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.

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PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1500722112 ◽

2015 ◽

Vol 112 (28) ◽

pp. 8638-8643 ◽

Cited By ~ 109

Author(s):

M. Cecilia Caino ◽

Jagadish C. Ghosh ◽

Young Chan Chae ◽

Valentina Vaira ◽

Dayana B. Rivadeneira ◽

...

Keyword(s):

Tumor Cell ◽

Cell Motility ◽

Cell Invasion ◽

Mammalian Target Of Rapamycin ◽

Membrane Dynamics ◽

Tumor Cell Invasion ◽

Transcriptional Reprogramming ◽

Tumor Cell Motility ◽

Molecular Therapies ◽

Mitochondrial Trafficking

Molecular therapies are hallmarks of “personalized” medicine, but how tumors adapt to these agents is not well-understood. Here we show that small-molecule inhibitors of phosphatidylinositol 3-kinase (PI3K) currently in the clinic induce global transcriptional reprogramming in tumors, with activation of growth factor receptors, (re)phosphorylation of Akt and mammalian target of rapamycin (mTOR), and increased tumor cell motility and invasion. This response involves redistribution of energetically active mitochondria to the cortical cytoskeleton, where they support membrane dynamics, turnover of focal adhesion complexes, and random cell motility. Blocking oxidative phosphorylation prevents adaptive mitochondrial trafficking, impairs membrane dynamics, and suppresses tumor cell invasion. Therefore, “spatiotemporal” mitochondrial respiration adaptively induced by PI3K therapy fuels tumor cell invasion, and may provide an important antimetastatic target.

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Tumor Cell Invasion in Glioblastoma

International Journal of Molecular Sciences ◽

10.3390/ijms21061932 ◽

2020 ◽

Vol 21 (6) ◽

pp. 1932 ◽

Cited By ~ 6

Author(s):

Arabel Vollmann-Zwerenz ◽

Verena Leidgens ◽

Giancarlo Feliciello ◽

Christoph A. Klein ◽

Peter Hau

Keyword(s):

Tumor Cell ◽

Cell Invasion ◽

Treatment Resistance ◽

Tumor Cell Invasion ◽

Surrounding Tissue ◽

Glioma Invasion ◽

Curative Therapy ◽

New Therapeutic Approaches ◽

Invasion Mechanisms ◽

Tumor Cell Motility

Glioblastoma (GBM) is a particularly devastating tumor with a median survival of about 16 months. Recent research has revealed novel insights into the outstanding heterogeneity of this type of brain cancer. However, all GBM subtypes share the hallmark feature of aggressive invasion into the surrounding tissue. Invasive glioblastoma cells escape surgery and focal therapies and thus represent a major obstacle for curative therapy. This review aims to provide a comprehensive understanding of glioma invasion mechanisms with respect to tumor-cell-intrinsic properties as well as cues provided by the microenvironment. We discuss genetic programs that may influence the dissemination and plasticity of GBM cells as well as their different invasion patterns. We also review how tumor cells shape their microenvironment and how, vice versa, components of the extracellular matrix and factors from non-neoplastic cells influence tumor cell motility. We further discuss different research platforms for modeling invasion. Finally, we highlight the importance of accounting for the complex interplay between tumor cell invasion and treatment resistance in glioblastoma when considering new therapeutic approaches.

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