GPNMB cooperates with neuropilin-1 to promote mammary tumor growth and engages integrin α5β1 for efficient breast cancer metastasis

Abstract

Glycoprotein nmb (GPNMB) promotes breast tumor growth and metastasis and its expression in tumor epithelium correlates with poor prognosis in breast cancer patients. Despite its biological and clinical significance, little is known regarding the molecular mechanisms engaged by GPNMB. Herein, we show that GPNMB engages distinct functional domains and mechanisms to promote primary tumor growth and metastasis. We demonstrate that neuropilin-1 (NRP-1) expression is increased in breast cancer cells that overexpress GPNMB. Interestingly, the GPNMB-driven increase in NRP-1 expression potentiated vascular endothelial growth factor signaling in breast cancer cells and was required for the growth, but not metastasis, of these cells in vivo. Interrogation of RNAseq data sets revealed a positive correlation between GPNMB and NRP-1 levels in human breast tumors. Furthermore, we ascribe pro-growth and pro-metastatic functions of GPNMB to its ability to bind α5β1 integrin and increase downstream signaling in breast cancer cells. We show that GPNMB enhances breast cancer cell adhesion to fibronectin, increases α5β1 expression and associates with this receptor through its RGD motif. GPNMB recruitment into integrin complexes activates Src and Fak signaling pathways in an RGD-dependent manner. Importantly, both the RGD motif and cytoplasmic tail of GPNMB are required to promote primary mammary tumor growth; however, only mutation of the RGD motif impaired the formation of lung metastases. Together, these findings identify novel and distinct molecular mediators of GPNMB-induced breast cancer growth and metastasis.

Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) and Cancer: A Novel Potential Therapeutic Target

“…In contradiction to previous reports on breast cancer characterizing GPNMB as a tumor suppressor expressed in normal epithelial cells, recent reports have identified it as a driver of primary tumor growth and invasion, promoting endothelial cell recruitment and potentiating lung and bone metastasis [17,18,20]. GPNMB was first implicated as a promoter of breast cancer metastasis when it was detected in elevated levels in select subpopulations of 4 T1 mouse mammary carcinoma cells that aggressively spread to the bone, lungs, and liver [4,18].…”

“…A study on breast cancer metastasis shed light on a novel interaction between the tumor-specific integrin α5β1 and the extracellular RGD domain of GPNMB to drive breast cancer cell metastasis, most likely via the FAK/Src pathway [20]. Plating BT549 breast cancer cells on fibronectin enhanced GPNMB/α5β1 interactions and FAK/Src signaling, as the integrin α5β1 serves as a receptor for fibronectin [20].…”

“…Plating BT549 breast cancer cells on fibronectin enhanced GPNMB/α5β1 interactions and FAK/Src signaling, as the integrin α5β1 serves as a receptor for fibronectin [20]. Of note, mutations in both the cytoplasmic tail (cytoplasmic tail truncation) and the extracellular RGD domain (RGD to RAA substitution) eliminated this process, suggesting that full length, membrane-bound GPNMB may be needed to mediate breast cancer cell invasion and growth in vitro .…”

Glycoprotein non-metastaticmelanoma protein B promotes glioma motility and angiogenesis through the Wnt/β-catenin signaling pathway

“…13 GPNMB also induces mammary tumor growth and metastasis by cooperating with neuropilin-1 (NRP-1) in human breast cancer. 20 In pancreatic cancer, GPNMB protein could regulate the apoptosis and proliferation capacity of cancer cells. 21 Herein, we showed that GPNMB silencing in glioma cells significantly decreased cellular proliferation and migration without affecting apoptosis in vitro, indicating the crucial role of high levels of endogenous GPNMB in glioma tumorigenesis.…”

Neuropilin Functions as an Essential Cell Surface Receptor

“…Moreover, this coupling has been reported in multiple pathological contexts. Nrp and integrin coupling have been associated with pancreatic cancer cell invasion (89), increased fibronectin fibril assembly (90), breast cancer adhesion to laminin (91), breast cancer initiation (92), cancer cell extravasation and metastasis (81), breast cancer growth (93), and stem cell fate determination (94). Current data indicate that integrin engagement by Nrp may be independent, cooperative, or competitive with VEGFR engagement and signaling (95,96).…”