Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Decoupling tumor cell metastasis from growth by cellular pilot protein TNFAIP8

Oncogene volume 40, pages 6456–6468 (2021)Cite this article

Subjects

Abstract

Cancer metastasis accounts for nearly 90% of all cancer deaths. Metastatic cancer progression requires both cancer cell migration to the site of the metastasis and subsequent proliferation after colonization. However, it has long been recognized that cancer cell migration and proliferation can be uncoupled; but the mechanism underlying this paradox is not well understood. Here we report that TNFAIP8 (tumor necrosis factor-α-induced protein 8), a “professional” transfer protein of phosphoinositide second messengers, promotes cancer cell migration or metastasis but inhibits its proliferation or cancer growth. TNFAIP8-deficient mice developed larger tumors, but TNFAIP8-deficient tumor cells completely lost their ability to migrate toward chemoattractants and were defective in colonizing lung tissues as compared to wild-type counterparts. Mechanistically, TNFAIP8 served as a cellular “pilot” of tumor cell migration by locally amplifying PI3K−AKT and Rac signals on the cell membrane facing chemoattractant; at the same time, TNFAIP8 also acted as a global inhibitor of tumor cell growth and proliferation by regulating Hippo signaling pathway. These findings help explain the migration−proliferation paradox of cancer cells that characterizes many cancers.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Roles of TNFAIP8 in murine tumorigenesis and tumor cell proliferation.
Fig. 2: Roles of TNFAIP8 in tumor cell migration in vitro and tumor cell trafficking in mice.
Fig. 3: The global impact of TNFAIP8 deficiency on tumor cell gene expression.
Fig. 4: Hippo- and myogenesis-related gene expression and YAP nuclear translocation.
Fig. 5: Activation of phosphoinositide second messengers and signals.
Fig. 6: Effect of TNFAIP8 loss and re-expression on tumor cells.
Fig. 7: Visualization of Rac1-GTP and pAKT473 signaling, and a working model.

Similar content being viewed by others

Data availability

RNA-seq data that support the findings of this study have been deposited in the ArrayExpress under accession nos. E-MTAB-10468.

References

  1. Leung H-W, Wang Z, Yue GG-L, Zhao S-M, Lee JK-M, Fung K-P, et al. Cyclopeptide RA-V inhibits cell adhesion and invasion in both estrogen receptor positive and negative breast cancer cells via PI3K/AKT and NF-κB signaling pathways. Biochimica et Biophysica Acta (BBA) - Mol Cell Res. 2015;1853:1827–40.

    Article  CAS  Google Scholar 

  2. Massague J, Obenauf AC. Metastatic colonization by circulating tumour cells. Nature. 2016;529:298–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Svensson S, Nilsson K, Ringberg A, Landberg G. Invade or proliferate? Two contrasting events in malignant behavior governed by p16(INK4a) and an intact Rb pathway illustrated by a model system of basal cell carcinoma. Cancer Res. 2003;63:1737–42.

    CAS  PubMed  Google Scholar 

  4. Kohrman AQ, Matus DQ. Divide or conquer: cell cycle regulation of invasive behavior. Trends Cell Biol. 2017;27:12–25.

    Article  CAS  PubMed  Google Scholar 

  5. Sun H, Gong S, Carmody RJ, Hilliard A, Li L, Sun J, et al. TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis. Cell. 2008;133:415–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Goldsmith JR, Fayngerts S, Chen YH. Regulation of inflammation and tumorigenesis by the TIPE family of phospholipid transfer proteins. Cell Mol. Immunol. 2017;14:482–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kumar D, Gokhale P, Broustas C, Chakravarty D, Ahmad I, Kasid U. Expression of SCC-S2, an antiapoptotic molecule, correlates with enhanced proliferation and tumorigenicity of MDA-MB 435 cells. Oncogene. 2004;23:612–6.

    Article  CAS  PubMed  Google Scholar 

  8. Liu T, Gao H, Chen X, Lou G, Gu L, Yang M, et al. TNFAIP8 as a predictor of metastasis and a novel prognostic biomarker in patients with epithelial ovarian cancer. Br J Cancer. 2013;109:1685–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yang M, Zhao Q, Wang X, Liu T, Yao G, Lou C, et al. TNFAIP8 overexpression is associated with lymph node metastasis and poor prognosis in intestinal-type gastric adenocarcinoma. Histopathology. 2014;65:517–26.

    Article  PubMed  Google Scholar 

  10. Hadisaputri YE, Miyazaki T, Suzuki S, Yokobori T, Kobayashi T, Tanaka N, et al. TNFAIP8 overexpression: clinical relevance to esophageal squamous cell carcinoma. Ann Surg Oncol. 2012;19:S589–596.

    Article  PubMed  Google Scholar 

  11. Zhang Y, Wang MY, He J, Wang JC, Yang YJ, Jin L, et al. Tumor necrosis factor-alpha induced protein 8 polymorphism and risk of non-Hodgkin’s lymphoma in a Chinese population: a case-control study. PLoS ONE. 2012;7:e37846.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Padmavathi G, Banik K, Monisha J, Bordoloi D, Shabnam B, Arfuso F, et al. Novel tumor necrosis factor-alpha induced protein eight (TNFAIP8/TIPE) family: Functions and downstream targets involved in cancer progression. Cancer Lett. 2018;432:260–71.

    Article  CAS  PubMed  Google Scholar 

  13. Colicelli J. Human RAS superfamily proteins and related GTPases. Sci STKE. 2004;2004:RE13.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Wang Z, Fayngerts S, Wang P, Sun H, Johnson DS, Ruan Q, et al. TIPE2 protein serves as a negative regulator of phagocytosis and oxidative burst during infection. Proc Natl Acad Sci USA. 2012;109:15413–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fayngerts SA, Wang Z, Zamani A, Sun H, Boggs AE, Porturas TP, et al. Direction of leukocyte polarization and migration by the phosphoinositide-transfer protein TIPE2. Nat Immunol. 2017;18:1353–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhao B, Lei QY, Guan KL. The Hippo-YAP pathway: new connections between regulation of organ size and cancer. Curr Opin Cell Biol. 2008;20:638–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kango-Singh M, Singh A. Regulation of organ size: insights from the Drosophila Hippo signaling pathway. Dev Dyn. 2009;238:1627–37.

    Article  CAS  PubMed  Google Scholar 

  18. Yu FX, Zhao B, Panupinthu N, Jewell JL, Lian I, Wang LH, et al. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell. 2012;150:780–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhao B, Li L, Lei Q, Guan KL. The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev. 2010;24:862–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Miller E, Yang J, DeRan M, Wu C, Su AI, Bonamy GM, et al. Identification of serum-derived sphingosine-1-phosphate as a small molecule regulator of YAP. Chem Biol. 2012;19:955–62.

    Article  CAS  PubMed  Google Scholar 

  21. Wettschureck N, Offermanns S. Mammalian G proteins and their cell type specific functions. Physiol Rev. 2005;85:1159–204.

    Article  CAS  PubMed  Google Scholar 

  22. Laliberte B, Wilson AM, Nafisi H, Mao H, Zhou YY, Daigle M, et al. TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation. J Cell Physiol. 2010;225:865–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019;47:W556–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Devalaraja S, To TKJ, Folkert IW, Natesan R, Alam MZ, Li M, et al. Tumor-derived retinoic acid regulates intratumoral monocyte differentiation to promote immune suppression. Cell. 2020;180:1098–114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Asokan SB, Johnson HE, Sondek J, Shutova MS, Svitkina TM, Haugh JM, et al. Lysophosphatidic acid provokes fibroblast chemotaxis through combinatorial regulation of myosin II. bioRxiv. 2019: 355610. https://doi.org/10.1101/355610.

  26. Basu S, Totty NF, Irwin MS, Sudol M, Downward J. Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol Cell. 2003;11:11–23.

    Article  CAS  PubMed  Google Scholar 

  27. Niture S, Dong X, Arthur E, Chimeh U, Niture SS, Zheng W, et al. Oncogenic role of tumor necrosis factor alpha-induced protein 8 (TNFAIP8). Cells. 2018;8:9.

    Article  PubMed Central  Google Scholar 

  28. Xing Y, Liu Y, Liu T, Meng Q, Lu H, Liu W, et al. TNFAIP8 promotes the proliferation and cisplatin chemoresistance of non-small cell lung cancer through MDM2/p53 pathway. Cell Commun Signal. 2018;16:43.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Xie Y, Zhou F, Zhao X. TNFAIP8 promotes cell growth by regulating the Hippo pathway in epithelial ovarian cancer. Exp Ther Med. 2018;16:4975–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Han Y, Tang Z, Zhao Y, Li Q, Wang E. TNFAIP8 regulates Hippo pathway through interacting with LATS1 to promote cell proliferation and invasion in lung cancer. Mol Carcinog. 2018;57:159–66.

    Article  CAS  PubMed  Google Scholar 

  31. Briata P, Lin WJ, Giovarelli M, Pasero M, Chou CF, Trabucchi M, et al. PI3K/AKT signaling determines a dynamic switch between distinct KSRP functions favoring skeletal myogenesis. Cell Death Differ. 2012;19:478–87.

    Article  CAS  PubMed  Google Scholar 

  32. Watt KI, Judson R, Medlow P, Reid K, Kurth TB, Burniston JG, et al. Yap is a novel regulator of C2C12 myogenesis. Biochem Biophys Res Commun. 2010;393:619–24.

    Article  CAS  PubMed  Google Scholar 

  33. Zhong M, Zhu M, Liu Y, Lin Y, Wang L, Ye Y, et al. TNFAIP8 promotes the migration of clear cell renal cell carcinoma by regulating the EMT. J Cancer. 2020;11:3061–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Day TF, Kallakury BVS, Ross JS, Voronel O, Vaidya S, Sheehan C, et al. Dual targeting of EGFR and IGF1R in the TNFAIP8 knockdown non-small cell lung cancer cells. Mol Cancer Res. 2019;17:1207–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sun H, Lou Y, Porturas T, Morrissey S, Luo G, Qi J, et al. Exacerbated experimental colitis in TNFAIP8-deficient mice. J Immunol. 2015;194:5736–42.

    Article  CAS  PubMed  Google Scholar 

  36. Sakurai T, He G, Matsuzawa A, Yu GY, Maeda S, Hardiman G, et al. Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell. 2008;14:156–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Maeda S, Kamata H, Luo JL, Leffert H, Karin M. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell. 2005;121:977–90.

    Article  CAS  PubMed  Google Scholar 

  38. Swann JB, Vesely MD, Silva A, Sharkey J, Akira S, Schreiber RD, et al. Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis. Proc Natl Acad Sci USA. 2008;105:652–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Schreiber TH, Podack ER. A critical analysis of the tumour immunosurveillance controversy for 3-MCA-induced sarcomas. Br J Cancer. 2009;101:381–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sun H, Lin M, Zamani A, Goldsmith JR, Boggs AE, Li M, et al. The TIPE molecular pilot that directs lymphocyte migration in health and inflammation. Sci Rep. 2020;10:6617.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Li T, Li X, Zamani A, Wang W, Lee CN, Li M, et al. c-Rel is a myeloid checkpoint for cancer immunotherapy. Nat Cancer. 2020;1:507–17.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Goldsmith JR, Spitofsky N, Zamani A, Hood R, Boggs A, Li X, et al. TNFAIP8 controls murine intestinal stem cell homeostasis and regeneration by regulating microbiome-induced Akt signaling. Nat Commun. 2020;11:2591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Moroishi T, Hayashi T, Pan WW, Fujita Y, Holt MV, Qin J, et al. The hippo pathway kinases LATS1/2 suppress cancer immunity. Cell. 2016;167:1525–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Drs. Warren Pear, Martha Jordan and T.S. Karin Eisinger for scientific inputs. We would like to thank Drs. Chin-Nien Lee, Mei Lin, Lei Guan, Ling Lu, Xu Chen, Lianxiang Luo and Shifeng Li, for valuable suggestions and technical supports. We are grateful to Dr. Daniel P. Beiting and Gordon Ruthel from Penn Vet Imaging Core for technical assistance.

Funding

This work was supported in part by grants from the National Institutes of Health (NIH), USA (R01AI143676 and R01AI1136945).

Author information

Author notes

  1. Li Zhang

    Present address: Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Mingyue Li, Xinyuan Li, Jason R. Goldsmith, Songlin Shi, Li Zhang, Ali Zamani, Lin Wan, Honghong Sun, Ting Li, Jiyeon Yu, Zienab Etwebi, Mayassa J. Bou-Dargham & Youhai H. Chen

  2. Faculty of Pharmaceutical Sciences, CAS Shenzhen Institute of Advanced Technology, Shenzhen, China

    Youhai H. Chen

Authors
  1. Mingyue Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xinyuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jason R. Goldsmith
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Songlin Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Li Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ali Zamani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lin Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Honghong Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ting Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jiyeon Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zienab Etwebi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mayassa J. Bou-Dargham
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Youhai H. Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ML conceived, designed and executed most of the experiments, analyzed the data, and wrote the paper. XL designed and performed bioinformatics analysis and edited the paper. JRG performed the Rac1 polarization and lipid ELISA, devised analytical methods, and edited the paper. SS and LZ performed tumor inductions. AZ helped to design plasmids. LW helped to perform some of experiments. HS, TL, JY, EZ, MJBD helped to complete animal experiments. YHC conceived and supervised this study and wrote the paper.

Corresponding authors

Correspondence to Mingyue Li or Youhai H. Chen.

Ethics declarations

Competing interests

YHC is a member of the advisory board of Amshenn Co. and Binde Co. All other authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, M., Li, X., Goldsmith, J.R. et al. Decoupling tumor cell metastasis from growth by cellular pilot protein TNFAIP8. Oncogene 40, 6456–6468 (2021). https://doi.org/10.1038/s41388-021-02035-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-021-02035-6

Search

Advanced search

Quick links