Cancer-Associated Fibroblasts (CAFs) were shown to orchestrate tumour-promoting inflammation in multiple malignancies, including breast cancer. However, the molecular pathways that govern the inflammatory role of CAFs are poorly characterised. In this study we found that fibroblasts sense damage-associated molecular patterns (DAMPs), and in response activate the NLRP3 inflammasome pathway, resulting in instigation of pro-inflammatory signalling and secretion of IL-1β. This upregulation was evident in CAFs in mouse and in human breast carcinomas. Moreover, CAF-derived inflammasome signalling facilitated tumour growth and metastasis, which was attenuated when NLRP3 or IL-1β were specifically ablated. Functionally, CAF-derived inflammasome promoted tumour progression and metastasis by modulating the tumour microenvironment towards an immune suppressive milieu and by upregulating the expression of adhesion molecules on endothelial cells. Our findings elucidate a mechanism by which CAFs promote breast cancer progression and metastasis, by linking the physiological tissue damage response of fibroblasts with tumour-promoting inflammation.

Ibrutinib sensitizes melanoma to immune checkpoint modulators following immunization with nano-vaccines by relieving immune-suppressing microenvironment One Sentence Summary: Combination of dendritic cell-targeted nano-vaccines with a myeloid-derived suppressor cell inhibitor and immune checkpoint modulators expands the host antitumor immune cells, restricts tumour growth and prolongs survival in an orthotopic melanoma model.

Highlights d CXCL10 is upregulated in metastases-associated astrocytes in vivo d Astrocyte-derived CXCL10 enhances melanoma cell migration toward astrocytes d CXCR3, the receptor for CXCL10, is upregulated in braintropic melanoma cells d Targeting CXCR3 expression attenuates the formation of melanoma brain metastases

Brain metastases are more common than primary CNS tumors, and confer grave prognosis on patients, as existing treatments have very limited efficacy. The tumor microenvironment has a central role in facilitating tumorigenesis and metastasis. In recent years, there has been much progress in our understanding of the functional role of the brain metastatic microenvironment. In this review we discuss the latest advances in brain metastasis research, with special emphasis on the role of the brain microenvironment and neuroinflammation, integrating insights from comparable findings in neuropathologies and primary CNS tumors. In addition, we overview findings on the formation of a hospitable metastatic niche, and point out the major gaps in knowledge towards developing new therapeutics that will co-target the stromal compartment, in an effort to improve the treatment and prevention of brain metastases.

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.