PXD073739

PXD073739 is an original dataset announced via ProteomeXchange.

Title	Targeting RANKL-Independent Osteoclastogenesis Overcomes Denosumab Resistance in ER+ Breast Cancer Bone Metastasis
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.
HostingRepository	iProX
AnnounceDate	2026-01-29
AnnouncementXML	Submission_2026-03-15_17:35:10.412.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jinpeng Luo
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2026-01-28 17:36:20	ID requested
⏵ 1	2026-03-15 17:35:10	announced

Dataset with its publication pending

submitter keyword: bone metastasis, breast cancer, osteoclastogenesis, large oncosomes

Chang Gong
contact affiliation	Sun Yat-sen Memorial Hospital
contact email	gchang@mail.sysu.edu.cn
lab head
Jinpeng Luo
contact affiliation	Sun Yat-sen Memorial Hospital
contact email	luojp8@mail2.sysu.edu.cn
dataset submitter

iProX dataset URI