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Septin 9 isoforms promote tumorigenesis in mammary epithelial cells by increasing migration and ECM degradation through metalloproteinase secretion at focal adhesions

Oncogene volume 38, pages 5839–5859 (2019)Cite this article

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A Correction to this article was published on 01 October 2019

This article has been updated

Abstract

The cytoskeletal interacting protein Septin 9 (SEPT9), a member of the septin gene family, has been proposed to have oncogenic functions. It is a known hot spot of retroviral tagging insertion and a fusion partner of both de novo and therapy-induced mixed lineage leukemia (MLL). Of all septins, SEPT9 holds the strongest link to cancer, especially breast cancer. Murine models of breast cancer frequently exhibit SEPT9 amplification in the form of double minute chromosomes, and about 20% of human breast cancer display genomic amplification and protein over expression at the SEPT9 locus. Yet, a clear mechanism by which SEPT9 elicits tumor-promoting functions is lacking. To obtain unbiased insights on molecular signatures of SEPT9 upregulation in breast tumors, we overexpressed several of its isoforms in breast cancer cell lines. Global transcriptomic profiling supports a role of SEPT9 in invasion. Functional studies reveal that SEPT9 upregulation is sufficient to increase degradation of the extracellular matrix, while SEPT9 downregulation inhibits this process. The degradation pattern is peripheral and associated with focal adhesions (FAs), where it is coupled with increased expression of matrix metalloproteinases (MMPs). SEPT9 overexpression induces MMP upregulation in human tumors and in culture models and promotes MMP3 secretion to the media at FAs. Downregulation of SEPT9 or chemical inhibition of septin filament assembly impairs recruitment of MMP3 to FAs. Our results indicate that SEPT9 promotes upregulation and both trafficking and secretion of MMPs near FAs, thus enhancing migration and invasion of breast cancer cells.

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Change history

  • 01 October 2019

    The original version of this Article contained an error in the author affiliations. Vladislav V. Verkhusha was incorrectly associated with the School of Mathematics, Statistics & Applied Mathematics, National University of Ireland Galway, Galway, Ireland. The correct affiliation is Anatomy and Structural Biology, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, USA.

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Acknowledgements

We would like to thank the following shared resources at the Albert Einstein College of Medicine: Molecular Cytogenetic Core, in particular Dr. Jidong Shan; and the Analytical Imaging Facility in particular Dr. Vera DesMarais. Research reported in this publication was supported by the Albert Einstein Cancer Center support grant of the National Institutes of Health under award number P30CA013330 as well as CA150344 to JC.

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Author notes

  1. These authors contributed equally: Jenna Marcus, Michal Bejerano-Sagie

Authors and Affiliations

  1. Departments of Obstetrics & Gynecology and Women’s Health, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, USA

    Jenna Marcus & Gary L. Goldberg

  2. Genetics, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, USA

    Michal Bejerano-Sagie, Nicole Patterson, Susmita Bagchi, Diana Connolly, Aaron Golden & Cristina Montagna

  3. School of Mathematics, Statistics & Applied Mathematics, National University of Ireland Galway, Galway, Ireland

    Vladislav V. Verkhusha & Aaron Golden

  4. Anatomy and Structural Biology, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, USA

    Ved P. Sharma & John Condeelis

  5. Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, USA

    Ved P. Sharma & John Condeelis

  6. Pathology, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, USA

    Cristina Montagna

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Correspondence to Cristina Montagna.

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Marcus, J., Bejerano-Sagie, M., Patterson, N. et al. Septin 9 isoforms promote tumorigenesis in mammary epithelial cells by increasing migration and ECM degradation through metalloproteinase secretion at focal adhesions. Oncogene 38, 5839–5859 (2019). https://doi.org/10.1038/s41388-019-0844-0

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