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Lysyl oxidase-like 2 (LOXL2) and E47 EMT factor: novel partners in E-cadherin repression and early metastasis colonization

Oncogene volume 34, pages 951–964 (2015)Cite this article

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Abstract

Epithelial–mesenchymal transition (EMT) has been associated with increased aggressiveness and acquisition of migratory properties providing tumor cells with the ability to invade into adjacent tissues. Downregulation of E-cadherin, a hallmark of EMT, is mediated by several transcription factors (EMT-TFs) that act also as EMT inducers, among them, Snail1 and the bHLH transcription factor E47. We previously described lysyl oxidase-like 2 (LOXL2), a member of the lysyl oxidase family, as a Snail1 regulator and EMT inducer. Here we show that LOXL2 is also an E47-interacting partner and functionally collaborates in the repression of E-cadherin promoter. Loss and gain of function analyses combined with in vivo studies in syngeneic breast cancer models demonstrate the participation of LOXL2 and E47 in tumor growth and their requirement for lung metastasis. Furthermore, LOXL2 and E47 contribute to early steps of metastatic colonization by cell and noncell autonomous functions regulating the recruitment of bone marrow progenitor cells to the lungs and by direct transcriptional regulation of fibronectin and cytokines TNFα, ANG-1 and GM-CSF. Moreover, fibronectin and GM-CSF proved to be necessary for LOXL2/E47-mediated modulation of tumor growth and lung metastasis.

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Acknowledgements

We thank members of A. Cano's group: Saleta Morales and Amalia Montes for technical support, Ana Villarejo and Fernando Salvador for help in flow cytometry and collagen crosslinking analyses, and Thomas Look, Manuel Fresno and Peter N. Cockerill for providing reagents, and Angela Nieto for reading the manuscript. The work was supported by the Spanish Ministry of Science and Innovation (SAF2010–21143; Consolider 2007-CS00017); AICR (12–1057) and ISCIII (RETIC- RD12/0036/0007) to AC, and Comunidad de Madrid (S2010/BMD-2302) to AC and GMB. EPC and VS are founded from the AICR grant.

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Author notes

  1. G Canesin

    Present address: 5Current address: Divisions of Cell and Experimental Pathology and Urology, Lund University, Clinical Research Centre, Skåne University Hospital, Malmö SE-20502, Sweden.,

  2. G Canesin and E P Cuevas: These authors contributed equally to this work.

Authors and Affiliations

  1. Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas ‘Alberto Sols’ CSIC-UAM, IdiPAZ, Madrid, Spain

    G Canesin, E P Cuevas, V Santos, C López-Menéndez, G Moreno-Bueno, F Portillo & A Cano

  2. Fundación MD Anderson International Madrid, Madrid, Spain

    G Moreno-Bueno

  3. Department of Pediatrics, Cell and Developmental Biology, Weill Cornell Medical College, New York, NY, USA

    Y Huang, H Peinado & D Lyden

  4. John A Burns School of Medicine, University of Hawaii, Honolulu, HI, USA

    K Csiszar

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Canesin, G., Cuevas, E., Santos, V. et al. Lysyl oxidase-like 2 (LOXL2) and E47 EMT factor: novel partners in E-cadherin repression and early metastasis colonization. Oncogene 34, 951–964 (2015). https://doi.org/10.1038/onc.2014.23

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