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Intratumoral heterogeneity of ADAM23 promotes tumor growth and metastasis through LGI4 and nitric oxide signals

Oncogene volume 34, pages 1270–1279 (2015)Cite this article

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Abstract

Intratumoral heterogeneity (ITH) represents an obstacle for cancer diagnosis and treatment, but little is known about its functional role in cancer progression. The A Desintegrin And Metalloproteinase 23 (ADAM23) gene is epigenetically silenced in different types of tumors, and silencing is often associated with advanced disease and metastasis. Here, we show that invasive breast tumors exhibit significant ADAM23-ITH and that this heterogeneity is critical for tumor growth and metastasis. We demonstrate that while loss of ADAM23 expression enhances invasion, it causes a severe proliferative deficiency and is not itself sufficient to trigger metastasis. Rather, we observed that, in ADAM23-heterotypic environments, ADAM23-negative cells promote tumor growth and metastasis by enhancing the proliferation and invasion of adjacent A23-positive cells through the production of LGI4 (Leucine-rich Glioma Inactivated 4) and nitric oxide (NO). Ablation of LGI4 and NO in A23-negative cells significantly attenuates A23-positive cell proliferation and invasion. Our work denotes a driving role of ADAM23-ITH during disease progression, shifting the malignant phenotype from the cellular to the tissue level. Our findings also provide insights for therapeutic intervention, enforcing the need to ascertain ITH to improve cancer diagnosis and therapy.

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Acknowledgements

We are grateful to Dr Andrew Simpson and Dr Raphael Parmigiani for critical reading of this manuscript and to Dr Rodrigo Perez, Dr Alicia Kowaltowski, Dr Beatriz Geronymo, Dr Camila Machado, Dr Vilma Martins, Dr Tiago dos Santos and Dr Anibal Vercesi for scientific discussions and technical assistance. This work was supported by grants from FAPESP (06/60219-2, 07/51194-9, 07/52920-5, 11/50541-2) and LICR.

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Authors and Affiliations

  1. Centro de Oncologia Molecular, Hospital Sírio Libanês, São Paulo, Brazil

    E T Costa, G F Barnabé, P F Asprino, M L Duarte & A A Camargo

  2. Ludwig Institute for Cancer Research (LICR), São Paulo, Brazil

    E T Costa, G F Barnabé, T R Machado, P F Asprino, F P Cavalher, M L Duarte & A A Camargo

  3. Ludwig Institute for Cancer Research (LICR), University of California, San Diego, CA, USA,

    M Li, M del Mar Inda, W Cavenee & F Furnari

  4. Departamento de Biologia Geral (ICB), Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

    A A M Dias

  5. Centro Internacional de Pesquisa, Hospital AC Camargo, São Paulo, Brazil

    E N Ferreira & D M Carraro

  6. Departamento de Bioquímica (IQ), Universidade de São Paulo, São Paulo, Brazil

    M H Nagai, B Malnic & H A Armelin

  7. Departamento de Urologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

    K R M Leite & R Chammas

  8. Departamento de Mastologia, Hospital Sírio Libanês, São Paulo, Brazil

    A C S D de Barros

  9. Instituto Butantan, São Paulo, Brazil

    H A Armelin

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Correspondence to A A Camargo.

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Costa, E., Barnabé, G., Li, M. et al. Intratumoral heterogeneity of ADAM23 promotes tumor growth and metastasis through LGI4 and nitric oxide signals. Oncogene 34, 1270–1279 (2015). https://doi.org/10.1038/onc.2014.70

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