Abstract
BackgroundMitochondrial dynamics underlies malignant transformation, cancer progression, and response to treatment. Current research presents conflicting evidence for functions of mitochondrial fission and fusion in tumor progression. Here, we investigated how mitochondrial fission and fusion states regulate underlying processes of cancer progression and metastasis in triple-negative breast cancer (TNBC).MethodsWe enforced mitochondrial fission and fusion states through chemical or genetic approaches and measured migration and invasion of TNBC cells in 2D and 3D in vitro models. We also utilized kinase translocation reporters (KTRs) to identify single cell effects of mitochondrial state on signaling cascades, PI3K/Akt/mTOR and Ras/Raf/MEK/ERK, commonly activated in TNBC. Furthermore, we determined effects of fission and fusion states on metastasis, bone destruction, and signaling in mouse models of breast cancer.ResultsEnforcing mitochondrial fission through chemical or genetic approaches inhibited migration, invasion, and metastasis in TNBC. Breast cancer cells with predominantly fissioned mitochondria exhibited reduced activation of Akt and ERK both in vitro and in mouse models of breast cancer. Treatment with leflunomide, a potent activator of mitochondrial fusion proteins, overcame inhibitory effects of fission on migration, signaling, and metastasis. Mining existing datasets for breast cancer revealed that increased expression of genes associated with mitochondrial fission correlated with improved survival in human breast cancer.ConclusionsIn TNBC, mitochondrial fission inhibits cellular processes and signaling pathways associated with cancer progression and metastasis. These data suggest that therapies driving mitochondrial fission may benefit patients with breast cancer.
Highlights
Mitochondrial dynamics underlies malignant transformation, cancer progression, and response to treatment
We show that opposing effects of mitochondrial fission and fusion extend to patients with breast cancer, where improved survival correlates with high levels of fission genes and low levels of genes driving mitochondrial fusion
Phosphatidylserine decarboxylase (PISD) reduces metastasis and osteolytic bone lesions Using an orthotopic xenograft model, we previously showed that overexpression of phosphatidylserine decarboxylase (PISD) in breast cancer cells significantly reduced local tumor growth [15]
Summary
Mitochondrial dynamics underlies malignant transformation, cancer progression, and response to treatment. As hubs for metabolism and biosynthesis, mitochondria adapt to meet energetic and anapleurotic demands of malignant transformation, unregulated proliferation, and tumor progression [1, 2]. Shifts between fission and fused states allow cells to adapt to changes in available nutrients and energy demands [4]. Does mitochondrial morphology regulate metabolic plasticity [5], but recent work points to broader functions for fission and fusion in signal transduction [6, 7]. Recent evidence suggests that mitochondrial morphology transitions control the release of ROS and ATP [13, 14], directly impacting cell function and survival. Functions of mitochondria as regulators of cell signaling suggest the balance between mitochondrial fission and fusion controls tumor progression and represents potential targets for therapy
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