Mitochondrial dynamics and metastasis

Abstract

Changes in cellular metabolism are now a recognized hallmark of cancer. Although this process is ripe with therapeutic potential in the clinic, its complexity and extraordinary plasticity have systematically defied dogmas and oversimplifications. Perhaps best exemplifying this intricacy is the role of mitochondria in cancer, which in just a few years has gone from largely unnoticed to pivotal disease driver. The underlying mechanisms are only beginning to emerge. However, there is now clear evidence linking the dynamic nature of mitochondria to the machinery of tumor cell motility and metastatic spreading. These studies may open fresh therapeutic options for patients with disseminated cancer, currently an incurable and mostly lethal condition.

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

“…Myc-mitochondrial signaling enables tumor cell motility. Recent studies have shown that mitochondrial trafficking to the cortical cytoskeleton fuels tumor cell movements (20). Consistent with this possibility, Myc silencing suppressed focal adhesion (FA) complex dynamics in PC3 cells (Fig.…”

“…A role of Myc in this process has remained controversial in the literature (37), as oncogenic Myc has been linked to inhibition of tumor cell invasion via suppression of Jun N-terminal protein kinase (JNK) activity (38) or sensitization to transforming growth factor ␤ (TGF-␤) signaling (39). Conversely, the data presented here showing that Myc transcriptionally controls an integrated cellular machinery for mitochondrial movements, which in turn fuels cell motility and invasion (20), points to this pathway as a ubiquitous aspect of Myc-driven tumors, important for metastatic competence, in vivo. In this context, mitochondrial trafficking to the cortical cytoskeleton at the leading edge of migration has been proposed as an efficient, "spatiotemporal" energy source to fuel membrane lamellipodium dynamics, persistent phosphorylation of cell motility kinases, and heightened tumor chemotaxis and invasion (23)(24)(25).…”

Subpopulation targeting of pyruvate dehydrogenase and GLUT1 decouples metabolic heterogeneity during collective cancer cell invasion

“…While the downregulation of mitochondrial pathways is a common feature of metabolic rewiring across invasive cancer cells and is a poor prognostic indicator 50 , these studies focus on the bulk of the tumor cell population and would likely not detect rare, specialized subpopulations that are sensitive to mitochondrial inhibitors 51 . Maintaining intact mitochondrial function is considered essential for cancer cell invasion and metastasis to occur 52,53 , and enhanced OXPHOS, mitochondrial biogenesis, and oxygen consumption rates are observed in invasive breast cancer and pancreatic cancer [54][55][56] .…”

ROCK1 activation-mediated mitochondrial translocation of Drp1 and cofilin are required for arnidiol-induced mitochondrial fission and apoptosis

“…These organelles are responsible for driving cell life and death through mitochondrial network structure homeostasis, which is determined by a balance of fission and fusion [1]. Mitochondrial fission is important for maintaining cellular functions, including cellular development and homeostasis, and apoptosis [2,3]. The cytoplasmic dynaminrelated GTPase Drp1 plays a key role in the regulation of mitochondrial fission.…”