سابِق|تال

يراقب RARRES2 إعادة برمجة الأيض الدهني ليتوسط تطور النقائل الدماغية في سرطان الثدي الثلاثي السلبي

  • role： Contribute equally, First author同等贡献者, 第一作者
  • Affiliation：

    Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

Yi-Qun Li1,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

Fang-Zhou Sun2,  
  • role： Contribute equally同等贡献者
  • Affiliation：

    State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

Chun-Xiao Li2,  
  • Affiliation：

    Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

Hong-Nan Mo1,  
  • Affiliation：

    State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

Yan-Tong Zhou2,  
  • Affiliation：

    Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

Dan Lv1,  
  • Affiliation：

    Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

Jing-Tong Zhai1,  
  • role： Corresponding author通信作者
  • Affiliation：

    State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

  • Email：qianhaili@pumc.edu.cn
  • Introduction：* qianhaili@pumc.edu.cn,
Hai-Li Qian2*,  
  • role： Corresponding author通信作者
  • Affiliation：

    Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

  • Email：mafei@cicams.ac.cn
  • Introduction：mafei@cicams.ac.cn
Fei Ma1*

ملخص

BackgroundTriple negative breast cancer (TNBC), the most aggressive subtype of breast cancer, is characterized by a high incidence of brain metastasis (BrM) and a poor prognosis. As the most lethal form of breast cancer, BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies. Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis (BCBrM), but the underlying mechanisms are far from being fully elucidated.MethodsThrough analysis of BCBrM transcriptome data from mice and patients, and immunohistochemical validation on patient tissues, we identified and verified the specific down-regulation of retinoic acid receptor responder 2 (RARRES2), a multifunctional adipokine and chemokine, in BrM of TNBC. We investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo studies. Key signaling pathway components were evaluated using multi-omics approaches. Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2.ResultsWe found that downregulation of RARRES2 is specifically associated with BCBrM, and that RARRES2 deficiency promoted BCBrM through lipid metabolic reprogramming. Mechanistically, reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue (PTEN)-mammalian target of rapamycin (mTOR)-sterol regulatory element-binding protein 1 (SREBP1) signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment.ConclusionsOur work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of BrM. RARRES2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.

مفهوم

RARRES2;Lipid metabolic reprogramming;Brain metastasis (BrM);Breast cancer

References

  1. 1..
    Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7–33.
  2. 2..
    Lin NU, Bellon JR, Winer EP. CNS metastases in breast cancer. J Clin Oncol. 2004;22(17):3608–17.
  3. 3..
    Lin NU, Vanderplas A, Hughes ME, Theriault RL, Edge SB, Wong YN, et al. Clinicopathologic features, patterns of recurrence, and survival among women with triple-negative breast cancer in the National Comprehensive Cancer Network. Cancer. 2012;118(22):5463–72.
  4. 4..
    Boire A, Brastianos PK, Garzia L, Valiente M. Brain metastasis. Nat Rev Cancer. 2020;20(1):4–11.
  5. 5..
    Sirhan Z, Thyagarajan A, Sahu RP. The efficacy of tucatinib-based therapeutic approaches for HER2-positive breast cancer. Mil Med Res. 2022;9(1):39.
  6. 6..
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.
  7. 7..
    Currie E, Schulze A, Zechner R, Walther TC, Farese RV Jr. Cellular fatty acid metabolism and cancer. Cell Metab. 2013;18(2):153–61.
  8. 8..
    Jin X, Demere Z, Nair K, Ali A, Ferraro GB, Natoli T, et al. A metastasis map of human cancer cell lines. Nature. 2020;588(7837):331–6.
  9. 9..
    Ferraro GB, Ali A, Luengo A, Kodack DP, Deik A, Abbott KL, et al. Fatty acid synthesis is required for breast cancer brain metastasis. Nat Cancer. 2021;2(4):414–28.
  10. 10..
    Zou Y, Watters A, Cheng N, Perry CE, Xu K, Alicea GM, et al. Polyunsaturated fatty acids from astrocytes activate PPARγ signaling in cancer cells to promote brain metastasis. Cancer Discov. 2019;9(12):1720–35.
  11. 11..
    Ernst MC, Sinal CJ. Chemerin: at the crossroads of inflammation and obesity. Trends Endocrinol Metab. 2010;21(11):660–7.
  12. 12..
    Goralski KB, McCarthy TC, Hanniman EA, Zabel BA, Butcher EC, Parlee SD, et al. Chemerin, a novel adipokine that regulates adipogenesis and adipocyte metabolism. J Biol Chem. 2007;282(38):28175–88.
  13. 13..
    Li JJ, Yin HK, Guan DX, Zhao JS, Feng YX, Deng YZ, et al. Chemerin suppresses hepatocellular carcinoma metastasis through CMKLR1-PTEN-Akt axis. Br J Cancer. 2018;118(10):1337–48.
  14. 14..
    Pachynski RK, Zabel BA, Kohrt HE, Tejeda NM, Monnier J, Swanson CD, et al. The chemoattractant chemerin suppresses melanoma by recruiting natural killer cell antitumor defenses. J Exp Med. 2012;209(8):1427–35.
  15. 15..
    Shin WJ, Zabel BA, Pachynski RK. Mechanisms and functions of chemerin in cancer: potential roles in therapeutic intervention. Front Immunol. 2018;9:2772.
  16. 16..
    Butler A, Hoffman P, Smibert P, Papalexi E, Satija R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol. 2018;36(5):411–20.
  17. 17..
    Gonzalez H, Mei W, Robles I, Hagerling C, Allen BM, Hauge Okholm TL, et al. Cellular architecture of human brain metastases. Cell. 2022;185(4):729-45.e20.
  18. 18..
    Su M, Pan T, Chen QZ, Zhou WW, Gong Y, Xu G, et al. Data analysis guidelines for single-cell RNA-seq in biomedical studies and clinical applications. Mil Med Res. 2022;9(1):68.
  19. 19..
    Ozawa T, James CD. Establishing intracranial brain tumor xenografts with subsequent analysis of tumor growth and response to therapy using bioluminescence imaging. J Vis Exp. 2010;13(41):1986.
  20. 20..
    Varešlija D, Priedigkeit N, Fagan A, Purcell S, Cosgrove N, O’Halloran PJ, et al. Transcriptome characterization of matched primary breast and brain metastatic tumors to detect novel actionable targets. J Natl Cancer Inst. 2019;111(4):388–98.
  21. 21..
    Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3(6):453–8.
  22. 22..
    Ricoult SJ, Yecies JL, Ben-Sahra I, Manning BD. Oncogenic PI3K and K-Ras stimulate de novo lipid synthesis through mTORC1 and SREBP. Oncogene. 2016;35(10):1250–60.
  23. 23..
    Dillon LM, Miller TW. Therapeutic targeting of cancers with loss of PTEN function. Curr Drug Targets. 2014;15(1):65–79.
  24. 24..
    Network CGA. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70.
  25. 25..
    Huang RSP, Haberberger J, McGregor K, Mata DA, Decker B, Hiemenz MC, et al. Clinicopathologic and genomic landscape of breast carcinoma brain metastases. Oncologist. 2021;26(10):835–44.
  26. 26..
    Rennier K, Shin WJ, Krug E, Virdi G, Pachynski RK. Chemerin reactivates PTEN and suppresses PD-L1 in tumor cells via modulation of a novel CMKLR1-mediated signaling cascade. Clin Cancer Res. 2020;26(18):5019–35.
  27. 27..
    Yoshimura T, Oppenheim JJ. Chemokine-like receptor 1 (CMKLR1) and chemokine (C-C motif) receptor-like 2 (CCRL2); two multifunctional receptors with unusual properties. Exp Cell Res. 2011;317(5):674–84.
  28. 28..
    Piomelli D, Astarita G, Rapaka R. A neuroscientist’s guide to lipidomics. Nat Rev Neurosci. 2007;8(10):743–54.
  29. 29..
    Zhu L, Huang J, Wang Y, Yang Z, Chen X. Chemerin causes lipid metabolic imbalance and induces passive lipid accumulation in human hepatoma cell line via the receptor GPR1. Life Sci. 2021;278:119530.
  30. 30..
    Balla T. Phosphoinositides: tiny lipids with giant impact on cell regulation. Physiol Rev. 2013;93(3):1019–137.
  31. 31..
    Ooms LM, Binge LC, Davies EM, Rahman P, Conway JR, Gurung R, et al. The inositol polyphosphate 5-phosphatase PIPP regulates AKT1-dependent breast cancer growth and metastasis. Cancer Cell. 2015;28(2):155–69.
  32. 32..
    Helfer G, Wu QF. Chemerin: a multifaceted adipokine involved in metabolic disorders. J Endocrinol. 2018;238(2):R79–94.
  33. 33..
    De Henau O, Degroot GN, Imbault V, Robert V, De Poorter C, McHeik S, et al. Signaling properties of chemerin receptors CMKLR1, GPR1 and CCRL2. PLoS One. 2016;11(10):e0164179.
  34. 34..
    Witzel I, Oliveira-Ferrer L, Pantel K, Muller V, Wikman H. Breast cancer brain metastases: biology and new clinical perspectives. Breast Cancer Res. 2016;18(1):8.
  35. 35..
    Manning BD, Toker A. AKT/PKB signaling: navigating the network. Cell. 2017;169(3):381–405.
  36. 36..
    Wang Y, Viscarra J, Kim SJ, Sul HS. Transcriptional regulation of hepatic lipogenesis. Nat Rev Mol Cell Biol. 2015;16(11):678–89.

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