Extension of Wavenumber Domain Focusing for spotlight COSMO-SkyMed SAR Data

In this work we describe a method to handle curved orbits in wavenumber domain focusing algorithm for high-resolution SAR data acquired by Low Earth Orbit satellites using spotlight mode. The stand..

Density-dependent regulation of ferroptosis depends on accumulation of extracellular metabolites

Ferroptosis is a type of cell death induced by the production of toxic iron-dependent lipid radicals. The use of ferroptosis in cancer therapy as a potential metastasis-suppressor mechanism has been gaining increasing attention in the last few years. Multiple cancer cell states, including those bearing a RAS mutation and those holding a mesenchymal phenotype, as well as dedifferentiated and drug-resistance cells, are sensitive to ferroptosis inducers. A critical tissue property which determines sensitivity to ferroptosis is cell density. For many years it has been known that cells seeded at high densities are more resistant, compared to those seeded at low densities, to what we know today as ferroptosis. However, whether and how the tissue microenvironment can regulate ferroptosis sensitivity in cancer cells remains poorly understood. This concept is important in light of the potential use of ferroptosis-inducing compounds as anti-cancer drugs, because it predicts if cancer cell arrangement could influence the response to therapy. Thus, shedding light on this mechanism could open new avenues to the precise utilisation or prevention of ferroptosis for therapeutic uses. In this study we show that ferroptosis can be regulated non-cell-autonomously. Cell crowding actively changes the composition of the extracellular environment by releasing important metabolites that in turn regulate cells susceptibility to ferroptosis. We found lactic acid, which provides ferroptosis resistance through the rewiring of the intracellular metabolism, to be the most enriched metabolite secreted by cells. Metabolomics analysis suggested that lactic acid empowers the glycerol shuttle in order to regenerate the mitochondrial ubiquinol pool, protecting cells from ferroptosis. This finding suggests the potential mechanism by which cell density provides protection from ferroptosis. Moreover, we demonstrated that this cell media conditioning also occurs when cancer cells are grown as spheroids, by co-culture of cancer cells with activated fibroblasts or even cell-autonomously by inhibition of lactate secretion. Finally, we found that such metabolic preconditioning can prime the ability of breast cancer cells to form lung metastasis. We think that this study could provide a new insight into how cancer cells can escape ferroptosis induction depending on their metabolic interactions and rewiring.Ferroptosis is a type of cell death induced by the production of toxic iron-dependent lipid radicals. The use of ferroptosis in cancer therapy as a potential metastasis-suppressor mechanism has been gaining increasing attention in the last few years. Multiple cancer cell states, including those bearing a RAS mutation and those holding a mesenchymal phenotype, as well as dedifferentiated and drug-resistance cells, are sensitive to ferroptosis inducers. A critical tissue property which determines sensitivity to ferroptosis is cell density. For many years it has been known that cells seeded at high densities are more resistant, compared to those seeded at low densities, to what we know today as ferroptosis. However, whether and how the tissue microenvironment can regulate ferroptosis sensitivity in cancer cells remains poorly understood. This concept is important in light of the potential use of ferroptosis-inducing compounds as anti-cancer drugs, because it predicts if cancer cell arrangement could influence the response to therapy. Thus, shedding light on this mechanism could open new avenues to the precise utilisation or prevention of ferroptosis for therapeutic uses. In this study we show that ferroptosis can be regulated non-cell-autonomously. Cell crowding actively changes the composition of the extracellular environment by releasing important metabolites that in turn regulate cells susceptibility to ferroptosis. We found lactic acid, which provides ferroptosis resistance through the rewiring of the intracellular metabolism, to be the most enriched metabolite secreted by cells. Metabolomics analysis suggested that lactic acid empowers the glycerol shuttle in order to regenerate the mitochondrial ubiquinol pool, protecting cells from ferroptosis. This finding suggests the potential mechanism by which cell density provides protection from ferroptosis. Moreover, we demonstrated that this cell media conditioning also occurs when cancer cells are grown as spheroids, by co-culture of cancer cells with activated fibroblasts or even cell-autonomously by inhibition of lactate secretion. Finally, we found that such metabolic preconditioning can prime the ability of breast cancer cells to form lung metastasis. We think that this study could provide a new insight into how cancer cells can escape ferroptosis induction depending on their metabolic interactions and rewiring

Mitochondrial fission links ECM mechanotransduction to metabolic redox homeostasis and metastatic chemotherapy resistance.

Metastatic breast cancer cells disseminate to organs with a soft microenvironment. Whether and how the mechanical properties of the local tissue influence their response to treatment remains unclear. Here we found that a soft extracellular matrix empowers redox homeostasis. Cells cultured on a soft extracellular matrix display increased peri-mitochondrial F-actin, promoted by Spire1C and Arp2/3 nucleation factors, and increased DRP1- and MIEF1/2-dependent mitochondrial fission. Changes in mitochondrial dynamics lead to increased production of mitochondrial reactive oxygen species and activate the NRF2 antioxidant transcriptional response, including increased cystine uptake and glutathione metabolism. This retrograde response endows cells with resistance to oxidative stress and reactive oxygen species-dependent chemotherapy drugs. This is relevant in a mouse model of metastatic breast cancer cells dormant in the lung soft tissue, where inhibition of DRP1 and NRF2 restored cisplatin sensitivity and prevented disseminated cancer-cell awakening. We propose that targeting this mitochondrial dynamics- and redox-based mechanotransduction pathway could open avenues to prevent metastatic relapse