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IMPAD1 and KDELR2 drive invasion and metastasis by enhancing Golgi-mediated secretion

Oncogene volume 39, pages 5979–5994 (2020)Cite this article

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Abstract

Non-small cell lung cancer (NSCLC) is the deadliest form of cancer worldwide, due in part to its proclivity to metastasize. Identifying novel drivers of invasion and metastasis holds therapeutic potential for the disease. We conducted a gain-of-function invasion screen, which identified two separate hits, IMPAD1 and KDELR2, as robust, independent drivers of lung cancer invasion and metastasis. Given that IMPAD1 and KDELR2 are known to be localized to the ER–Golgi pathway, we studied their common mechanism of driving in vitro invasion and in vivo metastasis and demonstrated that they enhance Golgi-mediated function and secretion. Therapeutically inhibiting matrix metalloproteases (MMPs) suppressed both IMPAD1- and KDELR2-mediated invasion. The hits from this unbiased screen and the mechanistic validation highlight Golgi function as one of the key cellular features altered during invasion and metastasis.

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Fig. 1: Novel screen identifies IMPAD1 and KDELR2 as drivers of lung cancer invasion and disease progression.
Fig. 2: IMPAD1 expression is sufficient to drive lung cancer invasion and metastasis.
Fig. 3: KDELR2 expression is sufficient to drive lung cancer invasion and metastasis.
Fig. 4: IMPAD1 or KDELR2 expression is necessary for invasive and metastatic ability of lung cancer cells.
Fig. 5: IMPAD1 and KDELR2 localize to the ER–Golgi pathway.
Fig. 6: IMPAD1 and KDELR2 independently induce Golgi-mediated secretion of proteases such as MMPs to drive lung cancer cell invasion.
Fig. 7: Working model for IMPAD1 and KDELR2 as part of the Golgi secretory cascade that regulate secretion of MMPs to drive NSCLC invasion and metastasis.

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Acknowledgements

This work was supported by the DoD CDMRP Lung cancer research award W81XWH-12–16294 (DLG and KLS), NIH/NCI K08 CA151651, NIH R37CA214609, the MD Anderson Physician-Scientist Program and Rexanna’s Foundation for Fighting Lung Cancer (DLG). DLG is an R. Lee Clark Fellow of the University of Texas MD Anderson Cancer Center, supported by the Jeane F. Shelby Scholarship Fund. The work was also supported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program. We would like to thank the UTMDACC Department of Veterinary Medicine Facility.

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Author notes

  1. These authors contributed equally: Rakhee Bajaj, Samrat T. Kundu

  2. Deceased: Kenneth L. Scott

Authors and Affiliations

  1. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Rakhee Bajaj, Samrat T. Kundu, Jared J. Fradette & Don L. Gibbons

  2. Department of Molecular and Human Genetics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA

    Caitlin L. Grzeskowiak

  3. Department of Medicine, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA

    Caitlin L. Grzeskowiak, Kenneth L. Scott & Chad J. Creighton

  4. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Don L. Gibbons

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  1. Rakhee Bajaj
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Contributions

Study conceptualization, design, and execution of project: RB, STK, KLS, and DLG. Data acquisition and statistical analysis: RB, STK, CLG, and CJC. Analysis, interpretation, and representation of data: RB and STK. Manuscript writing, critical revision, and preparation of figures and tables: RB, STK, and DLG. Overall supervision and execution: STK and DLG.

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Correspondence to Samrat T. Kundu or Don L. Gibbons.

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Bajaj, R., Kundu, S.T., Grzeskowiak, C.L. et al. IMPAD1 and KDELR2 drive invasion and metastasis by enhancing Golgi-mediated secretion. Oncogene 39, 5979–5994 (2020). https://doi.org/10.1038/s41388-020-01410-z

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