Inhibition of extracellular vesicle‐derived miR‐146a‐5p decreases progression of melanoma brain metastasis via Notch pathway dysregulation in astrocytes

Abstract

Melanoma has the highest propensity of all cancers to metastasize to the brain with a large percentage of late‐stage patients developing metastases in the central nervous system (CNS). It is well known that metastasis establishment, cell survival, and progression are affected by tumour‐host cell interactions where changes in the host cellular compartments likely play an important role. In this context, miRNAs transferred by tumour derived extracellular vesicles (EVs) have previously been shown to create a favourable tumour microenvironment. Here, we show that miR‐146a‐5p is highly expressed in human melanoma brain metastasis (MBM) EVs, both in MBM cell lines as well as in biopsies, thereby modulating the brain metastatic niche. Mechanistically, miR‐146a‐5p was transferred to astrocytes via EV delivery and inhibited NUMB in the Notch signalling pathway. This resulted in activation of tumour‐promoting cytokines (IL‐6, IL‐8, MCP‐1 and CXCL1). Brain metastases were significantly reduced following miR‐146a‐5p knockdown. Corroborating these findings, miR‐146a‐5p inhibition led to a reduction of IL‐6, IL‐8, MCP‐1 and CXCL1 in astrocytes. Following molecular docking analysis, deserpidine was identified as a functional miR‐146a‐5p inhibitor, both in vitro and in vivo. Our results highlight the pro‐metastatic function of miR‐146a‐5p in EVs and identifies deserpidine for targeted adjuvant treatment.

Notch signaling pathway in cancer: from mechanistic insights to targeted therapies

“… 289 Similarly, miR-146a-5p is transferred to astrocytes via extracellular vesicles, down-regulating NUMB and activating the Notch pathway, thereby promoting melanoma brain metastasis. 290 Conversely, in the context of PTEN deficiency, Notch1 and Notch2 exhibit anti-tumor effects in BRAFV600E/PTEN-null-driven melanoma genesis. 291 Likewise, Rad et al reported that Notch4 acts as a tumor suppressor in melanoma.…”

Cutaneous Melanoma: A Review of Multifactorial Pathogenesis, Immunohistochemistry, and Emerging Biomarkers for Early Detection and Management

“…miR-221 plasma levels are increased in melanoma patients, and are correlated with stage, recurrence, and disease progression [123]. Rigg E. et al demonstrated that miR-146a-5p is overexpressed in melanoma brain metastases and its knockdown results in a reduction of metastatic lesions [124]. On the contrary, other types of microRNA such as mirR-211, miR-542 3p, or miR-152-3p are downregulated in invasive melanomas [125].…”

Role and Therapeutic Potential of Non-coding RNAs in Astrocytes during Neonatal Brain Injury

“…miR-146a shows aberrant expression or function in neuroinflammatory diseases [109] and indirectly down-regulates pro-inflammatory factors (e.g., IL-1β, IL-6, and TNF-α [110]) as well as promotes oligodendrocyte precursor cells (OPCs) differentiation [111]. In addition, a study transferred miR-146a-5p to astrocyte via extracellular vesicles (EVs) and revealed its ability to inhibit the Notch signaling pathway [112]. It suggests that miR-146a may play a critical role in neurons and glial cells in the immature brain.…”