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Tumour-derived exosomal piR-25783 promotes omental metastasis of ovarian carcinoma by inducing the fibroblast to myofibroblast transition

Oncogene volume 42, pages 421–433 (2023)Cite this article

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Abstract

Ovarian carcinoma inherently possesses a distinct metastatic organotropism for the adipose-rich omentum, contributing to disease progression. Although the premetastatic microenvironment (PMM) has been known to often play a prometastatic role during the process, incomplete mechanistic insight into PMM formation has prevented its therapeutic targeting. Omental fibroblasts can be activated by tumour cells to differentiate into myofibroblasts, termed the fibroblast-to-myofibroblast transition (FMT), which, in turn, enhances cancer aggressiveness. Here, we report crosstalk between cancer cells and omental fibroblasts through exosomal piR-25783, which fuels tumour metastasis. Tumour cell-secreted exosomal piR-25783 activates the TGF-β/SMAD2/SMAD3 pathway in fibroblasts and promotes the FMT in the omentum along with the secretion of various cytokines and elevation of proliferative, migratory, and invasive properties, contributing to the formation of PMMs. Furthermore, piR-25783-induced myofibroblasts promote tumour implantation and growth in the omentum. In addition, the overexpression of piR-25783 in ovarian carcinoma is associated with unfavourable clinicopathological characteristics and shorter survival. In this study, we provide molecular, functional, and translational evidence suggesting that exosomal piR-25783 plays an important role in the formation of PMMs and the development of metastatic diseases in vitro and in vivo and may serve as a potential therapeutic target for ovarian carcinoma with metastasis.

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Fig. 1: Exosomes promote the formation of the omental premetastatic microenvironment in vivo.
Fig. 2: Exosomes promote the activation of myofibroblasts in vitro.
Fig. 3: Candidate piRNAs in OCDE associated with omental metastasis and myofibroblast activation.
Fig. 4: Exosomal piR-25783 derived from ovarian carcinoma cells activates myofibroblasts in vitro.
Fig. 5: Exosomal piR-25783 derived from ovarian carcinoma cells activates PMMs in vivo.
Fig. 6: Exosomal piR-25783 activates myofibroblasts via the TGF-β/SMAD2/SMAD3 pathway.
Fig. 7: piR-25783-induced myofibroblasts promote omental metastasis of OvCa.

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Data availability

The datasets generated and/or analysed during the current study are available from the corresponding author upon reasonable request.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    Article  Google Scholar 

  2. Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, et al. Ovarian cancer statistics, 2018. CA Cancer J Clin. 2018;68:284–96.

    Article  Google Scholar 

  3. Kuroki L, Guntupalli SR. Treatment of epithelial ovarian cancer. BMJ. 2020;371:m3773.

    Article  Google Scholar 

  4. Worzfeld T, Pogge von Strandmann E, Huber M, Adhikary T, Wagner U, Reinartz S, et al. The unique molecular and cellular microenvironment of ovarian cancer. Front Oncol. 2017;7:24.

    Article  Google Scholar 

  5. Barbolina MV. Molecular mechanisms regulating organ-specific metastases in epithelial ovarian carcinoma. Cancers. 2018;10:444.

  6. Tan DS, Agarwal R, Kaye SB. Mechanisms of transcoelomic metastasis in ovarian cancer. Lancet Oncol. 2006;7:925–34.

    Article  Google Scholar 

  7. Schild T, Low V, Blenis J, Gomes AP. Unique metabolic adaptations dictate distal organ-specific metastatic colonization. Cancer Cell. 2018;33:347–54.

    Article  CAS  Google Scholar 

  8. Paiva AE, Lousado L, Guerra DAP, Azevedo PO, Sena IFG, Andreotti JP, et al. Pericytes in the premetastatic niche. Cancer Res. 2018;78:2779–86.

    Article  CAS  Google Scholar 

  9. Lee W, Ko SY, Mohamed MS, Kenny HA, Lengyel E, Naora H. Neutrophils facilitate ovarian cancer premetastatic niche formation in the omentum. J Exp Med. 2019;216:176–94.

    Article  CAS  Google Scholar 

  10. Kim H, Chung H, Kim J, Choi DH, Shin Y, Kang YG, et al. Macrophages-triggered sequential remodeling of endothelium-interstitial matrix to form pre-metastatic niche in microfluidic tumor microenvironment. Adv Sci. 2019;6:1900195.

    Article  Google Scholar 

  11. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6:392–401.

    Article  CAS  Google Scholar 

  12. Hiratsuka S, Watanabe A, Sakurai Y, Akashi-Takamura S, Ishibashi S, Miyake K, et al. The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat Cell Biol. 2008;10:1349–55.

    Article  CAS  Google Scholar 

  13. Giles AJ, Reid CM, Evans JD, Murgai M, Vicioso Y, Highfill SL, et al. Activation of hematopoietic stem/progenitor cells promotes immunosuppression within the pre-metastatic niche. Cancer Res. 2016;76:1335–47.

    Article  CAS  Google Scholar 

  14. Wu S, Xing X, Wang Y, Zhang X, Li M, Wang M, et al. The pathological significance of LOXL2 in pre-metastatic niche formation of HCC and its related molecular mechanism. Eur J Cancer. 2021;147:63–73.

    Article  CAS  Google Scholar 

  15. Zeng Z, Li Y, Pan Y, Lan X, Song F, Sun J, et al. Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis. Nat Commun. 2018;9:5395.

    Article  CAS  Google Scholar 

  16. Cai J, Tang H, Xu L, Wang X, Yang C, Ruan S, et al. Fibroblasts in omentum activated by tumor cells promote ovarian cancer growth, adhesion and invasiveness. Carcinogenesis. 2012;33:20–29.

    Article  CAS  Google Scholar 

  17. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214:199–210.

    Article  CAS  Google Scholar 

  18. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367:eaau6977.

    Article  CAS  Google Scholar 

  19. Kahlert C, Kalluri R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med. 2013;91:431–7.

    Article  CAS  Google Scholar 

  20. Feng W, Dean DC, Hornicek FJ, Shi H, Duan Z. Exosomes promote pre-metastatic niche formation in ovarian cancer. Mol Cancer. 2019;18:124.

    Article  Google Scholar 

  21. Fang T, Lv H, Lv G, Li T, Wang C, Han Q, et al. Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat Commun. 2018;9:191.

    Article  Google Scholar 

  22. Freedman JE, Gerstein M, Mick E, Rozowsky J, Levy D, Kitchen R, et al. Diverse human extracellular RNAs are widely detected in human plasma. Nat Commun. 2016;7:11106.

    Article  CAS  Google Scholar 

  23. Jia S, Zhang Q, Wang Y, Wang Y, Liu D, He Y, et al. PIWI-interacting RNA sequencing profiles in maternal plasma-derived exosomes reveal novel non-invasive prenatal biomarkers for the early diagnosis of nonsyndromic cleft lip and palate. EBioMedicine. 2021;65:103253.

    Article  CAS  Google Scholar 

  24. Ge L, Zhang N, Li D, Wu Y, Wang H, Wang J. Circulating exosomal small RNAs are promising non-invasive diagnostic biomarkers for gastric cancer. J Cell Mol Med. 2020;24:14502–13.

    Article  CAS  Google Scholar 

  25. Fonseca Cabral G, Azevedo Dos Santos Pinheiro J, Vidal AF, Santos S, Ribeiro-Dos-Santos A. piRNAs in gastric cancer: a new approach towards translational research. Int J Mol Sci. 2020;21:2126.

    Article  Google Scholar 

  26. Kurth HM, Mochizuki K. 2’-O-methylation stabilizes Piwi-associated small RNAs and ensures DNA elimination in Tetrahymena. RNA. 2009;15:675–85.

    Article  CAS  Google Scholar 

  27. Weng W, Li H, Goel A. Piwi-interacting RNAs (piRNAs) and cancer: emerging biological concepts and potential clinical implications. Biochim Biophys Acta Rev Cancer. 2019;1871:160–9.

    Article  CAS  Google Scholar 

  28. Liu Y, Dou M, Song X, Dong Y, Liu S, Liu H, et al. The emerging role of the piRNA/piwi complex in cancer. Mol Cancer. 2019;18:123.

    Article  Google Scholar 

  29. D’Urso M, Kurniawan NA. Mechanical and physical regulation of fibroblast-myofibroblast transition: from cellular mechanoresponse to tissue pathology. Front Bioeng Biotechnol. 2020;8:609653.

    Article  Google Scholar 

  30. Peinado H, Zhang H, Matei IR, Costa-Silva B, Hoshino A, Rodrigues G, et al. Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer. 2017;17:302–17.

    Article  CAS  Google Scholar 

  31. Alharthi A, Verma A, Sabbineni H, Adil MS, Somanath PR. Distinct effects of pharmacological inhibition of stromelysin1 on endothelial-to-mesenchymal transition and myofibroblast differentiation. J Cell Physiol. 2021;236:5147–61.

    Article  CAS  Google Scholar 

  32. Michalik M, Wojcik-Pszczola K, Paw M, Wnuk D, Koczurkiewicz P, Sanak M, et al. Fibroblast-to-myofibroblast transition in bronchial asthma. Cell Mol Life Sci. 2018;75:3943–61.

    Article  CAS  Google Scholar 

  33. Haque S, Morris JC. Transforming growth factor-beta: a therapeutic target for cancer. Hum Vaccin Immunother. 2017;13:1741–50.

    Article  Google Scholar 

  34. Massague J. TGFbeta in Cancer. Cell. 2008;134:215–30.

    Article  CAS  Google Scholar 

  35. Schlingensiepen KH, Jaschinski F, Lang SA, Moser C, Geissler EK, Schlitt HJ, et al. Transforming growth factor-beta 2 gene silencing with trabedersen (AP 12009) in pancreatic cancer. Cancer Sci. 2011;102:1193–200.

    Article  CAS  Google Scholar 

  36. Ehata S, Hanyu A, Fujime M, Katsuno Y, Fukunaga E, Goto K, et al. Ki26894, a novel transforming growth factor-beta type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line. Cancer Sci. 2007;98:127–33.

    Article  CAS  Google Scholar 

  37. Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer. 2020;20:174–86.

    Article  CAS  Google Scholar 

  38. Zheng X, Huang M, Xing L, Yang R, Wang X, Jiang R, et al. The circRNA circSEPT9 mediated by E2F1 and EIF4A3 facilitates the carcinogenesis and development of triple-negative breast cancer. Mol Cancer. 2020;19:73.

    Article  CAS  Google Scholar 

  39. Chen C, Luo Y, He W, Zhao Y, Kong Y, Liu H, et al. Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer. J Clin Invest. 2020;130:404–21.

    Article  CAS  Google Scholar 

  40. Chen L, Guo P, He Y, Chen Z, Chen L, Luo Y, et al. HCC-derived exosomes elicit HCC progression and recurrence by epithelial-mesenchymal transition through MAPK/ERK signalling pathway. Cell Death Dis. 2018;9:513.

    Article  Google Scholar 

  41. Yang SS, Ma S, Dou H, Liu F, Zhang SY, Jiang C, et al. Breast cancer-derived exosomes regulate cell invasion and metastasis in breast cancer via miR-146a to activate cancer associated fibroblasts in tumor microenvironment. Exp Cell Res. 2020;391:111983.

    Article  CAS  Google Scholar 

  42. Ringuette Goulet C, Bernard G, Tremblay S, Chabaud S, Bolduc S, Pouliot F. Exosomes induce fibroblast differentiation into cancer-associated fibroblasts through TGFbeta signaling. Mol Cancer Res. 2018;16:1196–204.

    Article  CAS  Google Scholar 

  43. Peng P, Yan Y, Keng S. Exosomes in the ascites of ovarian cancer patients: origin and effects on anti-tumor immunity. Oncol Rep. 2011;25:749–62.

    CAS  Google Scholar 

  44. Naora H, Montell DJ. Ovarian cancer metastasis: integrating insights from disparate model organisms. Nat Rev Cancer. 2005;5:355–66.

    Article  CAS  Google Scholar 

  45. Bowtell DD, Bohm S, Ahmed AA, Aspuria PJ, Bast RC Jr., Beral V, et al. Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer. Nat Rev Cancer. 2015;15:668–79.

    Article  CAS  Google Scholar 

  46. Zhang Y, Cai H, Chen S, Sun D, Zhang D, He Y. Exosomal transfer of miR-124 inhibits normal fibroblasts to cancer-associated fibroblasts transition by targeting sphingosine kinase 1 in ovarian cancer. J Cell Biochem. 2019;120:13187–201.

    Article  CAS  Google Scholar 

  47. Jiang K, Chen H, Fang Y, Chen L, Zhong C, Bu T, et al. Exosomal ANGPTL1 attenuates colorectal cancer liver metastasis by regulating Kupffer cell secretion pattern and impeding MMP9 induced vascular leakiness. J Exp Clin Cancer Res. 2021;40:21.

    Article  CAS  Google Scholar 

  48. Pippadpally S, Venkatesh T. Deciphering piRNA biogenesis through cytoplasmic granules, mitochondria and exosomes. Arch Biochem Biophys. 2020;695:108597.

    Article  CAS  Google Scholar 

  49. Li F, Yuan P, Rao M, Jin CH, Tang W, Rong YF, et al. piRNA-independent function of PIWIL1 as a co-activator for anaphase promoting complex/cyclosome to drive pancreatic cancer metastasis. Nat Cell Biol. 2020;22:425–38.

    Article  CAS  Google Scholar 

  50. Zhang SJ, Yao J, Shen BZ, Li GB, Kong SS, Bi DD, et al. Role of piwi-interacting RNA-651 in the carcinogenesis of non-small cell lung cancer. Oncol Lett. 2018;15:940–6.

    CAS  Google Scholar 

  51. Li D, Luo Y, Gao Y, Yang Y, Wang Y, Xu Y, et al. piR-651 promotes tumor formation in non-small cell lung carcinoma through the upregulation of cyclin D1 and CDK4. Int J Mol Med. 2016;38:927–36.

    Article  CAS  Google Scholar 

  52. Tang X, Xie X, Wang X, Wang Y, Jiang X, Jiang H. The combination of piR-823 and eukaryotic initiation factor 3 B (EIF3B) activates hepatic stellate cells via upregulating TGF-beta1 in liver fibrogenesis. Med Sci Monit. 2018;24:9151–65.

    Article  CAS  Google Scholar 

  53. Han H, Fan G, Song S, Jiang Y, Qian CA, Zhang W, et al. piRNA-30473 contributes to tumorigenesis and poor prognosis by regulating m6A RNA methylation in DLBCL. Blood. 2020;137:1603–14.

    Article  Google Scholar 

  54. Li Y, Wu X, Gao H, Jin JM, Li AX, Kim YS, et al. Piwi-interacting RNAs (piRNAs) are dysregulated in renal cell carcinoma and associated with tumor metastasis and cancer-specific survival. Mol Med. 2015;21:381–8.

    Article  Google Scholar 

  55. Mai D, Zheng Y, Guo H, Ding P, Bai R, Li M, et al. Serum piRNA-54265 is a new biomarker for early detection and clinical surveillance of human colorectal cancer. Theranostics. 2020;10:8468–78.

    Article  CAS  Google Scholar 

  56. Shao H, Im H, Castro CM, Breakefield X, Weissleder R, Lee H. New technologies for analysis of extracellular vesicles. Chem Rev. 2018;118:1917–50.

    Article  CAS  Google Scholar 

  57. Attwell D, Mishra A, Hall CN, O’Farrell FM, Dalkara T. What is a pericyte? J Cereb Blood Flow Metab. 2016;36:451–5.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81772781, 81903012, 81902665). The authors acknowledge the use of Biorender that is used to create Graphical Abstract.

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  1. These authors contributed equally: Guoqing Li, Xiaoqing Yi, Shi Du.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Guoqing Li, Xiaoqing Yi, Shi Du, Lanqing Gong, Qiulei Wu, Jing Cai, Si Sun, Ying Cao, Le Chen, Linjuan Xu & Zehua Wang

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Contributions

ZW and LX conceived the project. GL and XY conducted most of the experimental work and wrote the manuscript. SD and LG performed the animal experiments. SS and LC collected the clinical samples. QW and YC analysed the clinical data. JC supervised the project. All authors read and approved the final manuscript.

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Correspondence to Linjuan Xu or Zehua Wang.

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All procedures involving human specimens were approved by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology (Wuhan, China). Written informed consent was obtained from all patients. All experimental procedures used in the animal studies were approved by the Tongji Medical College’s Animal Care and Use Committee, Huazhong University of Science and Technology.

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Li, G., Yi, X., Du, S. et al. Tumour-derived exosomal piR-25783 promotes omental metastasis of ovarian carcinoma by inducing the fibroblast to myofibroblast transition. Oncogene 42, 421–433 (2023). https://doi.org/10.1038/s41388-022-02560-y

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