Depletion of mitochondrial protease OMA1 alters proliferative properties and promotes metastatic growth of breast cancer cells

Abstract Metastatic competence of cancer cells is influenced by many factors including metabolic alterations and changes in mitochondrial biogenesis and protein homeostasis. While it is generally accepted that mitochondria play important roles in tumorigenesis, the respective molecular events that regulate aberrant cancer cell proliferation remain to be clarified. Therefore, understanding the mechanisms underlying the role of mitochondria in cancer progression has potential implications in the development of new therapeutic strategies. We show that low expression of mitochondrial quality control protease OMA1 correlates with poor overall survival in breast cancer patients. Silencing OMA1 in vitro in patient-derived metastatic breast cancer cells isolated from the metastatic pleural effusion and atypical ductal hyperplasia mammary tumor specimens (21MT-1 and 21PT) enhances the formation of filopodia, increases cell proliferation (Ki67 expression), and induces epithelial-mesenchymal transition (EMT). Mechanistically, loss of OMA1 results in alterations in the mitochondrial protein homeostasis, as reflected by enhanced expression of canonic mitochondrial unfolded protein response genes. These changes significantly increase migratory properties in metastatic breast cancer cells, indicating that OMA1 plays a critical role in suppressing metastatic competence of breast tumors. Interestingly, these results were not observed in OMA1-depleted non-tumorigenic MCF10A mammary epithelial cells. This newly identified reduced activity/levels of OMA1 provides insights into the mechanisms leading to breast cancer development, promoting malignant progression of cancer cells and unfavorable clinical outcomes, which may represent possible prognostic markers and therapeutic targets for breast cancer treatment.

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Metastatic breast cancer cells induce altered microglial morphology and electrical excitability in vivo

10.1101/636159 ◽

2019 ◽

Cited By ~ 1

Author(s):

Anna Simon ◽

Ming Yang ◽

Joanne L. Marrison ◽

Andrew D. James ◽

Peter J. O’Toole ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Inflammatory Response ◽

Cancer Cells ◽

Brain Tumours ◽

Breast Cancer Cells ◽

Critical Role ◽

Field Potential ◽

Metastatic Breast ◽

Optical Window

AbstractBackgroundAn emerging problem in the treatment of breast cancer is the increasing incidence of metastases to the brain. Metastatic brain tumours are incurable and can cause epileptic seizures and cognitive impairment, so better understanding of this niche, and the cellular mechanisms, is urgently required. Microglia are the resident brain macrophage population, becoming “activated” by neuronal injury, eliciting an inflammatory response. Microglia promote proliferation, angiogenesis and invasion in brain tumours and metastases. However, the mechanisms underlying microglial involvement appear complex and better models are required to improve understanding of function.MethodsHere, we sought to address this need by developing a model to study metastatic breast cancer cell-microglial interactions using intravital imaging combined with ex vivo electrophysiology. We implanted an optical window on the parietal bone to facilitate observation of cellular behaviour in situ in the outer cortex of heterozygous Cx3cr1GFP/+ mice. Results: We detected GFP-expressing microglia in Cx3cr1GFP/+ mice up to 350 µm below the window without significant loss of resolution. When DsRed-expressing metastatic MDA-MB-231 breast cancer cells were implanted in Matrigel under the optical window, significant accumulation of activated microglia around invading tumour cells could be observed. This inflammatory response resulted in significant cortical disorganisation and aberrant spontaneously-occurring local field potential spike events around the metastatic site.ConclusionsThese data suggest that peritumoral microglial activation and accumulation may play a critical role in local tissue changes underpinning aberrant cortical activity, which offers a possible mechanism for the disrupted cognitive performance and seizures seen in patients with metastatic breast cancer.

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TGF-β-Smad2 dependent activation of CDC 25A plays an important role in cell proliferation through NFAT activation in metastatic breast cancer cells

Cellular Signalling ◽

10.1016/j.cellsig.2013.11.013 ◽

2014 ◽

Vol 26 (2) ◽

pp. 240-252 ◽

Cited By ~ 15

Author(s):

Suman Sengupta ◽

Samir Jana ◽

Arindam Bhattacharyya

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Metastatic Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Metastatic Breast ◽

Nfat Activation

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Maintenance of epithelial traits and resistance to mesenchymal reprogramming promote proliferation in metastatic breast cancer

10.1101/2020.03.19.998823 ◽

2020 ◽

Cited By ~ 3

Author(s):

Laura Eichelberger ◽

Massimo Saini ◽

Helena Domínguez Moreno ◽

Corinna Klein ◽

Johanna M. Bartsch ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Metastatic Breast ◽

Breast Cancer Patients ◽

Mesenchymal Transition ◽

Cancer Subtypes ◽

Stage Iv Breast Cancer

AbstractDespite important advances in the treatment of breast cancer, the 5-year survival rate for patients with distant metastasis remains less than 30%. Metastasis is a complex, multi-step process beginning with local invasion and ending with the outgrowth of systemically disseminated cells into actively proliferating metastases that ultimately cause the destruction of vital organs. It is this last step that limits patient survival and, at the same time, remains the least understood mechanistically. Here, we focus on understanding determinants of metastatic outgrowth using metastatic effusion biopsies from stage IV breast cancer patients. By modelling metastatic outgrowth through xenograft transplantation, we show that tumour initiation potential of patient-derived metastatic breast cancer cells across breast cancer subtypes is strongly linked to high levels of EPCAM expression. Breast cancer cells with high EPCAM levels are highly plastic and, upon induction of epithelial-mesenchymal transition (EMT), readily adopt mesenchymal traits while maintaining epithelial identity. In contrast, low EPCAM levels are caused by the irreversible reprogramming to a mesenchymal state with concomitant suppression of metastatic outgrowth. The ability of breast cancer cells to retain epithelial traits is tied to a global epigenetic program that limits the actions of EMT-transcription factor ZEB1, a suppressor of epithelial genes. Our results provide direct evidence that maintenance of epithelial identity is required for metastatic outgrowth while concomitant expression of mesenchymal markers enables plasticity. In contrast, loss of epithelial traits is characteristic of an irreversible mesenchymal reprogramming associated to a deficiency for metastatic outgrowth. Collectively, our data provide a framework for the intricate intercalation of mesenchymal and epithelial traits in metastatic growth.

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RUNX/CBFβ transcription factor complexes promote the phenotypic plasticity of metastatic breast cancer cells

10.1101/562538 ◽

2019 ◽

Author(s):

Ran Ran ◽

Hannah Harrison ◽

Nur Syamimi Ariffin ◽

Rahna Ayub ◽

Henry J Pegg ◽

...

Keyword(s):

Breast Cancer ◽

Transcription Factor ◽

Metastatic Breast Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Breast Cancer Cells ◽

Metastatic Cancer ◽

Metastatic Breast ◽

Mesenchymal Transition

AbstractEpithelial to mesenchymal transition (EMT) is a dynamic process that drives cancer cell plasticity and is thought to play a major role in metastasis. Here we show that the plasticity of metastatic breast cancer cells can be promoted by the activity of the RUNX transcription factors. We demonstrate that the RUNX co-regulator CBFβ is essential to maintain the mesenchymal phenotype of triple-negative breast cancer cells and that CBFβ-depleted cells undergo a mesenchymal to epithelial transition (MET) and re-organise into acini-like structures, reminiscent of those formed by epithelial breast cells. We subsequently show, using an inducible CBFβ system, that the MET can be reversed, thus demonstrating the plasticity of RUNX/CBFβ-mediated EMT. Moreover, the MET can be reversed by expression of the EMT transcription factor Slug whose expression is dependent on CBFβ, RUNX1 and RUNX2. Finally, we demonstrate that loss of CBFβ inhibits the ability of metastatic breast cancer cells to invade bone cell cultures and suppresses their ability to form bone metastasesin vivo. Together our findings demonstrate that the RUNX/CBFβ complexes can determine the plasticity of the metastatic cancer cell phenotypes, suggesting that their regulation in different micro-environments may play a key role in the establishment of metastatic tumours.

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