Myc Regulation of a Mitochondrial Trafficking Network Mediates Tumor Cell Invasion and Metastasis

ABSTRACT

The Myc gene is a universal oncogene that promotes aggressive cancer, but its role in metastasis has remained elusive. Here, we show that Myc transcriptionally controls a gene network of subcellular mitochondrial trafficking that includes the atypical mitochondrial GTPases RHOT1 and RHOT2, the adapter protein TRAK2, the anterograde motor Kif5B, and an effector of mitochondrial fission, Drp1. Interference with this pathway deregulates mitochondrial dynamics, shuts off subcellular organelle movements, and prevents the recruitment of mitochondria to the cortical cytoskeleton of tumor cells. In turn, this inhibits tumor chemotaxis, blocks cell invasion, and prevents metastatic spreading in preclinical models. Therefore, Myc regulation of mitochondrial trafficking enables tumor cell motility and metastasis.

KEYWORDS:

• Myc
• cell invasion
• metastasis
• mitochondria

ACKNOWLEDGMENTS

We thank James Hayden and Frederick Keeney of The Wistar Institute Imaging Core Facility for assistance with time-lapse videomicroscopy. We also thank Samantha Soldan (The Wistar Institute) for her help with intrasplenic surgeries in mice.

This work was supported by National Institutes of Health (NIH) grants P01 CA140043 (D.C.A., D.W.S., L.R.L., and D.I.G.), R35 CA220446 (D.C.A.), R00 CA204593 (B.J.A.), and R50 CA211199 (A.V.K.). The support for shared resources utilized in this study was provided by Cancer Center support grant (CCSG) P30 CA010815 and NIH grants S10 OD023586 and S10 OD023658 to The Wistar Institute.

We declare no competing financial interest.

E.A., B.J.A., C.V.D., and D.C.A. conceived the project; E.A. performed experiments of Myc regulation of gene expression, mitochondrial trafficking, cell invasion, and metastasis in xenograft and syngeneic tumor models; J.H.S. performed experiments for mitochondrial fractionation; J.C.G. also performed immunohistochemistry on tissue slides; E.A. and I.B. performed experiments for mitochondrial dynamics; A.V.K. performed bioinformatics analysis; E.A., L.R.L., D.I.G., C.V.D., and D.C.A. analyzed data; A.K. performed experiments of 3D spheroid invasions; D.W.S. coordinated metabolomics studies; and E.A. and D.C.A. wrote the paper.