IMPAD1 and KDELR2 drive invasion and metastasis by enhancing Golgi-mediated secretion
- 3 August 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 39 (37), 5979-5994
- https://doi.org/10.1038/s41388-020-01410-z
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.Funding Information
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (K08 CA151651)
- United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs (W81XWH-12-16294)
- U.S. Department of Health & Human Services | National Institutes of Health (R37CA214609)
This publication has 48 references indexed in Scilit:
- ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expressionJCI Insight, 2012
- Acrp30 inhibits leptin-induced metastasis by downregulating the JAK/STAT3 pathway via AMPK activation in aggressive SPEC-2 endometrial cancer cellsOncology Reports, 2012
- Identification of ERp29 as a biomarker for predicting nasopharyngeal carcinoma response to radiotherapyOncology Reports, 2011
- Chondrodysplasia and Abnormal Joint Development Associated with Mutations in IMPAD1, Encoding the Golgi-Resident Nucleotide Phosphatase, gPAPPAmerican Journal of Human Genetics, 2011
- Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expressionGenes & Development, 2009
- Expression Signatures of Metastatic Capacity in a Genetic Mouse Model of Lung AdenocarcinomaPLOS ONE, 2009
- Vesicular trafficking and secretion of matrix metalloproteinases-2, -9 and tissue inhibitor of metalloproteinases-1 in neuronal cellsMolecular and Cellular Neuroscience, 2008
- A role for a lithium-inhibited Golgi nucleotidase in skeletal development and sulfationProceedings of the National Academy of Sciences of the United States of America, 2008
- JAWS coordinates chondrogenesis and synovial joint positioningDevelopment, 2008
- Metastasis: a therapeutic target for cancerNature Clinical Practice Oncology, 2008