STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis

Priego, Neibla; Zhu, Lucía; Monteiro, Cátia; Mulders, Manon; Wasilewski, David; Bindeman, Wendy; Doglio, Laura; Martínez, Liliana Galbis; Martínez‐Sáez, Elena; Cajal, Santiago Ramón y; Megı́as, Diego; Hernández-Encinas, Elena; Blanco‐Aparicio, Carmen; Martínez, Lola; Zarzuela, Eduardo; Muñoz, Javier; Fustero‐Torre, Coral; Piñeiro-Yáñez, Elena; Hernández-Laín, Aurelio; Bertero, Luca; Poli, Valeria; Sánchez-Martínez, Melchor; Menendez, Javier A.; Soffietti, Riccardo; Bosch-Barrera, Joaquim; Valiente, Manuel

doi:10.1038/s41591-018-0044-4

Cited by 315 publications

(411 citation statements)

References 70 publications

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“…Tumor-associated astrocytes react to the GBM microenvironment with an altered phenotype, 60 and were recently shown to promote glioma growth. 32,61 We show here that astrocytes secrete TGM2 in response to radiation, which supports stemness and radiation resistance of GBM cells. Inhibition of TGM2 decreased survival of tumor cells in an ex vivo organotypic slice model of GBM, and was previously shown to increase survival in a glioma xenograft model.…”

Section: Discussionsupporting

confidence: 58%

The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2

Berg

Marques²,

Pantazopoulou

et al. 2020

Preprint

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The tumor microenvironment plays an essential role in supporting glioma stemness and radioresistance; however, little is known about how the microenvironment responds to radiation. Here, we found that astrocytes, when pre-irradiated, increased stemness and survival of co-cultured glioma cells. Tumor-naïve brains increased reactive astrocytes in response to radiation, and mice subjected to radiation prior to implantation of glioma cells developed more aggressive tumors. We identified extracellular matrix derived from irradiated astrocytes as a major driver of this phenotype, and astrocyte-derived transglutaminase 2 (TGM2) as a promoter of glioma stemness and radioresistance. TGM2 inhibitors abrogated glioma stemness induced by irradiated astrocytes. TGM2 inhibition reduced survival of glioma cells in in vitro and ex vivo tumor models.These data suggest that irradiation of the brain results in the formation of a tumor-supportive microenvironment. Therapeutic targeting of radiation-induced, astrocyte-derived extracellular matrix proteins may enhance the efficacy of standard of care radiotherapy in glioma.

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Section: Discussionsupporting

confidence: 58%

The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2

Berg

Marques²,

Pantazopoulou

et al. 2020

Preprint

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“…A recent study showed that regulatory T cells reduce astrocyte reaction (including A1 markers) after stroke, through amphiregulin, IL6, and STAT3 signaling (Ito et al, ). Alternatively, phospho‐STAT3 + reactive astrocytes found around brain metastatic cells reduce CD8 + lymphocyte recruitment and increase the number of CD74 + macrophage/microglia, which are more permissive to metastatic proliferation [(Priego et al, ), Figure r]. Proliferating, juxta‐vascular reactive astrocytes were also shown to inhibit monocyte infiltration following SWI (Frik et al, ).…”

Section: How Do Reactive Astrocytes Interact With Other Innate Immunementioning

confidence: 99%

Questions and (some) answers on reactive astrocytes

Escartin

Guillemaud

Sauvage

2019

Glia

220

180

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Astrocytes are key cellular partners for neurons in the central nervous system. Astrocytes react to virtually all types of pathological alterations in brain homeostasis by significant morphological and molecular changes. This response was classically viewed as stereotypical and is called astrogliosis or astrocyte reactivity. It was long considered as a nonspecific, secondary reaction to pathological conditions, offering no clues on disease‐causing mechanisms and with little therapeutic value. However, many studies over the last 30 years have underlined the crucial and active roles played by astrocytes in physiology, ranging from metabolic support, synapse maturation, and pruning to fine regulation of synaptic transmission. This prompted researchers to explore how these new astrocyte functions were changed in disease, and they reported alterations in many of them (sometimes beneficial, mostly deleterious). More recently, cell‐specific transcriptomics revealed that astrocytes undergo massive changes in gene expression when they become reactive. This observation further stressed that reactive astrocytes may be very different from normal, nonreactive astrocytes and could influence disease outcomes. To make the picture even more complex, both normal and reactive astrocytes were shown to be molecularly and functionally heterogeneous. Very little is known about the specific roles that each subtype of reactive astrocytes may play in different disease contexts. In this review, we have interrogated researchers in the field to identify and discuss points of consensus and controversies about reactive astrocytes, starting with their very name. We then present the emerging knowledge on these cells and future challenges in this field.

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“…The reciprocal interactions between astrocytes and metastatic tumor cells were shown to promote brain metastasis in multiple studies . Proinflammatory signaling by astrocytes was suggested to facilitate melanoma brain metastasis . However, the mechanisms that instigate astrocyte‐mediated neuroinflammation during brain metastases formation are not well characterized.…”

Section: Discussionmentioning

confidence: 99%

“…44 Proinflammatory signaling by astrocytes was suggested to facilitate melanoma brain metastasis. 18,45 However, the mechanisms that instigate astrocyte-mediated neuroinflammation during brain metastases formation are not well characterized. Here we show that melanoma-derived EVs/exosomes instigate a proinflammatory gene signature in primary astrocytes.…”

Section: Discussionmentioning

confidence: 99%

Melanoma‐derived extracellular vesicles instigate proinflammatory signaling in the metastatic microenvironment

Lahav

Adler

Zait

et al. 2019

Intl Journal of Cancer

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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.

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STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis

Cited by 315 publications

References 70 publications

The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2

The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2

Questions and (some) answers on reactive astrocytes

Melanoma‐derived extracellular vesicles instigate proinflammatory signaling in the metastatic microenvironment

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