Inhibition of extracellular vesicle-derived miR-146a-5p decreases progression of melanoma brain metastasis via Notch pathway dysregulation in astrocytes.
Rigg, Emma; Wang, Jiwei; Xue, Zhiweiet al.
2023 • In Journal of Extracellular Vesicles, 12 (10), p. 12363
[en] Melanoma has the highest propensity of all cancers to metastasize to the brain with a large percentage of late-stage patients developing metastases in the central nervous system (CNS). It is well known that metastasis establishment, cell survival, and progression are affected by tumour-host cell interactions where changes in the host cellular compartments likely play an important role. In this context, miRNAs transferred by tumour derived extracellular vesicles (EVs) have previously been shown to create a favourable tumour microenvironment. Here, we show that miR-146a-5p is highly expressed in human melanoma brain metastasis (MBM) EVs, both in MBM cell lines as well as in biopsies, thereby modulating the brain metastatic niche. Mechanistically, miR-146a-5p was transferred to astrocytes via EV delivery and inhibited NUMB in the Notch signalling pathway. This resulted in activation of tumour-promoting cytokines (IL-6, IL-8, MCP-1 and CXCL1). Brain metastases were significantly reduced following miR-146a-5p knockdown. Corroborating these findings, miR-146a-5p inhibition led to a reduction of IL-6, IL-8, MCP-1 and CXCL1 in astrocytes. Following molecular docking analysis, deserpidine was identified as a functional miR-146a-5p inhibitor, both in vitro and in vivo. Our results highlight the pro-metastatic function of miR-146a-5p in EVs and identifies deserpidine for targeted adjuvant treatment.
Disciplines :
Oncology
Author, co-author :
Rigg, Emma ; Department of Biomedicine, University of Bergen, Bergen, Norway
Wang, Jiwei; Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, China ; Department of Biomedicine, University of Bergen, Bergen, Norway ; Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
Xue, Zhiwei; Department of Biomedicine, University of Bergen, Bergen, Norway ; Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
Lunavat, Taral R; Department of Biomedicine, University of Bergen, Bergen, Norway ; Department of Neurology, Molecular Neurogenetics Unit-West, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
Liu, Guowei; Department of Biomedicine, University of Bergen, Bergen, Norway ; Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
Hoang, Tuyen; Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, China
Parajuli, Himalaya ; Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, China
Han, Mingzhi; Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, China ; Department of Biomedicine, University of Bergen, Bergen, Norway ; Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
Bjerkvig, Rolf; Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, China
Nazarov, Petr V; Bioinformatics Platform and Multiomics Data Science Research Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg
Nicot, Nathalie; LuxGen Genome Center, Luxembourg Institute of Health, Laboratoire National de Santé, Dudelange, Luxembourg
KREIS, Stephanie ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
WURTH-MARGUE, Christiane ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
TETSI NOMIGNI, Milène ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
Utikal, Jochen; Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany ; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany ; DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
Miletic, Hrvoje; Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, China ; Department of Pathology, Haukeland University Hospital, Bergen, Norway
Sundstrøm, Terje; Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway ; Department of Clinical Medicine, University of Bergen, Bergen, Norway
Ystaas, Lars A R; Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, China
Li, Xingang; Department of Biomedicine, University of Bergen, Bergen, Norway ; Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
Thorsen, Frits; Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, China ; Department of Biomedicine, University of Bergen, Bergen, Norway ; Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway ; Molecular Imaging Center, Department of Biomedicine, University of Bergen, Bergen, Norway
Inhibition of extracellular vesicle-derived miR-146a-5p decreases progression of melanoma brain metastasis via Notch pathway dysregulation in astrocytes.
National Natural Science Foundation of China Helse Vest Universitetet i Bergen Norges Forskningsråd Kreftforeningen
Funding text :
The TEM, confocal and MR imaging was performed at The Molecular Imaging Centre, Department of Biomedicine, University of Bergen, Norway. Technical assistance from Aurea Castilho, Department of Biomedicine, University of Bergen, is highly appreciated. This work was supported by the Norwegian Cancer Society (182716), The Western Norway Regional Health Authority (F‐12856‐D11661), The Norwegian Research Council (315566), the University of Bergen, The National Natural Science Foundation of China (82073219, 82203760), the Department of Science & Technology of Shandong Province (ZR2020QH182), and Luxembourg National Research Fund (C21/BM/15739125/DIOMEDES).
Achrol, A. S., Rennert, R. C., Anders, C., Soffietti, R., Ahluwalia, M. S., Nayak, L., Peters, S., Arvold, N. D., Harsh, G. R., Steeg, P. S., & Chang, S. D. (2019). Brain metastases. Nature Reviews Disease Primers, 5, 5.
Alles, J., Fehlmann, T., Fischer, U., Backes, C., Galata, V., Minet, M., Hart, M., Abu-Halima, M., Grässer, F. A., Lenhof, H. P., Keller, A., & Meese, E. (2019). An estimate of the total number of true human miRNAs. Nucleic Acids Research, 47, 3353–3364.
Anvari, A., Sasanpour, P., & Rajabzadeh Kheradmardi, M. (2021). Radiotherapy and immunotherapy in melanoma brain metastases. Hematology/Oncology and Stem Cell Therapy, 16, 1–20.
Bartel, D. P. (2018). Metazoan microRNAs. Cell, 173, 20–51.
Bischof, K., Knappskog, S., Hjelle, S. M., Stefansson, I., Woie, K., Salvesen, H. B., Gjertsen, B. T., & Bjorge, L. (2019). Influence of p53 isoform expression on survival in high-grade serous ovarian cancers. Scientific Reports, 9, 5244.
Boire, A., Brastianos, P. K., Garzia, L., & Valiente, M. (2020). Brain metastasis. Nature Reviews Cancer, 20, 4–11.
Burn, L., Gutowski, N., Whatmore, J., Giamas, G., & Pranjol, M. Z. I. (2021). The role of astrocytes in brain metastasis at the interface of circulating tumour cells and the blood brain barrier. Frontiers in Bioscience (Landmark Ed), 26, 590–601.
Cacho-Diaz, B., Garcia-Botello, D. R., Wegman-Ostrosky, T., Reyes-Soto, G., Ortiz-Sanchez, E., & Herrera-Montalvo, L. A. (2020). Tumor microenvironment differences between primary tumor and brain metastases. Journal of Translational Medicine, 18, 1.
Cesi, G., Philippidou, D., Kozar, I., Kim, Y. J., Bernardin, F., Van Niel, G., Wienecke-Baldacchino, A., Felten, P., Letellier, E., Dengler, S., Nashan, D., Haan, C., & Kreis, S. (2018). A new ALK isoform transported by extracellular vesicles confers drug resistance to melanoma cells. Molecular Cancer, 17, 145.
Cesi, G., Walbrecq, G., Margue, C., & Kreis, S. (2016). Transferring intercellular signals and traits between cancer cells: Extracellular vesicles as “homing pigeons”. Cell Communication and Signaling, 14, 13.
Dhawan, P., & Richmond, A. (2002). Role of CXCL1 in tumorigenesis of melanoma. Journal of Leukocyte Biology, 72, 9–18.
Dika, E., Riefolo, M., Porcellini, E., Broseghini, E., Ribero, S., Senetta, R., Osella-Abate, S., Scarfì, F., Lambertini, M., Veronesi, G., Patrizi, A., Fanti, P. A., & Ferracin, M. (2020). Defining the prognostic role of MicroRNAs in cutaneous melanoma. Journal of Investigative Dermatology, 140, 2260–2267.
Escartin, C., Galea, E., Lakatos, A., O'Callaghan, J. P., Petzold, G. C., Serrano-Pozo, A., Steinhäuser, C., Volterra, A., Carmignoto, G., Agarwal, A., Allen, N. J., Araque, A., Barbeito, L., Barzilai, A., Bergles, D. E., Bonvento, G., Butt, A. M., Chen, W. C., Cohen-Salmon, M., … Verkhratsky, A. (2021). Reactive astrocyte nomenclature, definitions, and future directions. Nature Neuroscience, 24, 312–325.
Fares, J., Cordero, A., Kanojia, D., & Lesniak, M. S. (2021). The network of cytokines in brain metastases. Cancers (Basel), 13, 142.
Forloni, M., Dogra, S. K., Dong, Y., Conte D., Jr., Ou, J., Zhu, L. J., Deng, A., Mahalingam, M., Green, M. R., & Wajapeyee, N. (2014). miR-146a promotes the initiation and progression of melanoma by activating Notch signaling. eLife, 3, e01460.
Geling, A., Steiner, H., Willem, M., Bally-Cuif, L., & Haass, C. (2002). A gamma-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish. Embo Reports, 3, 688–694.
Gowda, R., Robertson, B. M., Iyer, S., Barry, J., Dinavahi, S. S., & Robertson, G. P. (2020). The role of exosomes in metastasis and progression of melanoma. Cancer Treatment Reviews, 85, 101975.
Hanniford, D., Zhong, J., Koetz, L., Gaziel-Sovran, A., Lackaye, D. J., Shang, S., Pavlick, A., Shapiro, R., Berman, R., Darvishian, F., Shao, Y., Osman, I., & Hernando, E. (2015). A miRNA-based signature detected in primary melanoma tissue predicts development of brain metastasis. Clinical Cancer Research, 21, 4903–4912.
Heiland, D. H., Ravi, V. M., Behringer, S. P., Frenking, J. H., Wurm, J., Joseph, K., Garrelfs, N. W. C., Strähle, J., Heynckes, S., Grauvogel, J., Franco, P., Mader, I., Schneider, M., Potthoff, A. L., Delev, D., Hofmann, U. G., Fung, C., Beck, J., Sankowski, R., … Prinz, M. (2019). Tumor-associated reactive astrocytes aid the evolution of immunosuppressive environment in glioblastoma. Nature Communications, 10, 2541.
Hristova, D. M., Fukumoto, T., Takemori, C., Gao, L., Hua, X., Wang, J. X., Li, L., Beqiri, M., Watters, A., Vultur, A., Gimie, Y., Rebecca, V., Samarkina, A., Jimbo, H., Nishigori, C., Zhang, J., Cheng, C., Wei, Z., Somasundaram, R., … Herlyn, M. (2021). NUMB as a therapeutic target for melanoma. The Journal of Investigative Dermatology, 142(7), 1882–1892.e5.
Hwang, S. J., Seol, H. J., Park, Y. M., Kim, K. H., Gorospe, M., Nam, D. H., & Kim, H. H. (2012). MicroRNA-146a suppresses metastatic activity in brain metastasis. Molecules and Cells, 34, 329–334.
Kim, M., Kizilbash, S. H., Laramy, J. K., Gampa, G., Parrish, K. E., Sarkaria, J. N., & Elmquist, W. F. (2018). Barriers to effective drug treatment for brain metastases: A multifactorial problem in the delivery of precision medicine. Pharmaceutical Research, 35, 177.
Kulkarni, B., Kirave, P., Gondaliya, P., Jash, K., Jain, A., Tekade, R. K., & Kalia, K. (2019). Exosomal miRNA in chemoresistance, immune evasion, metastasis and progression of cancer. Drug Discovery Today, 24, 2058–2067.
Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J.-J., Rutkowski, P., Lao, C. D., Cowey, C. L., Schadendorf, D., Wagstaff, J., Dummer, R., Ferrucci, P. F., Smylie, M., Hogg, D., Hill, A., Márquez-Rodas, I., Haanen, J., Guidoboni, M., Maio, M., Schöffski, P., … Wolchok, J. D. (2019). Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. New England Journal of Medicine, 381, 1535–1546.
Liu, X., Fang, H., Chen, H., Jiang, X., Fang, D., Wang, Y., & Zhu, D. (2012). An artificial miRNA against HPSE suppresses melanoma invasion properties, correlating with a down-regulation of chemokines and MAPK phosphorylation. PLoS ONE, 7, e38659.
Lunavat, T. R., Cheng, L., Einarsdottir, B. O., Olofsson Bagge, R., Veppil Muralidharan, S., Sharples, R. A., Lässer, C., Gho, Y. S., Hill, A. F., Nilsson, J. A., & Lötvall, J. (2017). BRAF(V600) inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells. PNAS, 114, E5930–e5939.
Obrador, E., Benlloch, M., Pellicer, J. A., Asensi, M., & Estrela, J. M. (2011). Intertissue flow of glutathione (GSH) as a tumor growth-promoting mechanism: Interleukin 6 induces GSH release from hepatocytes in metastatic B16 melanoma-bearing mice. Journal of Biological Chemistry, 286, 15716–15727.
Peinado, H., Zhang, H., Matei, I. R., Costa-Silva, B., Hoshino, A., Rodrigues, G., Psaila, B., Kaplan, R. N., Bromberg, J. F., Kang, Y., Bissell, M. J., Cox, T. R., Giaccia, A. J., Erler, J. T., Hiratsuka, S., Ghajar, C. M., & Lyden, D. (2017). Pre-metastatic niches: Organ-specific homes for metastases. Nature Reviews Cancer, 17, 302–317.
Placone, A. L., Quiñones-Hinojosa, A., & Searson, P. C. (2016). The role of astrocytes in the progression of brain cancer: Complicating the picture of the tumor microenvironment. Tumor Biology, 37, 61–69.
Pozzi, S., Scomparin, A., Ben-Shushan, D., Yeini, E., Ofek, P., Nahmad, A. D., Soffer, S., Ionescu, A., Ruggiero, A., Barzel, A., Brem, H., Hyde, T. M., Barshack, I., Sinha, S., Ruppin, E., Weiss, T., Madi, A., Perlson, E., Slutsky, I., … Satchi-Fainaro, R. (2022). MCP-1/CCR2 axis inhibition sensitizes the brain microenvironment against melanoma brain metastasis progression. JCI Insight, 7, e154804.
Pu, W., Shang, Y., Shao, Q., & Yuan, X. (2018). miR-146a promotes cell migration and invasion in melanoma by directly targeting SMAD4. Oncology Letters, 15, 7111–7117.
Pushpakom, S., Iorio, F., Eyers, P. A., Escott, K. J., Hopper, S., Wells, A., Doig, A., Guilliams, T., Latimer, J., McNamee, C., Norris, A., Sanseau, P., Cavalla, D., & Pirmohamed, M. (2019). Drug repurposing: Progress, challenges and recommendations. Nature Reviews Drug Discovery, 18, 41–58.
Raimo, M., Orso, F., Grassi, E., Cimino, D., Penna, E., De Pitta, C., Stadler, M. B., Primo, L., Calautti, E., Quaglino, P., Provero, P., & Taverna, D. (2016). miR-146a exerts differential effects on melanoma growth and metastatization. Molecular Cancer Research, 14, 548–562.
Rishi, A., & Yu, H. M. (2020). Current treatment of melanoma brain metastasis. Current Treatment Options in Oncology, 21, 45.
Rodrigues, G., Hoshino, A., Kenific, C. M., Matei, I. R., Steiner, L., Freitas, D., Kim, H. S., Oxley, P. R., Scandariato, I., Casanova-Salas, I., Dai, J., Badwe, C. R., Gril, B., Tešić Mark, M., Dill, B. D., Molina, H., Zhang, H., Benito-Martin, A., … Lyden, D. (2019). Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis. Nature Cell Biology, 21, 1403–1412.
Rossi, S., Cordella, M., Tabolacci, C., Nassa, G., D'Arcangelo, D., Senatore, C., Pagnotto, P., Magliozzi, R., Salvati, A., Weisz, A., Facchiano, A., & Facchiano, F. (2018). TNF-alpha and metalloproteases as key players in melanoma cells aggressiveness. Journal of Experimental & Clinical Cancer Research, 37, 326.
Si, W., Shen, J., Zheng, H., & Fan, W. (2019). The role and mechanisms of action of microRNAs in cancer drug resistance. Clinical Epigenetics, 11, 25.
Stamatovic, S. M., Keep, R. F., Kunkel, S. L., & Andjelkovic, A. V. (2003). Potential role of MCP-1 in endothelial cell tight junction ‘opening’: Signaling via Rho and Rho kinase. Journal of Cell Science, 116, 4615–4628.
Sun, Z., Shi, K., Yang, S., Liu, J., Zhou, Q., Wang, G., Song, J., Li, Z., Zhang, Z., & Yuan, W. (2018). Effect of exosomal miRNA on cancer biology and clinical applications. Molecular Cancer, 17, 147.
Sundstrøm, T., Daphu, I., Wendelbo, I., Hodneland, E., Lundervold, A., Immervoll, H., Skaftnesmo, K. O., Babic, M., Jendelova, P., Sykova, E., Lund-Johansen, M., Bjerkvig, R., & Thorsen, F. (2013). Automated tracking of nanoparticle-labeled melanoma cells improves the predictive power of a brain metastasis model. Cancer Research, 73, 2445–2456.
Tamas, F., Balasa, R., Manu, D., Gyorki, G., Chinezu, R., Tamas, C., & Bălașa, A. (2022). The importance of small extracellular vesicles in the cerebral metastatic process. International Journal of Molecular Sciences, 23(3), 1449.
Tawbi, H. A.-H., Forsyth, P. A. J., Hodi, F. S., Lao, C. D., Moschos, S. J., Hamid, O., Atkins, M. B., Lewis, K., Thomas, R. P., Glaspy, J. A., Jang, S., Algazi, A. P., Khushalani, N. I., Postow, M. A., Pavlick, A. C., Ernstoff, M. S., Reardon, D. A., Puzanov, I., Kudchadkar, R. R., … Margolin, K. A. (2019). Efficacy and safety of the combination of nivolumab (NIVO) plus ipilimumab (IPI) in patients with symptomatic melanoma brain metastases (CheckMate 204). Journal of Clinical Oncology, 37, 9501.
Théry, C., Witwer, K. W., Aikawa, E., Alcaraz, M. J., Anderson, J. D., Andriantsitohaina, R., Antoniou, A., Arab, T., Archer, F., Atkin-Smith, G. K., Ayre, D. C., Bach, J. M., Bachurski, D., Baharvand, H., Balaj, L., Baldacchino, S., Bauer, N. N., Baxter, A. A., … Zuba-Surma, E. K. (2018). Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. Journal of Extracellular Vesicles, 7, 1535750.
Tominaga, N., Kosaka, N., Ono, M., Katsuda, T., Yoshioka, Y., Tamura, K., Lötvall, J., Nakagama, H., & Ochiya, T. (2015). Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood–brain barrier. Nature Communications, 6, 6716.
Valadi, H., Ekström, K., Bossios, A., Sjöstrand, M., Lee, J. J., & Lötvall, J. O. (2007). Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell Biology, 9, 654–659.
Wasilewski, D., Priego, N., Fustero-Torre, C., & Valiente, M. (2017). Reactive astrocytes in brain metastasis. Frontiers in Oncology, 7, 298.
Weiss, J. M., Downie, S. A., Lyman, W. D., & Berman, J. W. (1998). Astrocyte-derived monocyte-chemoattractant protein-1 directs the transmigration of leukocytes across a model of the human blood-brain barrier. Journal of Immunology, 161, 6896–6903.
Xing, F., Kobayashi, A., Okuda, H., Watabe, M., Pai, S. K., Pandey, P. R., Hirota, S., Wilber, A., Mo, Y. Y., Moore, B. E., Liu, W., Fukuda, K., Iiizumi, M., Sharma, S., Liu, Y., Wu, K., Peralta, E., & Watabe, K. (2013). Reactive astrocytes promote the metastatic growth of breast cancer stem-like cells by activating Notch signalling in brain. EMBO Molecular Medicine, 5, 384–396.
Yao, Y., & Tsirka, S. E. (2014). Monocyte chemoattractant protein-1 and the blood-brain barrier. Cellular and Molecular Life Sciences, 71, 683–697.
Zhang, H., Zhong, D., Zhang, Z., Dai, X., & Chen, X. (2009). Liquid chromatography/tandem mass spectrometry method for the quantification of deserpidine in human plasma: Application to a pharmacokinetic study. Journal of Chromatography B, Analytical Technologies in the Biomedical and Life Sciences, 877, 3221–3225.
Zhang, L., Xie, H., & Cui, L. (2018). Activation of astrocytes and expression of inflammatory cytokines in rats with experimental autoimmune encephalomyelitis. Experimental and Therapeutic Medicine, 16, 4401–4406.
Zhang, L., Zhang, S., Yao, J., Lowery, F. J., Zhang, Q., Huang, W. C., Li, P., Li, M., Wang, X., Zhang, C., Wang, H., Ellis, K., Cheerathodi, M., McCarty, J. H., Palmieri, D., Saunus, J., Lakhani, S., Huang, S., Sahin, A. A., … Yu, D. (2015). Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature, 527, 100–104.
Zhang, Y., Zhao, J., Ding, M., Su, Y., Cui, D., Jiang, C., Zhao, S., Jia, G., Wang, X., Ruan, Y., Jing, Y., Xia, S., & Han, B. (2020). Loss of exosomal miR-146a-5p from cancer-associated fibroblasts after androgen deprivation therapy contributes to prostate cancer metastasis. Journal of Experimental & Clinical Cancer Research, 39, 282.
Zhao, S., Mi, Y., Zheng, B., Wei, P., Gu, Y., Zhang, Z., Xu, Y., Cai, S., Li, X., & Li, D. (2022). Highly-metastatic colorectal cancer cell released miR-181a-5p-rich extracellular vesicles promote liver metastasis by activating hepatic stellate cells and remodelling the tumour microenvironment. Journal of Extracellular Vesicles, 11, e12186.
Zou, Y., Watters, A., Cheng, N., Perry, C. E., Xu, K., Alicea, G. M., Parris, J. L. D., Baraban, E., Ray, P., Nayak, A., Xu, X., Herlyn, M., Murphy, M. E., Weeraratna, A. T., Schug, Z. T., & Chen, Q. (2019). Polyunsaturated fatty acids from astrocytes activate PPARγ signaling in cancer cells to promote brain metastasis. Cancer Discovery, 9, 1720–1735.
