Tumour extracellular vesicles induce neutrophil extracellular traps to promote lymph node metastasis

• Published in: Journal of extracellular vesicles Vol. 12; no. 8; pp. e12341 - n/a
• Main Authors: Su, Xin, Brassard, Ariane, Bartolomucci, Alexandra, Dhoparee‐Doomah, Iqraa, Qiu, Qian, Tsering, Thupten, Rohanizadeh, Ramin, Koufos, Olivia, Giannias, Betty, Bourdeau, France, Feng, Lixuan, Messina‐Pacheco, Julia, Leo, Sabrina, Sangwan, Veena, Quail, Daniela, Tankel, James, Spicer, Jonathan, Burnier, Julia Valdemarin, Bailey, Swneke Donovan, Ferri, Lorenzo, Cools‐Lartigue, Jonathan
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.08.2023; John Wiley and Sons Inc; Wiley
• Subjects: Animal models; Animals; cancer; Cancer therapies; Chemotherapy; Cytotoxicity; Endothelial Cells; Environmental changes; Experiments; Extracellular Traps; Extracellular Vesicles; Immunotherapy; Inflammation; Leukocytes (neutrophilic); lymph node; Lymph nodes; Lymph Nodes - pathology; Lymphatic Metastasis - pathology; Lymphatic system; Melanoma; Metastases; Metastasis; NETs; Neutrophils; Tumors; NETs; cancer; metastasis; neutrophils; lymph node
• ISSN: 2001-3078; 2001-3078
• DOI: 10.1002/jev2.12341

Lymph nodes (LNs) are frequently the first sites of metastasis. Currently, the only prognostic LN assessment is determining metastatic status. However, there is evidence suggesting that LN metastasis is facilitated by the formation of a pre‐metastatic niche induced by tumour derived extracellular vehicles (EVs). Therefore, it is important to detect and modify the LN environmental changes. Earlier work has demonstrated that neutrophil extracellular traps (NETs) can sequester and promote distant metastasis. Here, we first confirmed that LN NETs are associated with reduced patient survival. Next, we demonstrated that NETs deposition precedes LN metastasis and NETs inhibition diminishes LN metastases in animal models. Furthermore, we discovered that EVs are essential to the formation of LN NETs. Finally, we showed that lymphatic endothelial cells secrete CXCL8/2 in response to EVs inducing NETs formation and the promotion of LN metastasis. Our findings reveal the role of EV‐induced NETs in LN metastasis and provide potential immunotherapeutic vulnerabilities that may occur early in the metastatic cascade. Illustrative demonstration of the LNs premetastatic niche formation induced by EVs and NETs. Primary tumour constantly secretes EVs, which were actively uptaken by LECs. LECs subsequently secretes CXCL8 or CXCL2 upon EV reception. CXCL8 and CXCL2 are both neutrophil chemoattractants and potent NETs inducers. The following neutrophil recruitment and NETs formation lead to increased LN metastasis burden.