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Targeting RANKL-Independent Osteoclastogenesis Overcomes Denosumab Resistance in ER+ Breast Cancer Bone Metastasis [RNA-seq]

ABSTRACT: Bone metastasis remains a major cause of morbidity in ER+ breast cancer, with RANKL inhibitor resistance emerging as a critical clinical challenge. Nearly 40% of patients develop progressive skeletal lesions despite denosumab therapy, highlighting an urgent need to identify resistance mechanisms and alternative therapeutic strategies. We identified a RANKL-independent osteoclast activation pathway mediated by the CRKL/circCCDC50/NFATc1 axis. Mechanistically, CRKL promotes EIF4A3-dependent circCCDC50 biogenesis, which is packaged into large oncosomes and transferred to osteoclast precursors. Nuclear circCCDC50 recruits CARM1 to epigenetically activate NFATc1 transcription, establishing a self-reinforcing loop that sustains osteolysis despite RANKL blockade. Pharmacological inhibition of CARM1 (TP-064) effectively suppresses osteoclastogenesis and bone metastasis in denosumab-resistant models. These findings reveal a targetable resistance mechanism and provide a clinically actionable strategy to overcome microenvironment-driven metastasis through dual targeting of tumor and bone niches.

ORGANISM(S): Homo sapiens

PROVIDER: GSE317129 | GEO | 2026/03/16

REPOSITORIES: GEO

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Targeting RANKL-Independent Osteoclastogenesis Overcomes Denosumab Resistance in ER+ Breast Cancer Bone Metastasis [circRNA-seq]

Project description:Bone metastasis remains a major cause of morbidity in ER+ breast cancer, with RANKL inhibitor resistance emerging as a critical clinical challenge. Nearly 40% of patients develop progressive skeletal lesions despite denosumab therapy, highlighting an urgent need to identify resistance mechanisms and alternative therapeutic strategies. We identified a RANKL-independent osteoclast activation pathway mediated by the CRKL/circCCDC50/NFATc1 axis. Mechanistically, CRKL promotes EIF4A3-dependent circCCDC50 biogenesis, which is packaged into large oncosomes and transferred to osteoclast precursors. Nuclear circCCDC50 recruits CARM1 to epigenetically activate NFATc1 transcription, establishing a self-reinforcing loop that sustains osteolysis despite RANKL blockade. Pharmacological inhibition of CARM1 (TP-064) effectively suppresses osteoclastogenesis and bone metastasis in denosumab-resistant models. These findings reveal a targetable resistance mechanism and provide a clinically actionable strategy to overcome microenvironment-driven metastasis through dual targeting of tumor and bone niches.

2026-03-16 | GSE317130 | GEO

Targeting RANKL-Independent Osteoclastogenesis Overcomes Denosumab Resistance in ER+ Breast Cancer Bone Metastasis

2026-01-29 | PXD073739 |

Immune modulation with RANKL-blockade through denosumab treatment in cancer patients

Project description:Denosumab is a fully human monoclonal antibody that binds receptor activator of nuclear factor-κB ligand (RANKL) and is routinely administered to cancer patients to reduce the incidence of new bone metastasis. RANK-RANKL regulates bone turnover by controlling osteoclast recruitment, development, and activity. However, this interaction also can regulate a broad range of immune cells including dendritic cells and medullary thymic epithelial cells (mTECs). Inhibition of the latter results in reduced thymic negative selection of T cells and could enhance the generation of tumor-specific T cells. We examined whether administering denosumab could modify modulate circulating immune cells in cancer patients. Blood was collected from 23 prostate cancer patients and 3 renal cell carcinoma patients, who provided written informed consent, with advanced disease who were receiving denosumab, prior to and during denosumab treatment. Using high-dimensional mass cytometry, we found that denosumab treatment by itself induced modest effects on circulating immune cell frequency and activation. We also found minimal changes in the circulating T cell repertoire and the frequency of new thymic emigrants with denosumab treatment. However, when we stratified patients by whether they were receiving chemotherapy and/or steroids, patients receiving these concomitant treatments showed significantly greater immune modulation, including an increase in the frequency of NK cells early and classical monocytes later. We also saw broad induction of CTLA-4 and TIM3 expression in circulating lymphocytes and some monocyte populations. These findings suggest that denosumab treatment by itself has modest immunomodulatory effects, but when combined with conventional cancer treatment, can lead to the induction of immunologic checkpoints.

2024-04-10 | GSE248774 | GEO

Comparison expression data from wild-type and NFATc1-deficient osteoclasts

Project description:Genetic deletion of Nfatc1 in mice results in profound osteoclast-poor osteopetrosis, a high bone mass state caused by a lack of osteoclast activity. We hypothesized that the family of NFATc1 regulated transcripts in the osteoclast would be enriched for genes associated with osteoclast function. We used microarrays profile gene expression in wild-type and NFATc1-deficient osteoclasts generated in vitro to identify NFATc1-dependent transcripts in osteoclasts. Bone marrow macrophages from wild-type and mice with an induced deficiency of NFATc1 (NFATc1 fl/fl MxCre+ mice where NFATc1 excision was induced by polyIC treatment) were cultured ex vivo in MCSF and RANKL for 3 days. 2 biological replicates were assayed for each genotype.

2012-08-18 | E-GEOD-37219 | biostudies-arrayexpress

Targeting RANKL-Independent Osteoclastogenesis Overcomes Denosumab Resistance in ER+ Breast Cancer Bone Metastasis [circRNA-seq]

Project description:Targeting RANKL-Independent Osteoclastogenesis Overcomes Denosumab Resistance in ER+ Breast Cancer Bone Metastasis [circRNA-seq]

| PRJNA1406137 | ENA

Targeting RANKL-Independent Osteoclastogenesis Overcomes Denosumab Resistance in ER+ Breast Cancer Bone Metastasis [RNA-seq]

Project description:Targeting RANKL-Independent Osteoclastogenesis Overcomes Denosumab Resistance in ER+ Breast Cancer Bone Metastasis [RNA-seq]

| PRJNA1406140 | ENA

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

A novel small molecule derived from Lentinula edodes targets PRDX1 to inhibit RANKL-induced osteoclast differentiation and rescues the osteoporotic phenotype [PRDX KO]

Project description:Bone remodeling, crucial for skeletal integrity, involves osteoclasts and osteoblasts. Osteoclastogenesis, regulated by NFATc1, is activated by c-Fos and NF-κB signaling in response to RANKL. Excessive RANKL signaling contributes to bone loss pathology. Here we reveal denatonium as an inhibitor of RANKL-induced osteoclast differentiation through the p65 pathway. RNA-seq identified downregulated osteoclast-related genes. Affinity chromatography pinpointed 35 denatonium-interacting proteins, with PRDX1 showing specificity. PRDX1 deficiency led to osteoporosis with increased osteoclast activity and enhanced RANKL-induced osteoclast formation. Denatonium blocked PRDX1 lysosomal degradation, stabilizing PRDX1. Through transcription factor binding site analysis, p65 emerged as a major target suppressed by the denatonium-PRDX1 interaction. Chromatin immunoprecipitation confirmed that the denatonium-PRDX1 complex inhibited p65 enrichment at promoter regions critical for osteoclast differentiation. In an osteoporosis animal model, denatonium treatment restored bone health. This study uncovers denatonium's novel role in bone formation regulation by selectively targeting PRDX1, suggesting its potential in osteoporosis treatment.

2024-06-30 | GSE248993 | GEO

A novel small molecule derived from Lentinula edodes targets PRDX1 to inhibit RANKL-induced osteoclast differentiation and rescues the osteoporotic phenotype [Denatonium]

2024-06-30 | GSE248992 | GEO

Identification of osteoclast coupling factors in humans reveals links between bone remodeling and energy metabolism II

Project description:Purpose: Identification of osteoclast derived coupling factors using Denosumab as a biological probe Method: harvested RNA from centrifuged bone biopsies (heterogeneous population containing bone lining cells, osteoblasts, osteoclasts and osteocytes, without in vitro culture Results: Identification of genes differentially regulated in denosumab treated participants that correlate with bone remodeling indices Conclusions: Using this approach we identified denosumab regulated genes that correlate with bone remodeling in the untreated participants and may represent novel osteoclast derived coupling factors. Of interest, we identified DPP4 to be suppressed in denosumab treated participants, providing a novel link between bone remodeling and energy metabolism.

2019-12-07 | GSE141610 | GEO

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