Melanoma-derived extracellular vesicles instigate proinflammatory signaling in the metastatic microenvironment.

The major cause of melanoma mortality is metastasis to distant organs, including lungs and brain. Reciprocal interactions of metastasizing tumor cells with stromal cells in secondary sites play a critical role in all stages of tumorigenesis and metastasis. Changes in the metastatic microenvironment were shown to precede clinically relevant metastases, and may occur prior to the arrival of disseminated tumor cells to the distant organ, thus creating a hospitable "premetastatic niche." Exosomes secreted by tumor cells were demonstrated to play an important role in the preparation of a hospitable metastatic niche. However, the functional role of melanoma-derived exosomes on metastatic niche formation, and the downstream pathways activated in stromal cells at the metastatic niche are largely unresolved. Here we show that extracellular vesicles (EVs) secreted by metastatic melanoma cells that spontaneously metastasize to lungs and to brain, activate proinflammatory signaling in lung fibroblasts and in astrocytes. Interestingly, unlike paracrine signaling by melanoma cells, EVs secreted by metastatic melanoma cells instigated a proinflammatory gene signature in lung fibroblasts but did not activate wound-healing functions, suggesting that tumor cell-secreted EVs activate distinct CAF characteristics and tumor-promoting functions. Moreover, melanoma-secreted EVs also activated proinflammatory signaling in astrocytes, indicating that EV-mediated reprogramming of stromal cells is a general mechanism of modulating the metastatic niche in multiple distant organs. Thus, our study demonstrates that melanoma-derived EVs reprogram tumor-promoting functions in stromal cells in a distinct manner, implicating a central role for tumor-derived EV signaling in promoting the formation of an inflammatory metastatic niche.

Gener Lahav T ，Adler O ，Zait Y ，Shani O ，Amer M ，Doron H ，Abramovitz L ，Yofe I ，Cohen N ，Erez N ... -  《-》

Extracellular vesicles of carcinoma-associated fibroblasts creates a pre-metastatic niche in the lung through activating fibroblasts.

Kong J ，Tian H ，Zhang F ，Zhang Z ，Li J ，Liu X ，Li X ，Liu J ，Li X ，Jin D ，Yang X ，Sun B ，Guo T ，Luo Y ，Lu Y ，Lin B ，Liu T ... -  《Molecular Cancer》

Exosome-dependent immune surveillance at the metastatic niche requires BAG6 and CBP/p300-dependent acetylation of p53.

Schuldner M ，Dörsam B ，Shatnyeva O ，Reiners KS ，Kubarenko A ，Hansen HP ，Finkernagel F ，Roth K ，Theurich S ，Nist A ，Stiewe T ，Paschen A ，Knittel G ，Reinhardt HC ，Müller R ，Hallek M ，von Strandmann EP ... -  《Theranostics》

Extracellular Vesicles-Based Cell-Cell Communication in Melanoma: New Perspectives in Diagnostics and Therapy.

Kluszczynska K ，Czyz M 《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Tumor-Stromal Cell Communication: Small Vesicles Signal Big Changes.

Reciprocal interactions between malignant and stromal cells create a local microenvironment that fosters tumor growth. Extracellular vesicles (EVs) such as exosomes, microvesicles, and large oncosomes are involved in tumor-stroma communication by shuttling signaling cargo and other molecules. Here we discuss how EVs released by cancer or stromal cells impact the proliferation, differentiation, and metabolism of tumors.

Wendler F ，Stamp GW ，Giamas G 《Trends in Cancer》