Tumor resistance to ferroptosis driven by Stearoyl-CoA Desaturase-1 (SCD1) in cancer cells and Fatty Acid Biding Protein-4 (FABP4) in tumor microenvironment promote tumor recurrence.

PROBLEM: Tumor recurrence is a major clinical issue that represents the principal cause of cancer-related deaths, with few targetable common pathways. Mechanisms by which residual tumors persist and progress under a continuous shift between hypoxia-reoxygenation after neoadjuvent-therapy are unknown. In this study, we investigated the role of lipid metabolism and tumor redox balance in tumor recurrence. METHODS: Lipidomics, proteomics and mass spectrometry imaging approaches where applied to mouse tumor models of recurrence. Genetic and pharmacological inhibitions of lipid mediators in tumors were used in vivo and in functional assays in vitro. RESULTS: We found that stearoyl-CoA desaturase-1 (SCD1) expressed by cancer cells and fatty acid binding protein-4 (FABP4) produced by tumor endothelial cells (TECs) and adipocytes in the tumor microenvironment (TME) are essential for tumor relapse in response to tyrosine kinase inhibitors (TKI) and chemotherapy. SCD1 and FABP4 were also found upregulated in recurrent human breast cancer samples and correlated with worse prognosis of cancer patients with different types of tumors. Mechanistically, SCD1 leads to fatty acid (FA) desaturation and FABP4 derived from TEM enhances lipid droplet (LD) in cancer cells, which cooperatively protect from oxidative stress-induced ferroptosis. We revealed that lipid mobilization and desaturation elicit tumor intrinsic antioxidant and anti-ferroptotic resources for survival and regrowth in a harsh TME. Inhibition of lipid transport from TME by FABP4 inhibitor reduced tumor regrowth and by genetic - or by pharmacological - targeting SCD1 in vivo, tumor regrowth was abolished completely. CONCLUSION: This finding unveils that it is worth taking advantage of tumor lipid addiction, as a tumor vulnerability to design novel treatment strategy to prevent cancer recurrence

Von Willebrand disease

peer reviewe

Reciprocal Interplay Between Fibrillar Collagens and Collagen-Binding Integrins: Implications in Cancer Progression and Metastasis.

Cancers are complex ecosystems composed of malignant cells embedded in an intricate microenvironment made of different non-transformed cell types and extracellular matrix (ECM) components. The tumor microenvironment is governed by constantly evolving cell-cell and cell-ECM interactions, which are now recognized as key actors in the genesis, progression and treatment of cancer lesions. The ECM is composed of a multitude of fibrous proteins, matricellular-associated proteins, and proteoglycans. This complex structure plays critical roles in cancer progression: it functions as the scaffold for tissues organization and provides biochemical and biomechanical signals that regulate key cancer hallmarks including cell growth, survival, migration, differentiation, angiogenesis, and immune response. Cells sense the biochemical and mechanical properties of the ECM through specialized transmembrane receptors that include integrins, discoidin domain receptors, and syndecans. Advanced stages of several carcinomas are characterized by a desmoplastic reaction characterized by an extensive deposition of fibrillar collagens in the microenvironment. This compact network of fibrillar collagens promotes cancer progression and metastasis, and is associated with low survival rates for cancer patients. In this review, we highlight how fibrillar collagens and their corresponding integrin receptors are modulated during cancer progression. We describe how the deposition and alignment of collagen fibers influence the tumor microenvironment and how fibrillar collagen-binding integrins expressed by cancer and stromal cells critically contribute in cancer hallmarks.info:eu-repo/semantics/publishe

Remodelling of the fibre-aggregate structure of collagen gels by cancer-associated fibroblasts: a time-resolved grey-tone image analysis based on stochastic modelling

peer reviewedSolid tumors consist of tumor cells associated with stromal and immune cells, secreted factors and extracellular matrix (ECM), that together constitute the tumor microenvironment. Among stromal cells, activated fibroblasts, known as cancer-associated fibroblasts (CAFs) are of particular interest. CAFs secrete a plethora of ECM components including collagen and modulate the architecture of the ECM, thereby influencing cancer cell migration. The characterization of the collagen fibre network and its space and time-dependent microstructural modifications is key to investigating the interactions between cells and the ECM. Developing image analysis tools for that purpose is still a challenge because the structural complexity of the collagen network calls for specific statistical descriptors. Moreover, the low signal-to-noise ratio of imaging techniques available for time-resolved studies rules out standard methods based on image segmentation. In this work, we develop a novel approach based on the stochastic modelling of the gel structure and on grey-tone image analysis. The method is then used to study the remodelling of a collagen matrix by migrating breast cancer-derived CAFs in a three-dimensional spheroid model of cellular invasion. Specifically, the structure of the collagen at the scale of a few microns is found to consist in regions with high fibre density separated by depleted regions, which can be thought of as aggregates and pores. The approach we develop captures this two-scale structure with a clipped Gaussian field model to describe the aggregates-and-pores large-scale structure, and a homogeneous Boolean model to describe the small-scale fibre network within the aggregates. The model parameters are identified by fitting the grey-tone histograms and correlation functions of confocal microscopy images. The method applies to unprocessed grey-tone images, and it can therefore be used with low magnification, noisy time-lapse reflectance images. When applied to the spheroid time-resolved images, the method reveals different matrix densification mechanisms for the matrix in direct contact or far from the cells

Nouveaux procédés de microscopie tridimensionnelle et algorithmes de traitement et quantification d'images pour étudier les modèles in vitro de sphéroïde associés au cancer

Recent progresses in 3D microscopy techniques revolutionise our way to study biological processes involved in cancer metastasis thanks to innovative imaging of biological models. In vitro spheroid model consists in an aggregate of one or several cell types labelled using fluorescent dyes or constructs and embedded in fibrillar type I collagen matrix. Studying spheroid invasion properties involves the use of various microscopy techniques and the development of adapted processing and quantification algorithms

Impact of cancer associated fibroblasts-derived cathepsin B on breast cancer progression

Tumors arise in a complex ecosystem gover ned by interactions established between cancer cells and the microenvironment. This one is constituted on one side by a multitude of different non-cancerous cell types (e.g.: stromal and immune cells) and on the other side by components of the extracellular matrix. During cancerogenesis fibroblasts are activated and differenciated into cancer associated fibroblasts (CAFs). Nevertheless, the precise functions of CAFs in cancer progression are not fully understood. Among proteases implicated in both ECM remodeling and cancer progression, cathepsin B (Ctsb), a lysosomial cystein protease, has been detected in cancer cells and in tumor-associated macrophages. Ctsb expression is associated with a poor prognosis in breast cancer patients. However, the contribution of CAF-derived Ctsb to tumor progression is unknown. By using the MMTV-PyMT mouse model of breast cancer, our preliminary data reveal that CAFs express Ctsb at higher levels than cancer cells. Our data show that Ctsb deficiency impairs the capacity of CAFs to interact with collagen fibers and strongly diminishes the migration of CAFs in a 3D spheroid model. Further more, we demonstrate that the invasion of Ctsb-/- CAFs is restored upon addition of conditioned medium collected from WT CAFs but Further more, the invasion of Ctsb-/- CAFs is restored upon addition of conditioned medium collected from wild-type (WT) CAFs but also by durotaxis or by deletion of Cathepsin Z (Ctsz). Collectively these data suggest that Ctsb represents a key regulator of the complex cross-talk established between CAFs, the ECM and cancer cells

Impact of cancer associated fibroblasts-derived cathepsin B on breast cancer progression

Tumors arise in a complex ecosystem gover ned by interactions established between cancer cells and the microenvironment. This one is constituted on one side by a multitude of different non-cancerous cell types (e.g.: stromal and immune cells) and on the other side by components of the extracellular matrix. During cancerogenesis fibroblasts are activated and differenciated into cancer associated fibroblasts (CAFs). Nevertheless, the precise functions of CAFs in cancer progression are not fully understood. Among proteases implicated in both ECM remodeling and cancer progression, cathepsin B (Ctsb), a lysosomial cystein protease, has been detected in cancer cells and in tumor-associated macrophages. Ctsb expression is associated with a poor prognosis in breast cancer patients. However, the contribution of CAF-derived Ctsb to tumor progression is unknown. By using the MMTV-PyMT mouse model of breast cancer, our preliminary data reveal that CAFs express Ctsb at higher levels than cancer cells. Our data show that Ctsb deficiency impairs the capacity of CAFs to interact with collagen fibers and strongly diminishes the migration of CAFs in a 3D spheroid model. Further more, we demonstrate that the invasion of Ctsb-/- CAFs is restored upon addition of conditioned medium collected from WT CAFs but Further more, the invasion of Ctsb-/- CAFs is restored upon addition of conditioned medium collected from wild-type (WT) CAFs but also by durotaxis or by deletion of Cathepsin Z (Ctsz). Collectively these data suggest that Ctsb represents a key regulator of the complex cross-talk established between CAFs, the ECM and cancer cells

Safety of Fully Automatic External Defibrillation by Untrained Lay Rescuers in the Presence of a Bystander

OBJECTIVE: Automated external defibrillators (AEDs) are becoming increasingly available in public places to be used by citizens in case of cardiac arrest. Most AEDs are semi-automatic (SAEDs), but some are fully automatic (FAEDs) and there is ongoing debate and concern that they may lead to inadvertent shocks to rescuers or bystanders because the timing of the shock is not controlled by the rescuer. We therefore compared the behaviour of untrained citizens using an FAED or an SAED in a simulated cardiac arrest scenario. DESIGN AND PARTICIPANTS: One hundred and seventy-six laypeople were randomised to use an FAED or an SAED (Lifepak CR+, Medtronic, Redmond, USA) in a simulated cardiac arrest scenario on a manikin (Ambu, Denmark) where a bystander was touching the victim's upper arm. Each rescuer's performance was recorded on video and analysed afterwards using a modified Cardiff Score. The rescuer or the bystander was considered unsafe if either of them touched the victim during shock delivery. RESULTS: Eleven cases could not be analysed because of technical problems. Fifteen participants violated the protocol making further analysis impossible. Of the remaining 150 participants, 68 used the FAED and 82 used the SAED. The rescuers were safe in 97/150 (65%) cases, without a difference between FAED and SAED. The bystander was safe in 25/68 (37%) cases in the FAED group versus 19/82 (23%) in the SAED group (p=0.07). Combined safety of both rescuer and bystander was observed in 23/68 (34%) cases in the FAED group versus 15/82 (18%) in the SAED group (p=0.03). CONCLUSIONS: Safety was not compromised when untrained lay rescuers used an FAED compared with an SAED. The observation of overall safer behaviour by FAED users in the presence of bystanders may be related to the additional instructions provided by the FAED, and the reduced interaction of the rescuer with the bystander when using the SAED

A membrane-type- matrix metalloproteinase (MT1-MMP) - discoidin domain receptor 1 axis regulates collagen-induced apoptosis in breast cancer cells

During tumour dissemination, invading breast carcinoma cells become confronted with a reactive stroma, a type I collagen-rich environment endowed with anti-proliferative and proapoptotic properties. To develop metastatic capabilities, tumour cells must acquire the capacity to cope with this novel microenvironment. How cells interact with and respond to their microenvironment during cancer dissemination remains poorly understood. To address the impact of type I collagen on the fate of tumour cells, human breast carcinoma MCF-7 cells were cultured within three-dimensional type I collagen gels (3D COL1). Using this experimental model, we demonstrate that membrane type-1 matrix metalloproteinase (MT1-MMP), a proteinase overexpressed in many aggressive tumours, promotes tumour progression by circumventing the collagen-induced up-regulation of BIK, a pro-apoptotic tumour suppressor, and hence apoptosis. A transcriptomic analysis was performed to decipher the molecular mechanisms regulating 3D COL1-induced apoptosis in human breast cancer cells. Control and MT1-MMP expressing MCF-7 cells were cultured on two-dimensional plastic plates or within 3D COL1 and a global transcriptional time-course analysis was performed. Shifting the cells from plastic plates to 3D COL1 activated a complex reprogramming of genes implicated in various biological processes. Bioinformatic analysis revealed a 3D COL1-mediated alteration of key cellular functions including apoptosis, cell proliferation, RNA processing and cytoskeleton remodelling. By using a panel of pharmacological inhibitors, we identified discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase specifically activated by collagen, as the initiator of 3D COL1-induced apoptosis. Our data support the concept that MT1-MMP contributes to the inactivation of the DDR1-BIK signalling axis through the cleavage of collagen fibres and/or the alteration of DDR1 receptor signalling unit, without triggering drastic alterations of the transcriptome of MCF-7 cells

Nouveaux procédés de microscopie tridimensionnelle et algorithmes de traitement et quantification d'images pour étudier les modèles biologiques associés au cancer

Recent progresses in 3D microscopy technologies revolutionise our way to study fundamental biological processes involved in cancer metastasis. We considered several in vitro and in vivo biological models, used various microscopy techniques and developed adapted processing, characterisation and quantification algorithms to study migration, invasion, angiogenesis lymphangiogenesis processes by analysing cell-to-cell and cell-to-matrix interactions