An atlas of inter- and intra-tumor heterogeneity of apoptosis competency in colorectal cancer tissue at single-cell resolution

Cancer cells’ ability to inhibit apoptosis is key to malignant transformation and limits response to therapy. Here, we performed multiplexed immunofluorescence analysis on tissue microarrays with 373 cores from 168 patients, segmentation of 2.4 million individual cells, and quantification of 18 cell lineage and apoptosis proteins. We identified an enrichment for BCL2 in immune, and BAK, SMAC, and XIAP in cancer cells. Ordinary differential equation-based modeling of apoptosis sensitivity at single-cell resolution was conducted and an atlas of inter- and intra-tumor heterogeneity in apoptosis susceptibility generated. Systems modeling at single-cell resolution identified an enhanced sensitivity of cancer cells to mitochondrial permeabilization and executioner caspase activation compared to immune and stromal cells, but showed significant inter- and intra-tumor heterogeneity.

BH3 Profiling Identifies Selective BCL-2 Dependence of Adult Early T-cell Progenitor (ETP) Subtype of Acute Lymphoblastic Leukemia (ALL) Patients

Early T-cell precursor (ETP) acute lymphoblastic leukemia (T-ALL) is a high-risk subtype of T-ALL and is associated with poor survival outcomes with chemotherapy. We previously showed that maturation stage of thymocytes distinguishes pro-survival dependencies of pediatric ETP-ALL (BCL-2 dependent) from non-ETP-ALL (BCL-XL dependent). Comparable data in adults are lacking. Our present study focuses on characterizing functional dependencies of adult ETP-ALL and T-ALL on BCL-2 family proteins. Using BH3 profiling on primary tumors, we report that similar to pediatric ALL, adult ETP-ALL is primarily dependent on BCL-2; however, unlike pediatric ALL, adult non-ETP-ALL is co-dependent on both BCL-2 and BCL-XL for survival. By measuring direct mitochondrial permeabilization and cell viability assays, we validated that BH3 profiling predicted on-target cytotoxicity of venetoclax in adult ETP-ALL and navitoclax plus venetoclax in adult T-ALL. These findings provide pre-clinical evidence for venetoclax and navitoclax as potentially efficacious combination therapy for adults with T-ALL.

An atlas of inter- and intra-tumor heterogeneity of apoptosis competency in colorectal cancer tissue at single cell resolution

Cancer cells' ability to inhibit apoptosis is key to malignant transformation and limits response to therapy. Here, we performed multiplexed immunofluorescence analysis on tissue microarrays with 373 cores from 168 patients, segmentation of 2.4 million individual cells and quantification of 20 cell lineage and apoptosis proteins. Ordinary differential equation-based modelling of apoptosis sensitivity at single cell resolution was conducted and an atlas of inter- and intra-tumor heterogeneity in apoptosis susceptibility generated. We identified an enrichment for BCL2 in immune, and BAK, SMAC and XIAP in cancer cells. ODE-based modelling at single cell resolution identified an enhanced sensitivity of cancer cells to mitochondrial permeabilization and executioner caspase activation compared to immune and stromal cells, with significant inter- and intra-tumor heterogeneity. However, we did not find increased spatial heterogeneity of apoptosis signaling in cancer cells, suggesting that such heterogeneity is an intrinsic, non-genomic property not increased by the process of malignant transformation.

Astaxanthin: The possible effects of this carotenoid on disease, inflammation and aging control. A meta-analysis

Astaxanthin (ATX), a red pigment that belongs to the xanthophyll subclass of carotenoids, has a strong antioxidant ability and can eliminate singlet oxygen (O2-) as well as hydrogen peroxide (H2O2) and lipid peroxidation. ATX can also prevent mitochondrial dysfunction by permeating and co-localizing within the mitochondria and inhibit the release of cytochrome c resulting from mitochondrial permeabilization and, thus, prevent mitochondrial-mediated apoptotic cell death. Due to its antioxidant capacity and modulating properties of cell signaling, ATX exhibits a variety of beneficial biological activities among them protection against UV damage, anti-inflammatory and immunomodulatory activity, metabolic syndrome (MS) relief, cardioprotective effects, antidiabetic activity, prevention of neuronal damage, anti-aging and anticancer activity. The aim of the present study was to evaluate what has been published about ATX in PubMed/Medline between 2020-2021. The results were distributed in four Tables as follows: Table 1-Publication types; Table 2- Proposal for evaluating the article in vivo; Table 3- Cells markers used in clinical studies in vivo; Table 4- Astaxanthin in human clinical trial. We could observe that the interest of the scientific community has been growing in relation to the benefits of ATX. The results presented in the articles evaluated in this meta-analysis showed us that AXT is already a reality as an option in treatments for various diseases, including glaucoma, heart and vascular injury, type 2 diabetes and fatty liver. We conclude that ATX may not only be a promising nutraceutical as an ally to alternative treatments of the pathologies mentioned above, but also as a powerful prophylactic in elderly individuals in prevention of diseases associated with aging.

Bcl-xL inhibits tBid and Bax via distinct mechanisms

The proteins of the Bcl-2 family are key regulators of apoptosis. They form a complex interaction network in the cytosol and in the cellular membranes, whose outcome determines mitochondrial permeabilization...

Involvement of mitophagy in cisplatin-induced cell death regulation

Mitophagy, the selective degradation of mitochondria via the autophagic pathway, is a vital mechanism of mitochondrial quality control in cells. The removal of malfunctioning or damaged mitochondria is essential for normal cellular physiology and tissue development. Stimulation of mitochondrial permeabilization and release of proapoptotic factors from the intermembrane space is an essential step in triggering the mitochondrial pathway of cell death. In this study, we analyzed the extent to which mitophagy interferes with cell death, attenuating the efficiency of cancer therapy. We show that stimulation of mitophagy suppressed cisplatin-induced apoptosis, while mitophagy inhibition stimulates apoptosis and autophagy. Suppression of mitophagy involved production of reactive oxygen species, and the fate of cell was dependent on the interplay between endoplasmic reticulum stress and autophagy.