Adhesion-mediated Squamous Cell Carcinoma Survival Through Ligand-independent Activation of Epidermal Growth Factor Receptor

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2004 Oct 7

PMID 15466396

Citations 48

Authors

Xiaodong Shen

Randall H Kramer

Affiliations

Soon will be listed here.

Abstract

The survival and growth of squamous epithelial cells require signals generated by integrin-matrix interactions. After conversion to squamous cell carcinoma, the cells remain sensitive to detachment-induced anoikis, yet in tumor cell aggregates, which are matrix-deficient, these cells are capable of suprabasal survival and proliferation. Their survival is enhanced through a process we call synoikis, whereby junctional adhesions between neighboring cells generate specific downstream survival signals. Here we show that in squamous cell carcinoma cells, E-cadherin-mediated cell-cell contacts specifically induce activation of epidermal growth factor receptor (EGFR). EGFR activation in turn triggers the ERK/MAPK signaling module, leading to elevation of anti-apoptotic Bcl-2. After intercellular adhesion, formation of adherens junctions triggers the formation of E-cadherin-EGFR complexes, correlating with EGFR transactivation. Analysis of the process with a dominant-negative EGFR mutant indicated that activation of EGFR is ligand-independent. Our data implicate cell-cell adhesion-induced activation of EGFR as a cooperative mechanism that generates compensatory survival signaling, protecting malignant cells from detachment-induced death.

Citing Articles

Cell Adhesion Molecules as Modulators of the Epidermal Growth Factor Receptor.

Kozlova I, Sytnyk V Cells. 2024; 13(22).

PMID: 39594667 PMC: 11592701. DOI: 10.3390/cells13221919.

Entosis: the core mechanism and crosstalk with other cell death programs.

Kim S, Lee D, Kim S, Overholtzer M Exp Mol Med. 2024; 56(4):870-876.

PMID: 38565900 PMC: 11059358. DOI: 10.1038/s12276-024-01227-w.

Therapeutic targeting of anoikis resistance in cutaneous melanoma metastasis.

Neuendorf H, Simmons J, Boyle G Front Cell Dev Biol. 2023; 11:1183328.

PMID: 37181747 PMC: 10169659. DOI: 10.3389/fcell.2023.1183328.

Plasma membrane proteoglycans syndecan-2 and syndecan-4 engage with EGFR and RON kinase to sustain carcinoma cell cycle progression.

Beauvais D, Nelson S, Adams K, Stueven N, Jung O, Rapraeger A J Biol Chem. 2022; 298(6):102029.

PMID: 35569509 PMC: 9190016. DOI: 10.1016/j.jbc.2022.102029.

Targeting regulated cell death (RCD) with small-molecule compounds in triple-negative breast cancer: a revisited perspective from molecular mechanisms to targeted therapies.

Liao M, Qin R, Huang W, Zhu H, Peng F, Han B J Hematol Oncol. 2022; 15(1):44.

PMID: 35414025 PMC: 9006445. DOI: 10.1186/s13045-022-01260-0.

References

Jost M, Huggett T, Kari C, Rodeck U . Matrix-independent survival of human keratinocytes through an EGF receptor/MAPK-kinase-dependent pathway. Mol Biol Cell. 2001; 12(5):1519-27. PMC: 34602. DOI: 10.1091/mbc.12.5.1519. View

Reardon D, Contessa J, Mikkelsen R, Valerie K, Amir C, Dent P . Dominant negative EGFR-CD533 and inhibition of MAPK modify JNK1 activation and enhance radiation toxicity of human mammary carcinoma cells. Oncogene. 1999; 18(33):4756-66. DOI: 10.1038/sj.onc.1202849. View

Damiano J, Hazlehurst L, Dalton W . Cell adhesion-mediated drug resistance (CAM-DR) protects the K562 chronic myelogenous leukemia cell line from apoptosis induced by BCR/ABL inhibition, cytotoxic drugs, and gamma-irradiation. Leukemia. 2001; 15(8):1232-9. DOI: 10.1038/sj.leu.2402179. View

Frisch S, Screaton R . Anoikis mechanisms. Curr Opin Cell Biol. 2001; 13(5):555-62. DOI: 10.1016/s0955-0674(00)00251-9. View

Ziober B, Silverman Jr S, Kramer R . Adhesive mechanisms regulating invasion and metastasis in oral cancer. Crit Rev Oral Biol Med. 2002; 12(6):499-510. DOI: 10.1177/10454411010120060401. View

Kovacs E, Ali R, McCormack A, Yap A . E-cadherin homophilic ligation directly signals through Rac and phosphatidylinositol 3-kinase to regulate adhesive contacts. J Biol Chem. 2001; 277(8):6708-18. DOI: 10.1074/jbc.M109640200. View

Carpenter G . EGF receptor transactivation mediated by the proteolytic production of EGF-like agonists. Sci STKE. 2002; 2000(15):pe1. DOI: 10.1126/stke.2000.15.pe1. View

Moro L, Dolce L, Cabodi S, Bergatto E, Boeri Erba E, Smeriglio M . Integrin-induced epidermal growth factor (EGF) receptor activation requires c-Src and p130Cas and leads to phosphorylation of specific EGF receptor tyrosines. J Biol Chem. 2002; 277(11):9405-14. DOI: 10.1074/jbc.M109101200. View

Chan T, Rodeck U, Chan A, Kimmelman A, Rittenhouse S, Panayotou G . Small GTPases and tyrosine kinases coregulate a molecular switch in the phosphoinositide 3-kinase regulatory subunit. Cancer Cell. 2002; 1(2):181-91. DOI: 10.1016/s1535-6108(02)00033-8. View

10.

Liu D, Aguirre Ghiso J, Estrada Y, Ossowski L . EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma. Cancer Cell. 2002; 1(5):445-57. DOI: 10.1016/s1535-6108(02)00072-7. View

11.

Gilmore A, Valentijn A, Wang P, Ranger A, Bundred N, OHare M . Activation of BAD by therapeutic inhibition of epidermal growth factor receptor and transactivation by insulin-like growth factor receptor. J Biol Chem. 2002; 277(31):27643-50. DOI: 10.1074/jbc.M108863200. View

12.

Bonner J, De los Santos J, Waksal H, Needle M, Trummel H, Raisch K . Epidermal growth factor receptor as a therapeutic target in head and neck cancer. Semin Radiat Oncol. 2002; 12(3 Suppl 2):11-20. DOI: 10.1053/srao.2002.34864. View

13.

Tran N, Adams D, Vaillancourt R, Heimark R . Signal transduction from N-cadherin increases Bcl-2. Regulation of the phosphatidylinositol 3-kinase/Akt pathway by homophilic adhesion and actin cytoskeletal organization. J Biol Chem. 2002; 277(36):32905-14. DOI: 10.1074/jbc.M200300200. View

14.

Raben D, Bianco C, Helfrich B, Weng E, Ciardiello F, Harari P . Interference with EGFR signaling: paradigm for improving radiation response in cancer treatment. Expert Rev Anticancer Ther. 2003; 2(4):461-71. DOI: 10.1586/14737140.2.4.461. View

15.

Gschwind A, Hart S, Fischer O, Ullrich A . TACE cleavage of proamphiregulin regulates GPCR-induced proliferation and motility of cancer cells. EMBO J. 2003; 22(10):2411-21. PMC: 155989. DOI: 10.1093/emboj/cdg231. View

16.

Sundfeldt K . Cell-cell adhesion in the normal ovary and ovarian tumors of epithelial origin; an exception to the rule. Mol Cell Endocrinol. 2003; 202(1-2):89-96. DOI: 10.1016/s0303-7207(03)00068-6. View

17.

Wong A, Gumbiner B . Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin. J Cell Biol. 2003; 161(6):1191-203. PMC: 2173007. DOI: 10.1083/jcb.200212033. View

18.

Lamb J, Ventura J, Hess P, Flavell R, Davis R . JunD mediates survival signaling by the JNK signal transduction pathway. Mol Cell. 2003; 11(6):1479-89. DOI: 10.1016/s1097-2765(03)00203-x. View

19.

Song L, Turkson J, Karras J, Jove R, Haura E . Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. Oncogene. 2003; 22(27):4150-65. DOI: 10.1038/sj.onc.1206479. View

20.

Reginato M, Mills K, Paulus J, Lynch D, Sgroi D, Debnath J . Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis. Nat Cell Biol. 2003; 5(8):733-40. DOI: 10.1038/ncb1026. View