Exosome Transfer from Stromal to Breast Cancer Cells Regulates Therapy Resistance Pathways

Boelens, Mirjam C.; Wu, Tony J.; Nabet, Barzin Y.; Xu, Baocheng; Qiu, Yu; Yoon, Taewon; Azzam, Diana J.; Victor, Christina Twyman-Saint; Wiemann, Brianne; Ishwaran, Hemant; Brugge, P.J. ter; Jonkers, Jos; Slingerland, Joyce M.; Minn, Andy J.

doi:10.1016/j.cell.2014.09.051

Cited by 668 publications

(617 citation statements)

References 53 publications

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“…exoRNA RN7SL1 was then transferred to breast cancer cells, activated RIG‐I signaling including STAT1 activation and ISG induction, which was proposed to promote aggressive development of cancer. In another work, the same group has demonstrated that RIG‐I activation by exoRNA can amplify NOTCH3 signaling, which is responsible for the expansion of tumor‐initiating cells and therapy resistance in ISG‐R breast cancer cells, which are mostly basal/triple‐negative breast cancer (TNBC) cells (Boelens et al , 2014). However, in our work done in different types of breast cancer cells, expression profiles of the down‐stream genes indicated that NOTCH3 signaling was not amplified when interferon signaling was activated.…”

Section: Discussionmentioning

confidence: 99%

Function of HNRNPC in breast cancer cells by controlling the dsRNA‐induced interferon response

et al. 2018

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Elevated expression of RNA binding protein HNRNPC has been reported in cancer cells, while the essentialness and functions of HNRNPC in tumors were not clear. We showed that repression of HNRNPC in the breast cancer cells MCF7 and T47D inhibited cell proliferation and tumor growth. Our computational inference of the key pathways and extensive experimental investigations revealed that the cascade of interferon responses mediated by RIG‐I was responsible for such tumor‐inhibitory effect. Interestingly, repression of HNRNPC resulted in accumulation of endogenous double‐stranded RNA (dsRNA), the binding ligand of RIG‐I. These up‐regulated dsRNA species were highly enriched by Alu sequences and mostly originated from pre‐mRNA introns that harbor the known HNRNPC binding sites. Such source of dsRNA is different than the recently well‐characterized endogenous retroviruses that encode dsRNA. In summary, essentialness of HNRNPC in the breast cancer cells was attributed to its function in controlling the endogenous dsRNA and the down‐stream interferon response. This is a novel extension from the previous understandings about HNRNPC in binding with introns and regulating RNA splicing.

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Section: Discussionmentioning

confidence: 99%

Function of HNRNPC in breast cancer cells by controlling the dsRNA‐induced interferon response

et al. 2018

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“…This finding suggests that 5′pppRNA exosomes transport stress-related signals to neighboring cells, priming them for 5′ppp-RNA detection. Interestingly, breast cancer stroma cells under stress deliver endogenous 5′pppRNAs that are recognized by RIG-I in tumor cells (54). Thus, a conserved intercellular pathway exists in which stress signals in the form of small RNAs are transported between cells via exosomes.…”

Section: Discussionmentioning

confidence: 99%

Sensing of latent EBV infection through exosomal transfer of 5′pppRNA

Baglio¹,

Eijndhoven²,

Koppers-Lalić

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

137

145

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Complex interactions between DNA herpesviruses and host factors determine the establishment of a life-long asymptomatic latent infection. The lymphotropic Epstein-Barr virus (EBV) seems to avoid recognition by innate sensors despite massive transcription of immunostimulatory small RNAs (EBV-EBERs). Here we demonstrate that in latently infected B cells, EBER1 transcripts interact with the lupus antigen (La) ribonucleoprotein, avoiding cytoplasmic RNA sensors. However, in coculture experiments we observed that latent-infected cells trigger antiviral immunity in dendritic cells (DCs) through selective release and transfer of RNA via exosomes. In ex vivo tonsillar cultures, we observed that EBER1-loaded exosomes are preferentially captured and internalized by human plasmacytoid DCs (pDCs) that express the TIM1 phosphatidylserine receptor, a known viraland exosomal target. Using an EBER-deficient EBV strain, enzymatic removal of 5′ppp, in vitro transcripts, and coculture experiments, we established that 5′pppEBER1 transfer via exosomes drives antiviral immunity in nonpermissive DCs. Lupus erythematosus patients suffer from elevated EBV load and activated antiviral immunity, in particular in skin lesions that are infiltrated with pDCs. We detected high levels of EBER1 RNA in such skin lesions, as well as EBV-microRNAs, but no intact EBV-DNA, linking non-cell-autonomous EBER1 presence with skin inflammation in predisposed individuals. Collectively, our studies indicate that virus-modified exosomes have a physiological role in the host-pathogen stand-off and may promote inflammatory disease.exosomes | EBV-EBER1 | innate sensing | dendritic cells | skin inflammation

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“…Besides TLRs, a recent study mentioned above showed that exosomes from stromal cells contained 5-Triphosphate RNAs, which could activate RIG-I in breast cancer cells and promote resistance to radiation therapy. 37 Decrease of NK cell cytotoxicity Natural killer (NK) cells are a typical cytotoxic lymphocyte in innate immunity and take a variety of strategies to kill cancer cells directly. 38 It has been reported that exosomes derived from anticancer drug-treated human HCC cells were rich in heat shock proteins, which could act as endogenous danger signals to stimulate NK cell-elicited antitumor responses in vitro.…”

Section: Polarization Of Tumor-promoting Macrophagesmentioning

confidence: 99%

The exosomes in tumor immunity

2015

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Exosomes are a kind of nanometric membrane vesicles and can be released by almost all kinds of cells, including cancer cells. As the important mediators in intercellular communications, exosomes mediate exchange of protein and genetic material derived from parental cells. Emerging evidences show that exosomes secreted by either host cells or cancer cells are involved in tumor initiation, growth, invasion and metastasis. Moreover, communications between immune cells and cancer cells via exosomes play dual roles in modulating tumor immunity. In this review, we focus on exosome-mediated immunosuppression via inhibition of antitumor responses elicited by immune cells (DCs, NK cells, CD4 C and CD8 C T cells, etc.) and induction of immunosuppressive or regulatory cell populations (MDSCs, Tregs and Bregs). Transfer of cytokines, microRNAs (miRNAs) and functional mRNAs by tumor-derived exosomes (TEXs) is crucial in the immune escape. Furthermore, exosomes secreted from several kinds of immune cells (DCs, CD4 C and CD8 C Tregs) also participate in immunosuppression. On the other hand, we summarize the current application of DCderived and modified tumor-derived exosomes as tumor vaccines. The potential challenges about exosome-based vaccines for clinical application are also discussed.

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Exosome Transfer from Stromal to Breast Cancer Cells Regulates Therapy Resistance Pathways

Cited by 668 publications

References 53 publications

Function of HNRNPC in breast cancer cells by controlling the dsRNA‐induced interferon response

Function of HNRNPC in breast cancer cells by controlling the dsRNA‐induced interferon response

Sensing of latent EBV infection through exosomal transfer of 5′pppRNA

The exosomes in tumor immunity

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