Schwann cell‐derived exosomes promote lung cancer progression via miRNA‐21‐5p

Abstract

Schwann cells (SCs), the primary glial cells of the peripheral nervous system, which have been identified in many solid tumors, play an important role in cancer development and progression by shaping the tumor immunoenvironment and supporting the development of metastases. Using different cellular, molecular, and genetic approaches with integrated bioinformatics analysis and functional assays, we revealed the role of human SC‐derived exosomal miRNAs in lung cancer progression in vitro and in vivo. We found that exosomal miRNA‐21 from SCs up‐regulated the proliferation, motility, and invasiveness of human lung cancer cells in vitro, which requires functional Rab small GTPases Rab27A and Rab27B in SCs for exosome release. We also revealed that SC exosomal miRNA‐21‐5p regulated the functional activation of tumor cells by targeting metalloprotease inhibitor RECK in tumor cells. Integrated bioinformatic analyses showed that hsa‐miRNA‐21‐5p is associated with poor prognosis in patients with lung adenocarcinoma and can promote lung cancer progression through multiple signaling pathways including the MAPK, PI3K/Akt, and TNF signaling. Furthermore, in mouse xenograft models, SC exosomes and SC exosomal hsa‐miRNA‐21‐5p augmented human lung cancer cell growth and lymph node metastasis in vivo. Together our data revealed, for the first time, that SC‐secreted exosomes and exosomal miRNA‐21‐5p promoted the proliferation, motility, and spreading of human lung cancer cells in vitro and in vivo. Thus, exosomal miRNA‐21 may play an oncogenic role in SC‐accelerated progression of lung cancer and this pathway may serve as a new therapeutic target for further evaluation.

How Schwann Cells Are Involved in Brain Metastasis

“…Finally, evidence suggests that SCs can play an active role in neoplastic cell invasion and the modulation of immune responses [23,29]. The most often identified mechanism in which this occurs is through the SC activation of M2 macrophages.…”

“…The secretion of paracrine signals or EVs can also accelerate the progression of certain lung cancers, such as lung adenocarcinoma and lung squamous cell carcinoma [29,35]. Paracrine signaling with glial cell line-derived neurotrophic factor (GDNF) from SCs, for example, can increase the invasion of tumor cells along the nerves of the lungs, which are highly innervated [11,37].…”

Schwann cells in the normal and pathological lung microenvironment

“…The results of a new study, using the in vitro and xenogeneic in vivo models of NSCLC, revealed that the promotion of tumor cell proliferation, survival, motility, and transmigration by human SC-conditioned medium was due to SC-derived exosomes ( Zhou et al, 2024 ). Evaluation of the expression and functional activity of SC exosomal microRNA demonstrated that hsa-miRNA-21-5P is responsible for upregulation of NSCLC cell longevity and motility.…”

“…These in vitro results were further confirmed by assessing the function of tumor cells transduced with miRNA-21-5p mimic and inhibitor. Additional analysis of tumor cells for intracellular signaling affected by miRNA-21 revealed that reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a matrix metalloproteinase (MMP) inhibitor, not only blocked the interaction with exosomal miR-21-5p but completely prevented activation of tumor cells when transfected into RECK knockout tumor cells in a mutant form ( Zhou et al, 2024 ).…”

“…The in vivo analysis of exosomal microRNA from SCs utilizing Cell Line-derived Tumor Xenograft models demonstrated that the presence of exosomal miRNA-21-5p was required for SC exosome-mediated stimulation of NSCLC growth in vivo . Importantly, by using EGFP-transfected tumor cells, it was also reported that SC exosomes significantly promoted the metastatic activity of tumor cells in vivo when miRNA-21-5p activity was not inhibited ( Zhou et al, 2024 ). Finally, the confirmation of the co-expression of S100B positive SCs and miRNA-21 in human lung cancer tissues and the demonstration of an association between hsa-miRNA-21-5P expression levels and poor prognosis for NSCLC patients supported the clinical significance and high translational potential of these new findings.…”