Implication of IZUMO2 in the Cell-in-cell Phenomenon: A Potential Therapeutic Target for Triple-negative Breast Cancer

Overview

Journal Thorac Cancer

Specialties Oncology
Pulmonary Medicine

Date 2024 Jan 23

PMID 38258402

Authors

Toshiya Higashi

Chiemi Saigo

Wakana Chikaishi

Hirokatsu Hayashi

Yuki Hanamatsu

Manabu Futamura

Nobuhisa Matsuhashi

Tamotsu Takeuchi

Affiliations

Soon will be listed here.

Abstract

Background: Triple-negative breast cancer (TNBC) is characterized by the loss of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. The aggressive clinicopathological features and resistance to currently available therapeutics of the disease warrant an urgent need for the development of novel alternate therapeutic options. We have previously reported adiponectin-expressing regulatory T cells (A-Tregs), which can induce apoptosis in TNBC through the cell-in-cell phenomenon. In this study, we aimed to elucidate the molecule that allows TNBC cells to engulf A-Tregs.

Methods: A monoclonal antibody, which repressed the engulfment of A-Tregs by TNBC cells, was developed. Immunoprecipitation followed by mass spectrometry and small interfering RNAs-mediated gene silencing was performed to characterize the antigen.

Results: We successfully generated a monoclonal antibody, designated G1D7, which abrogated the engulfment of A-Tregs by TNBC and subsequent A-Treg-mediated apoptosis. G1D7 detected the immunoglobulin-like type I membrane protein IZUMO2, a molecule related to IZUMO1 that is essential for cell-cell membrane binding and fusion of sperm to oocyte.

Conclusion: The findings highlight the importance of IZUMO2 on TNBC cells in facilitating the cell-in-cell phenomenon by A-Tregs.

Citing Articles

Implication of IZUMO2 in the cell-in-cell phenomenon: A potential therapeutic target for triple-negative breast cancer.

Higashi T, Saigo C, Chikaishi W, Hayashi H, Hanamatsu Y, Futamura M Thorac Cancer. 2024; 15(7):513-518.

PMID: 38258402 PMC: 10912533. DOI: 10.1111/1759-7714.15189.

References

Kita S, Fukuda S, Maeda N, Shimomura I . Native adiponectin in serum binds to mammalian cells expressing T-cadherin, but not AdipoRs or calreticulin. Elife. 2019; 8. PMC: 6822988. DOI: 10.7554/eLife.48675. View

Kohler G, Milstein C . Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975; 256(5517):495-7. DOI: 10.1038/256495a0. View

Nakamura S, Suzuki M, Sugimoto A, Tsuji-Takayama K, Yamamoto M, Otani T . IL-2-independent generation of FOXP3(+)CD4(+)CD8(+)CD25(+) cytotoxic regulatory T cell lines from human umbilical cord blood. Exp Hematol. 2007; 35(2):287-96. DOI: 10.1016/j.exphem.2006.10.011. View

Inoue N, Ikawa M, Isotani A, Okabe M . The immunoglobulin superfamily protein Izumo is required for sperm to fuse with eggs. Nature. 2005; 434(7030):234-8. DOI: 10.1038/nature03362. View

Chung S, Nagaraju G, Nagalingam A, Muniraj N, Kuppusamy P, Walker A . ADIPOQ/adiponectin induces cytotoxic autophagy in breast cancer cells through STK11/LKB1-mediated activation of the AMPK-ULK1 axis. Autophagy. 2017; 13(8):1386-1403. PMC: 5584870. DOI: 10.1080/15548627.2017.1332565. View

CAILLEAU R, Young R, Olive M, REEVES Jr W . Breast tumor cell lines from pleural effusions. J Natl Cancer Inst. 1974; 53(3):661-74. PMC: 7364228. DOI: 10.1093/jnci/53.3.661. View

Lee S . H-cadherin, a novel cadherin with growth inhibitory functions and diminished expression in human breast cancer. Nat Med. 1996; 2(7):776-82. DOI: 10.1038/nm0796-776. View

Hanamatsu Y, Saigo C, Takeuchi T . Adiponectin-expressing Treg cells in experimental thymic tumor model. Thorac Cancer. 2023; 14(4):432-433. PMC: 9891853. DOI: 10.1111/1759-7714.14792. View

Takeuchi M, Inoue T, Otani T, Yamasaki F, Nakamura S, Kibata M . Cell-in-cell structures formed between human cancer cell lines and the cytotoxic regulatory T-cell line HOZOT. J Mol Cell Biol. 2010; 2(3):139-51. DOI: 10.1093/jmcb/mjq002. View

10.

Towbin H, Staehelin T, Gordon J . Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979; 76(9):4350-4. PMC: 411572. DOI: 10.1073/pnas.76.9.4350. View

11.

Chikaishi W, Higashi T, Hayashi H, Hanamatsu Y, Kito Y, Futamura M . Potential activity of adiponectin-expressing regulatory T cells against triple-negative breast cancer cells through the cell-in-cell phenomenon. Thorac Cancer. 2023; 14(20):1941-1945. PMC: 10344742. DOI: 10.1111/1759-7714.14940. View

12.

Zhang Y, Cao H, Chen J, Li Y, Xu A, Wang Y . Adiponectin-expressing Treg facilitate T lymphocyte development in thymic nurse cell complexes. Commun Biol. 2021; 4(1):344. PMC: 7966800. DOI: 10.1038/s42003-021-01877-w. View

13.

Brukman N, Nakajima K, Valansi C, Flyak K, Li X, Higashiyama T . A novel function for the sperm adhesion protein IZUMO1 in cell-cell fusion. J Cell Biol. 2022; 222(2). PMC: 9671554. DOI: 10.1083/jcb.202207147. View

14.

Takeuchi T, Misaki A, Fujita J, Sonobe H, Ohtsuki Y . T-cadherin (CDH13, H-cadherin) expression downregulated surfactant protein D in bronchioloalveolar cells. Virchows Arch. 2001; 438(4):370-5. DOI: 10.1007/s004280000385. View

15.

Bianchini G, De Angelis C, Licata L, Gianni L . Treatment landscape of triple-negative breast cancer - expanded options, evolving needs. Nat Rev Clin Oncol. 2021; 19(2):91-113. DOI: 10.1038/s41571-021-00565-2. View

16.

Takeuchi T, Misaki A, Chen B, Ohtsuki Y . H-cadherin expression in breast cancer. Histopathology. 1999; 35(1):87-8. DOI: 10.1046/j.1365-2559.1999.0728c.x. View

17.

Yu Z, Tang S, Ma H, Duan H, Zeng Y . Association of serum adiponectin with breast cancer: A meta-analysis of 27 case-control studies. Medicine (Baltimore). 2019; 98(6):e14359. PMC: 6380750. DOI: 10.1097/MD.0000000000014359. View

18.

Higashi T, Saigo C, Chikaishi W, Hayashi H, Hanamatsu Y, Futamura M . Implication of IZUMO2 in the cell-in-cell phenomenon: A potential therapeutic target for triple-negative breast cancer. Thorac Cancer. 2024; 15(7):513-518. PMC: 10912533. DOI: 10.1111/1759-7714.15189. View

19.

Clark S, Naz R . Presence and incidence of izumo antibodies in sera of immunoinfertile women and men. Am J Reprod Immunol. 2013; 69(3):256-63. DOI: 10.1111/aji.12060. View

20.

Brochu-Gaudreau K, Rehfeldt C, Blouin R, Bordignon V, Murphy B, Palin M . Adiponectin action from head to toe. Endocrine. 2010; 37(1):11-32. DOI: 10.1007/s12020-009-9278-8. View