RESEARCH HIGHLIGHTS
MICROENVIRONMENT
Small containers, important cargo
exosomes can alter the transcriptomes of target cells to promote therapeutic resistance, as well as tumour initiation and progression
The role of exosomes as mediators between cancer cells and the microenvironment has gained increasing attention. Two studies have provided further information on the part these small vesicles play in tumour progression and resistance to therapy. Boelens et al. were interested in how stromal communication with cancer cells can influence treatment response. The authors had previously characterized a gene signature for radiation resistance that included many interferon-stimulated genes (ISGs), termed the interferon-related DNA damage resistance signature (IRDS). As ISGs can be regulated by the microenvironment, the authors examined ISG expression in xenografts derived from the metastatic breast cancer cell line MDA-MB‑231 alone or co-injected with fibroblasts. Tumours containing both cancer cells and fibroblasts showed high expression of several IRDS genes, including STAT1, and maintained proliferation after radiation treatment, whereas tumours from breast cancer cells alone had lower IRDS expression and regressed after radiation treatment. The authors also identified two groups of breast cancer cells: IRDS responders (IRDS-Rs) — in which interaction with fibroblasts induced IRDS genes and conferred protection against radiation (mediated by STAT1) — and IRDS non-responders (IRDS-NRs), in which interaction with fibroblasts
Lara Crow / NPG
failed to induce IRDS or protect against radiation. Through computational analysis, the pattern recognition receptor RIG‑I was identified as the mediator of fibroblast-induced upregulation of STAT1 and IRDS genes. Indeed, knocking down RIG-I in IRDS-Rs inhibited IRDS gene induction and radiation protection in cancer cells after co-culture with fibroblasts. Conditioned media from IRDS-Rs cultured with fibroblasts upregulated IRDS genes in breast cancer cells, suggesting the presence of a secreted factor that is capable of activating RIG-I in these cells. The authors found that this paracrine induction of IRDS genes was triggered by an increase in the number of exosomes after coculture, which were transferred from stromal cells to breast cancer cells. Further experiments showed that these exosomes contained 5ʹ-triphosphate RNA that can activate RIG-I signalling in breast cancer cells. Breast cancer cells separated from fibroblasts by a transwell filter that allowed exosome transfer retained IRDS induction but lost resistance to radiation, suggesting that RIG-I mediates radiation resistance in a juxtacrine way. A computational analysis of the interactome between IRDS-Rs and fibroblasts revealed that expression of NOTCH3 was increased in IRDS-Rs, and its membrane-bound ligand JAG1 was induced in fibroblasts. The authors found that STAT1 (which mediates fibroblast-induced expression of IRDS genes in cancer cells) was required for the transcription of NOTCH3 and NOTCH target genes. Inhibition of the NOTCH pathway with a γ-secretase inhibitor after radiotherapy reversed the protection conferred by fibroblasts and eliminated xenograft tumours in 30% of mice.
NATURE REVIEWS | CANCER
So, stromal exosomes transfer 5ʹ‑triphosphate RNA to mediate activation of RIG-I signalling in breast cancer cells, which then — through STAT1 — cooperates with NOTCH3 to expand radiation-resistant cells. Melo et al. investigated the contribution of microRNAs (miRNAs) contained in exosomes to tumour progression. The authors analysed exosomes secreted by breast cancer cell lines (such as MDA-MB‑231) and by non-tumorigenic human mammary epithelial cells (MCF10A cells), and observed that six miRNAs, all of which have been widely implicated in cancer progression, were increased in cancer exosomes. Incubating purified exosomes for different periods of time showed an enrichment of miRNAs over time, suggesting active miRNA biogenesis in exosomes. Further analysis revealed the presence of pre-miRNA, as well as the required proteins to process them (the key components of the RISC-loading complex). Incubation of MCF10A cells with MDA-MB‑231‑derived exosomes induced oncogenic trans criptome changes in MCF10A cells, and MCF10A cells exposed to cancer exosomes could then form tumours when implanted into nude mice. Moreover, exosomes isolated from the serum of patients with breast cancer also induced MCF10A cell tumori genesis, whereas exosomes from healthy donors did not. These two papers describe how exosomes can alter the transcriptomes of target cells to promote therapeutic resistance, as well as tumour initiation and progression, opening new possibilities for developing exosome-based biomarkers and therapies. M. Teresa Villanueva ORIGINAL RESEARCH PAPERS Boelens, M. C. et al. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell 159, 499–513 (2014) | Melo, S. A. et al. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 26, 707–721 (2014)
VOLUME 14 | DECEMBER 2014 © 2014 Macmillan Publishers Limited. All rights reserved
MICROENVIRONMENT
Small containers, important cargo
exosomes can alter the transcriptomes of target cells to promote therapeutic resistance, as well as tumour initiation and progression
The role of exosomes as mediators between cancer cells and the microenvironment has gained increasing attention. Two studies have provided further information on the part these small vesicles play in tumour progression and resistance to therapy. Boelens et al. were interested in how stromal communication with cancer cells can influence treatment response. The authors had previously characterized a gene signature for radiation resistance that included many interferon-stimulated genes (ISGs), termed the interferon-related DNA damage resistance signature (IRDS). As ISGs can be regulated by the microenvironment, the authors examined ISG expression in xenografts derived from the metastatic breast cancer cell line MDA-MB‑231 alone or co-injected with fibroblasts. Tumours containing both cancer cells and fibroblasts showed high expression of several IRDS genes, including STAT1, and maintained proliferation after radiation treatment, whereas tumours from breast cancer cells alone had lower IRDS expression and regressed after radiation treatment. The authors also identified two groups of breast cancer cells: IRDS responders (IRDS-Rs) — in which interaction with fibroblasts induced IRDS genes and conferred protection against radiation (mediated by STAT1) — and IRDS non-responders (IRDS-NRs), in which interaction with fibroblasts
Lara Crow / NPG
failed to induce IRDS or protect against radiation. Through computational analysis, the pattern recognition receptor RIG‑I was identified as the mediator of fibroblast-induced upregulation of STAT1 and IRDS genes. Indeed, knocking down RIG-I in IRDS-Rs inhibited IRDS gene induction and radiation protection in cancer cells after co-culture with fibroblasts. Conditioned media from IRDS-Rs cultured with fibroblasts upregulated IRDS genes in breast cancer cells, suggesting the presence of a secreted factor that is capable of activating RIG-I in these cells. The authors found that this paracrine induction of IRDS genes was triggered by an increase in the number of exosomes after coculture, which were transferred from stromal cells to breast cancer cells. Further experiments showed that these exosomes contained 5ʹ-triphosphate RNA that can activate RIG-I signalling in breast cancer cells. Breast cancer cells separated from fibroblasts by a transwell filter that allowed exosome transfer retained IRDS induction but lost resistance to radiation, suggesting that RIG-I mediates radiation resistance in a juxtacrine way. A computational analysis of the interactome between IRDS-Rs and fibroblasts revealed that expression of NOTCH3 was increased in IRDS-Rs, and its membrane-bound ligand JAG1 was induced in fibroblasts. The authors found that STAT1 (which mediates fibroblast-induced expression of IRDS genes in cancer cells) was required for the transcription of NOTCH3 and NOTCH target genes. Inhibition of the NOTCH pathway with a γ-secretase inhibitor after radiotherapy reversed the protection conferred by fibroblasts and eliminated xenograft tumours in 30% of mice.
NATURE REVIEWS | CANCER
So, stromal exosomes transfer 5ʹ‑triphosphate RNA to mediate activation of RIG-I signalling in breast cancer cells, which then — through STAT1 — cooperates with NOTCH3 to expand radiation-resistant cells. Melo et al. investigated the contribution of microRNAs (miRNAs) contained in exosomes to tumour progression. The authors analysed exosomes secreted by breast cancer cell lines (such as MDA-MB‑231) and by non-tumorigenic human mammary epithelial cells (MCF10A cells), and observed that six miRNAs, all of which have been widely implicated in cancer progression, were increased in cancer exosomes. Incubating purified exosomes for different periods of time showed an enrichment of miRNAs over time, suggesting active miRNA biogenesis in exosomes. Further analysis revealed the presence of pre-miRNA, as well as the required proteins to process them (the key components of the RISC-loading complex). Incubation of MCF10A cells with MDA-MB‑231‑derived exosomes induced oncogenic trans criptome changes in MCF10A cells, and MCF10A cells exposed to cancer exosomes could then form tumours when implanted into nude mice. Moreover, exosomes isolated from the serum of patients with breast cancer also induced MCF10A cell tumori genesis, whereas exosomes from healthy donors did not. These two papers describe how exosomes can alter the transcriptomes of target cells to promote therapeutic resistance, as well as tumour initiation and progression, opening new possibilities for developing exosome-based biomarkers and therapies. M. Teresa Villanueva ORIGINAL RESEARCH PAPERS Boelens, M. C. et al. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell 159, 499–513 (2014) | Melo, S. A. et al. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 26, 707–721 (2014)
VOLUME 14 | DECEMBER 2014 © 2014 Macmillan Publishers Limited. All rights reserved
