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Numb exon 9 inclusion regulates Integrinβ5 surface expression and promotes breast cancer metastasis

Oncogene volume 41, pages 2079–2094 (2022)Cite this article

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Abstract

The endocytic adaptor protein Numb acts as a tumor suppressor through downregulation of oncogenic pathways in multiple cancer types. The identification of splicing alterations giving rise to changes in Numb protein isoform expression indicate that Numb also has tumor promoting activity, though the underlying mechanisms are unknown. Here we report that NUMB exon 9 inclusion, which results in production of a protein isoform with an additional 49 amino acids, is a feature of multiple cancer types including all subtypes of breast cancer and correlates with worse progression-free survival. Specific deletion of exon 9-included Numb isoforms (Exon9in) from breast cancer cells reduced cell growth and prevents spontaneous lung metastasis in a mouse model. Quantitative proteome profiling showed that loss of Exon9in causes downregulation of membrane receptors and adhesion molecules, as well as proteins involved in extracellular matrix organization and the epithelial-mesenchymal transition (EMT) state. In addition, exon 9 deletion caused remodeling of the endocytic network, decreased ITGβ5 surface localization, cell spreading on vitronectin and downstream signaling to ERK and SRC. Together these observations suggest that Exon9in isoform expression disrupts the endocytic trafficking functions of Numb, resulting in increased surface expression of ITGβ5 as well as other plasma membrane proteins to promote cell adhesion, EMT, and tumor metastasis.

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Fig. 1: NUMB exon 9 inclusion is increased in multiple cancer types, including all breast cancer subtypes.
Fig. 2: Deletion of Numb exon 9 in breast cancer cells impairs cell growth.
Fig. 3: Exon9in Numb isoforms are required for spontaneous lung metastasis in an orthotopic breast cancer xenograft model.
Fig. 4: Quantitative proteomic analysis of exon 9 deleted cells identifies altered abundance of cell surface receptors and proteins associated with EMT and ECM organization.
Fig. 5: Numb isoforms regulate surface expression of integrin β5.
Fig. 6: Numb isoforms differentially regulate integrin β5 clustering at the cell surface and downstream signaling.

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Data availability

The TMT labeling proteomics data can be downloaded from MASSIVE MSV00087458.

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Acknowledgements

The authors thank the following: Michael Reedijk and Qiang Shen for assistance with mouse xenograft experiments, SPARC Molecular Analysis for TMT mass spectrometry, Amanda Luck for mouse colony maintenance and caliper measurements, Nesrin Sabha for help with IHC staining, and Kim Lau and Paul Paroutis (The Imaging Facility, The Hospital for Sick Children) for their assistance with TIRF microscopy and imaging analysis. This work was supported with funds from the Canadian Institutes of Health Research to CJM (FRN 106507).

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Authors and Affiliations

  1. Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, ON, M5G 2M9, Canada

    Yangjing Zhang, Kamal Othman & C. Jane McGlade

  2. The Arthur and Sonia Labatt Brain Tumour Research Centre, 555 University Avenue, Toronto, ON, M5G 1X8, Canada

    Yangjing Zhang, Sascha E. Dho, Kamal Othman, Jessica Lapierre, Andrew Bondoc & C. Jane McGlade

  3. Program in Cell Biology, 555 University Avenue, Toronto, ON, M5G 1X8, Canada

    Sascha E. Dho, Jessica Lapierre, Andrew Bondoc & C. Jane McGlade

  4. SPARC BioCentre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada

    Craig D. Simpson

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YZ, SED, and CS performed experiments, acquired and analyzed data, drafted and critically reviewed the manuscript; KO, JL, and AB acquired and analyzed data. CJM supervised YZ, SED, KO, JL, AB, analyzed and interpreted data, drafted and revised the manuscript.

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Correspondence to C. Jane McGlade.

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Zhang, Y., Dho, S.E., Othman, K. et al. Numb exon 9 inclusion regulates Integrinβ5 surface expression and promotes breast cancer metastasis. Oncogene 41, 2079–2094 (2022). https://doi.org/10.1038/s41388-022-02225-w

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