Abstract
Metastasis accounts for over 90% of cancer-related deaths, yet the mechanisms guiding this process remain unclear. Secreted nucleoside diphosphate kinase A and B (NDPK) support breast cancer metastasis. Proteomic evidence confirms their presence in breast cancer-derived extracellular vesicles (EVs). We investigated the role of EV-associated NDPK in modulating the host microenvironment in favor of pre-metastatic niche formation. We measured NDPK expression and activity in EVs isolated from triple-negative breast cancer (MDA-MB-231) and non-tumorigenic mammary epithelial (HME1) cells using flow cytometry, western blot, and ATP assay. We evaluated the effects of EV-associated NDPK on endothelial cell migration, vascular remodeling, and metastasis. We further assessed MDA-MB-231 EV-induced proteomic changes in support of pre-metastatic lung niche formation. NDPK-B expression and phosphotransferase activity were enriched in MDA-MB-231 EVs that promote vascular endothelial cell migration and disrupt monolayer integrity. MDA-MB-231 EV-treated mice demonstrate pulmonary vascular leakage and enhanced experimental lung metastasis, whereas treatment with an NDPK inhibitor or a P2Y1 purinoreceptor antagonist blunts these effects. We identified perturbations to the purinergic signaling pathway in experimental lungs, lending evidence to support a role for EV-associated NDPK-B in lung pre-metastatic niche formation and metastatic outgrowth. These studies prompt further evaluation of NDPK-mediated EV signaling using targeted genetic silencing approaches.
Highlights
Breast cancer is the second leading cause of cancer death in women, with survival rates heavily influenced by disease stage, tumor grade, and receptor status
Reduced nm23-H1 mRNA and nucleoside diphosphate kinase A and B (NDPK) expression levels have long been reported in solid tumors, and loss of nm23 correlates with disease progression and metastasis in several cancers
Among these, elevated nm23 expression was reported in sera of patients with breast cancer [31], colorectal cancer [34,35], neuroblastoma [36], renal carcinoma [37], and hematological malignancies [38]
Summary
Breast cancer is the second leading cause of cancer death in women, with survival rates heavily influenced by disease stage, tumor grade, and receptor status. While the 5-year relative survival rate for women diagnosed with ductal carcinoma in situ remains high, women diagnosed with distant-stage breast cancer see a dramatic decrease in their odds of survival, dropping from a near 99% 5-year survival rate for localized breast cancer to only 27% [1]. Cooperative and antagonistic signaling by tumor-secreted factors dictate PMN formation and abet CTCs in immune evasion, extravasation, and distant neocolonization. Such fine-tuned interactions with the distant microenvironment are observed during the early stages of primary tumor development and mediate the escape from indolence to metastatic outgrowth [3,4,5]. Tumor-derived EVs have been shown to facilitate paracrine-like and organotropic dialogue between primary tumor cells and the PMN [8,9]
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