Coronin 1C promotes triple-negative breast cancer invasiveness through regulation of MT1-MMP traffic and invadopodia function

Castagnino, Alessia; Castro-Castro, Antonio; Irondelle, Marie; Guichard, A; Lodillinsky, Catalina; Fuhrmann, Laetitia; Vacher, Sophie; Agüera-González, Sonia; Zagryazhskaya-Masson, Anna; Romao, Maryse; Kesrouani, Carole; Noegel, Angelika A.; Dubois, Thierry; Raposo, Graça; Bear, James E.; Clemen, Christoph S.; Vincent‐Salomon, Anne; Bièche, Ivan; Chavrier, Philippe

doi:10.1038/s41388-018-0422-x

Cited by 41 publications

(42 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Collagen degradation is also a requirement in the DCIS intraductal xenograft tumor model for the transition from in situ-to-invasive carcinoma ( 17,18 ). We thus assessed the collagen degradation activity of DCIS cells embedded into a 3D type I collagen matrix for 12 h and stained with an antibody that specifically recognizes the collagenase-cleaved ¾ fragment of collagen I ( 17,33,34 ). Importantly, cells were treated with drugs, or confined for several hours, and then were embedded in the 3D collagen gel in the absence of any further DNA damaging condition.…”

Section: Resultsmentioning

confidence: 99%

Compromised nuclear envelope integrity drives tumor cell invasion

Nader

Agüera-González

Routet

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

While mutations leading to a fragile envelope of the cell nucleus are well known to cause diseases such as muscular dystrophies or accelerated aging, the pathophysiological consequences of the recently discovered mechanically induced nuclear envelope ruptures in cells harboring no mutation are less known. Here we show that repeated loss of nuclear envelope integrity in nuclei experiencing mechanical constraints promotes senescence in nontransformed cells, and induces an invasive phenotype including increased collagen degradation in human breast cancer cells, both in vitro and in a mouse xenograft model of breast cancer progression. We show that these phenotypic changes are due to the presence of chronic DNA damage and activation of the ATM kinase. In addition, we found that depletion of the cytoplasmic exonuclease TREX1 is sufficient to abolish the DNA damage in mechanically challenged nuclei and to suppress the phenotypes associated with the loss of nuclear envelope integrity. Our results also show that TREX1-dependent DNA damage induced by physical confinement of tumor cells inside the mammary duct drives the progression of in situ breast carcinoma to the invasive stage. We propose that DNA damage in mechanically challenged nuclei could affect the pathophysiology of crowded tissues by modulating proliferation and extracellular matrix degradation of normal and transformed cells. Main text:( 16,21-23 ), and corresponds to cells squeezing each other as they move. These deformed nuclei were also more often positive for γH2AX than less deformed ones, and in general displayed more intense γH2AX staining than nuclei in the bulk of the tumor ( Fig. 1A-C). This suggests that, at the in situ stage of human breast carcinoma, strands of motile cells at the periphery of the tumor exhibit pronounced nuclear deformation, associated with elevated DNA damage.We then investigated a xenograft mouse model based on the intraductal (intra-nipple) injection of transformed human breast MCF10DCIS.com (DCIS) cells, which are derived from the nontransformed MCF10A cell line, and that recapitulates the transition from in situ to invasive stages of breast cancer progression ( 17,24 ). Tumors at various stages were analyzed. In situ tumors (further divided in early and advanced stages based on the continuity of the myoepithelial layer) are characterized by a myoepithelial layer (stained with smooth muscle actin) surrounding human xenograft cells that were identified by the human-specific KU70 antibody. In order to verify whether human tumor cells similarly experience DNA damage in the tumor xenografts, tumor sections were stained with γH2AX ( Fig. 1E-F, Fig. S1A). Similar to human tumor specimens, xenograft tumors displayed numerous deformed nuclei, mostly found at the periphery of the tumor mass, close to the myoepithelium, especially in ducts inflated with large tumors (Fig. 1E-F), and enriched in regions showing micro-invasive foci. Strikingly, these regions were also enriched in γH2AX-positive nuclei (Fig. 1F). Since γH2AX is also known...

show abstract

Section: Resultsmentioning

confidence: 99%

Compromised nuclear envelope integrity drives tumor cell invasion

Nader

Agüera-González

Routet

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Notably, when we mined for proteins differentially expressed between primary and metastatic UM-EVs (MEL270 UM-EVs vs. OMM2.5 UM-EVs), we found that primary UM-derived EVs were enriched for proteins involved in the regulation of cell growth (i.e., PCNA and CDK1) [ 67 , 68 ] and in metastatic organotropism (i.e., integrins, Coronin 1C and CD151) [ 56 , 85 , 86 ]. Coronin 1C is highly expressed in invasive human cancers and correlates positively with increased metastatic risk [ 85 ]. CD151 is a tetraspanin associated with tumor metastasis, and is correlated with poor prognosis, decreased overall survival and increased recurrence [ 86 ].…”

Section: Discussionmentioning

confidence: 99%

Uveal Melanoma-Derived Extracellular Vesicles Display Transforming Potential and Carry Protein Cargo Involved in Metastatic Niche Preparation

Tsering

Laskaris

Abdouh

et al. 2020

Cancers

View full text Add to dashboard Cite

Extracellular vesicles (EVs) carry molecules derived from donor cells and are able to alter the properties of recipient cells. They are important players during the genesis and progression of tumors. Uveal melanoma (UM) is the most common primary intraocular tumor in adults and is associated with a high rate of metastasis, primarily to the liver. However, the mechanisms underlying this process are poorly understood. In the present study, we analyzed the oncogenic potential of UM-derived EVs and their protein signature. We isolated and characterized EVs from five UM cell lines and from normal choroidal melanocytes (NCMs). BRCA1-deficient fibroblasts (Fibro-BKO) were exposed to the EVs and analyzed for their growth in vitro and their reprograming potential in vivo following inoculation into NOD-SCID mice. Mass spectrometry of proteins from UM-EVs and NCM-EVs was performed to determine a protein signature that could elucidate potential key players in UM progression. In-depth analyses showed the presence of exosomal markers, and proteins involved in cell-cell and focal adhesion, endocytosis, and PI3K-Akt signaling pathway. Notably, we observed high expression levels of HSP90, HSP70 and integrin V in UM-EVs. Our data bring new evidence on the involvement of UM-EVs in cancer progression and metastasis.

show abstract

“…Although our data are seemingly at odds with these over-expression observations, we would point out that correlation does not automatically mean causation and hypotheses derived from expression data must be tested with functional experiments. Indeed, some experiments using either RNAi depletion or over-expression in cell lines show that Coronin 1C is a positive regulator of proliferation and invasion in breast cancer and lung-squamous cell carcinoma 34 , 35 , 87 . Additionally, Coronin 1C was shown to enhance MT1-MMP trafficking to the cell surface in an orthotopic injection model of breast cancer 87 , which is again seemingly at odds with our results.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, some experiments using either RNAi depletion or over-expression in cell lines show that Coronin 1C is a positive regulator of proliferation and invasion in breast cancer and lung-squamous cell carcinoma 34 , 35 , 87 . Additionally, Coronin 1C was shown to enhance MT1-MMP trafficking to the cell surface in an orthotopic injection model of breast cancer 87 , which is again seemingly at odds with our results. However, recent data using genetic deletion of Coronin 1C in a GEM model of glioblastoma showed no change in time of survival with or without Coronin 1C 88 , further supporting the idea that Coronin 1C impacts tumor progression differently between cancer types.…”

Section: Discussionmentioning

confidence: 99%

Coronin 1C inhibits melanoma metastasis through regulation of MT1-MMP-containing extracellular vesicle secretion

Tagliatela

Hempstead

Hibshman

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

is overexpressed in multiple tumors, leading to the widely held view that this gene drives tumor progression, but this hypothesis has not been rigorously tested in melanoma. Here, we combined a conditional knockout of Coronin 1C with a genetically engineered mouse model of PTEN/ BRAF-driven melanoma. Loss of Coronin 1C in this model increases both primary tumor growth rates and distant metastases. Coronin 1C-null cells isolated from this model are more invasive in vitro and produce more metastatic lesions in orthotopic transplants than Coronin 1C-reexpressing cells due to the shedding of extracellular vesicles (EVs) containing MT1-MMP. Interestingly, these vesicles contain melanosome markers suggesting a melanoma-specific mechanism of EV release, regulated by Coronin 1C, that contributes to the high rates of metastasis in melanoma. Melanoma is the deadliest form of skin cancer with a high propensity for metastatic spread 1,2. The most common genetic drivers of melanoma are BRAF-activating mutations such as V600E, often found in conjunction with loss of tumor suppressors such as PTEN 3-5. If caught in its early stages, melanoma is treatable by surgical resection, but prognosis worsens significantly with the occurrence of in-transit, regional, or distant metastasis. Clinically, up to 54% of metastatic melanoma patients show tumor dissemination to the brain, 77% to the liver, and 85% to the lung 6. The high rate of metastasis in melanoma is poorly understood, but may be linked to lineage-specific factors that impact vesicular trafficking, secretion, degradation, and overall cell migration 7,8. The extracellular matrix (ECM) is an important substrate for tumor cell migration, but it also acts as a physical barrier whose degradation by matrix metalloproteinases (MMPs) is thought to be a critical step in tumor dissemination 9-11. MMPs are a family of both transmembrane (designated "membrane-type" or "MT") and secreted catalytic enzymes capable of cleaving ECM proteins and other substrates. Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a particularly important pro-invasive MMP across many cancer types 12 and whose expression closely correlates with invasion and metastasis 13-15. MT1-MMP is also unique in its ability to both directly cleave a wide range of ECM proteins including collagen types I, II, and III, laminin 1 and 5, and fibronectin, as well as activate pro-MMP2 16. The trafficking of MT1-MMP to and from the plasma membrane (PM) and other membrane structures is surprisingly complex, but critical for the protein's function during tumor invasion and metastasis. Phosphorylation of the cytoplasmic tail initiates internalization of MT1-MMP from the PM by both clathrin-mediated and caveolin-mediated routes 13. Internalized vesicles traffic through the endolysosomal pathway, resulting in redirection to other areas of the PM or to the lysosome for degradation 17. MT1-MMP recycling has been shown to involve various flotilins 18 and SNARE proteins 19-22 , as well as a variety of Rab proteins including Rab5, Rab7 1...

show abstract

Coronin 1C promotes triple-negative breast cancer invasiveness through regulation of MT1-MMP traffic and invadopodia function

Cited by 41 publications

References 62 publications

Compromised nuclear envelope integrity drives tumor cell invasion

Compromised nuclear envelope integrity drives tumor cell invasion

Uveal Melanoma-Derived Extracellular Vesicles Display Transforming Potential and Carry Protein Cargo Involved in Metastatic Niche Preparation

Coronin 1C inhibits melanoma metastasis through regulation of MT1-MMP-containing extracellular vesicle secretion

Contact Info

Product

Resources

About