitivity to cisplatin-based chemotherapy and a high cure rate, although with possible serious adverse effects. In the search for tumor suppressive drugs, the RANKL inhibitor Denosumab, used to treat osteoporosis came up as a candidate since RANKL signaling was recently identified in the testis. RANKL signals through the receptor RANK and this signaling is antagonized by the decoy receptor OPG. Here, we demonstrate expression of RANKL, RANK, and OPG in germ cell neoplasia in situ (GCNIS), TGCTs, and TGCT-derived cell lines. RANKL inhibition reduced proliferation of seminoma-derived TCam-2 cells but had no effect on embryonal carcinoma-derived NTera2 cells in vitro. Denosumab did not potentiate the effect of cisplatin treatment in vitro but inhibition of RANKL in vivo resulted in reduced tumor growth in a TCam-2 but not a NTera2 xenograft model. Moreover, Denosumab treatment decreased proliferation in human testicular GCNIS tissue culture in vitro. In TGCT patients, serum RANKL was not linked with tumor burden, relapse, or other prognostic markers. In conclusion, this study shows that the RANKL signaling system is expressed in GCNIS and seminoma where RANKL inhibition suppress tumor growth in vitro and in vivo. Future studies are needed to determine whether RANKL is important for the malignant transformation and the transition from GCNIS to invasive tumors.

2022-04-19 | GSE197389 | GEO

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