Impad1 and Syt11 work in an epistatic pathway that regulates EMT-mediated vesicular trafficking to drive lung cancer invasion and metastasis

Rakhee Bajaj; B Leticia Rodriguez; William K Russell; Amanda N Warner; Lixia Diao; Jing Wang; Maria G Raso; Wei Lu; Khaja Khan; Luisa S Solis; Harsh Batra; Ximing Tang; Jared F Fradette; Samrat T Kundu; Don L Gibbons

doi:10.1016/j.celrep.2022.111429

Impad1 and Syt11 work in an epistatic pathway that regulates EMT-mediated vesicular trafficking to drive lung cancer invasion and metastasis

Cell Rep. 2022 Sep 27;40(13):111429. doi: 10.1016/j.celrep.2022.111429.

Authors

Rakhee Bajaj¹, B Leticia Rodriguez², William K Russell³, Amanda N Warner¹, Lixia Diao⁴, Jing Wang⁴, Maria G Raso⁵, Wei Lu⁵, Khaja Khan⁵, Luisa S Solis⁵, Harsh Batra⁵, Ximing Tang⁵, Jared F Fradette¹, Samrat T Kundu², Don L Gibbons⁶

Affiliations

¹ Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; UTHealth Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX 77030, USA.
² Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
³ Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
⁴ Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁵ Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
⁶ Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: dlgibbon@mdanderson.org.

Abstract

Lung cancer is a highly aggressive and metastatic disease responsible for approximately 25% of all cancer-related deaths in the United States. Using high-throughput in vitro and in vivo screens, we have previously established Impad1 as a driver of lung cancer invasion and metastasis. Here we elucidate that Impad1 is a direct target of the epithelial microRNAs (miRNAs) miR-200 and miR∼96 and is de-repressed during epithelial-to-mesenchymal transition (EMT); thus, we establish a mode of regulation of the protein. Impad1 modulates Golgi apparatus morphology and vesicular trafficking through its interaction with a trafficking protein, Syt11. These changes in Golgi apparatus dynamics alter the extracellular matrix and the tumor microenvironment (TME) to promote invasion and metastasis. Inhibiting Impad1 or Syt11 disrupts the cancer cell secretome, regulates the TME, and reverses the invasive or metastatic phenotype. This work identifies Impad1 as a regulator of EMT and secretome-mediated changes during lung cancer progression.

Keywords: CP: Cancer; Golgi exocytosis; Golgi morphology; Impad1; Syt11; epithelial-to-mesenchymal transition; extracellular matrix; invasion; lung cancer; metastasis; secretome; tumor immune microenvironment; tumor microenvironment; vesicular trafficking.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Cell Line, Tumor
Cell Movement
Epithelial-Mesenchymal Transition / genetics
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms* / pathology
MicroRNAs* / metabolism
Neoplasm Invasiveness / genetics
Neoplasm Metastasis
Synaptotagmins / metabolism
Tumor Microenvironment

Substances

MicroRNAs
SYT11 protein, human
Synaptotagmins

Abstract

Publication types

MeSH terms

Substances

Grants and funding