Abstract
Fasting exerts beneficial effects in mice and humans, including protection from chemotherapy toxicity. To explore the involved mechanisms, we collect blood from humans and mice before and ...after 36 or 24 hours of fasting, respectively, and measure lipid composition of erythrocyte membranes, circulating micro RNAs (miRNAs), and RNA expression at peripheral blood mononuclear cells (PBMCs). Fasting coordinately affects the proportion of polyunsaturated versus saturated and monounsaturated fatty acids at the erythrocyte membrane; and reduces the expression of insulin signaling-related genes in PBMCs. When fasted for 24 hours before and 24 hours after administration of oxaliplatin or doxorubicin, mice show a strong protection from toxicity in several tissues. Erythrocyte membrane lipids and PBMC gene expression define two separate groups of individuals that accurately predict a differential protection from chemotherapy toxicity, with important clinical implications. Our results reveal a mechanism of fasting associated with lipid homeostasis, and provide biomarkers of fasting to predict fasting-mediated protection from chemotherapy toxicity.
Abstract
The Pan-Cancer Analysis of Whole Genomes (PCAWG) project generated a vast amount of whole-genome cancer sequencing resource data. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole ...Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumor types, we provide a user’s guide to the five publicly available online data exploration and visualization tools introduced in the PCAWG marker paper. These tools are ICGC Data Portal, UCSC Xena, Chromothripsis Explorer, Expression Atlas, and PCAWG-Scout. We detail use cases and analyses for each tool, show how they incorporate outside resources from the larger genomics ecosystem, and demonstrate how the tools can be used together to understand the biology of cancers more deeply. Together, the tools enable researchers to query the complex genomic PCAWG data dynamically and integrate external information, enabling and enhancing interpretation.
In the current model of the pathogenesis of polycythemia vera (PV), the JAK2V617F mutation arises in hematopoietic stem cells (HSCs) that maintain the disease, while erythroid precursor populations ...expand, resulting in excessive red blood cell production. We examined the role of these specific cell populations using a conditional Jak2V617F knockin murine model. We demonstrate that the most immature long-term (LT) HSCs are solely responsible for initiating and maintaining the disease in vivo and that Jak2V617F mutant LT-HSCs dominate hematopoiesis over time. When we induced Jak2V617F expression in erythropoietin receptor expressing precursor cells, the mice developed elevated hematocrit, expanded erythroid precursors, and suppressed erythropoietin levels. However, the disease phenotype was significantly attenuated compared with mice expressing Jak2V617F in LT-HSCs. In addition to developing a PV phenotype, all mice transplanted with Jak2V617F LT-HSCs underwent myelofibrotic transformation over time. These findings recapitulate the development of post-PV myelofibrosis in human myeloproliferative neoplasms. In aggregate, these results demonstrate the distinct roles of LT-HSCs and erythroid precursors in the pathogenesis of PV.
We present a simple but powerful procedure to extract Gene Ontology (GO) terms that are significantly over- or under-represented in sets of genes within the context of a genome-scale experiment (DNA ...microarray, proteomics, etc.). Said procedure has been implemented as a web application, FatiGO, allowing for easy and interactive querying. FatiGO, which takes the multiple-testing nature of statistical contrast into account, currently includes GO associations for diverse organisms (human, mouse, fly, worm and yeast) and the TrEMBL/Swissprot GOAnnotations@EBI correspondences from the European Bioinformatics Institute. Availability: http://fatigo.bioinfo.cnio.es
An open question in aggressive cancers such as melanoma is how malignant cells can shift the immune system to pro-tumorigenic functions. Here we identify midkine (MDK) as a melanoma-secreted driver ...of an inflamed, but immune evasive, microenvironment that defines poor patient prognosis and resistance to immune checkpoint blockade. Mechanistically, MDK was found to control the transcriptome of melanoma cells, allowing for coordinated activation of nuclear factor-κB and downregulation of interferon-associated pathways. The resulting MDK-modulated secretome educated macrophages towards tolerant phenotypes that promoted CD8
T cell dysfunction. In contrast, genetic targeting of MDK sensitized melanoma cells to anti-PD-1/anti-PD-L1 treatment. Emphasizing the translational relevance of these findings, the expression profile of MDK-depleted tumors was enriched in key indicators of a good response to immune checkpoint blockers in independent patient cohorts. Together, these data reveal that MDK acts as an internal modulator of autocrine and paracrine signals that maintain immune suppression in aggressive melanomas.
The ongoing COVID-19 pandemic is one of the biggest health challenges of recent decades. Among the causes of mortality triggered by SARS-CoV-2 infection, the development of an inflammatory "cytokine ...storm" (CS) plays a determinant role. Here, we used transcriptomic data from the bronchoalveolar lavage fluid (BALF) of COVID-19 patients undergoing a CS to obtain gene-signatures associated to this pathology. Using these signatures, we interrogated the Connectivity Map (CMap) dataset that contains the effects of over 5000 small molecules on the transcriptome of human cell lines, and looked for molecules which effects on transcription mimic or oppose those of the CS. As expected, molecules that potentiate immune responses such as PKC activators are predicted to worsen the CS. In addition, we identified the negative regulation of female hormones among pathways potentially aggravating the CS, which helps to understand the gender-related differences in COVID-19 mortality. Regarding drugs potentially counteracting the CS, we identified glucocorticoids as a top hit, which validates our approach as this is the primary treatment for this pathology. Interestingly, our analysis also reveals a potential effect of MEK inhibitors in reverting the COVID-19 CS, which is supported by in vitro data that confirms the anti-inflammatory properties of these compounds.
Epidemiological studies indicate that patients suffering from Alzheimer's disease have a lower risk of developing lung cancer, and suggest a higher risk of developing glioblastoma. Here we explore ...the molecular scenarios that might underlie direct and inverse co-morbidities between these diseases. Transcriptomic meta-analyses reveal significant numbers of genes with inverse patterns of expression in Alzheimer's disease and lung cancer, and with similar patterns of expression in Alzheimer's disease and glioblastoma. These observations support the existence of molecular substrates that could at least partially account for these direct and inverse co-morbidity relationships. A functional analysis of the sets of deregulated genes points to the immune system, up-regulated in both Alzheimer's disease and glioblastoma, as a potential link between these two diseases. Mitochondrial metabolism is regulated oppositely in Alzheimer's disease and lung cancer, indicating that it may be involved in the inverse co-morbidity between these diseases. Finally, oxidative phosphorylation is a good candidate to play a dual role by decreasing or increasing the risk of lung cancer and glioblastoma in Alzheimer's disease.
Comorbidity is a medical condition attracting increasing attention in healthcare and biomedical research. Little is known about the involvement of potential molecular factors leading to the emergence ...of a specific disease in patients affected by other conditions. We present here a disease interaction network inferred from similarities between patients' molecular profiles, which significantly recapitulates epidemiologically documented comorbidities. Furthermore, we identify disease patient-subgroups that present different molecular similarities with other diseases, some of them opposing the general tendencies observed at the disease level. Analyzing the generated patient-subgroup network, we identify genes involved in such relations, together with drugs whose effects are potentially associated with the observed comorbidities. All the obtained associations are available at the disease PERCEPTION portal (http://disease-perception.bsc.es).
Despite extensive insights into the underlying genetics and biology of acute myeloid leukemia (AML), overall survival remains poor and new therapies are needed. We found that casein kinase 1 α ...(Csnk1a1), a serine-threonine kinase, is essential for AML cell survival in vivo. Normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected by shRNA-mediated knockdown of Csnk1a1. To identify downstream mediators of Csnk1a1 critical for leukemia cells, we performed an in vivo pooled shRNA screen and gene expression profiling. We found that Csnk1a1 knockdown results in decreased Rps6 phosphorylation, increased p53 activity, and myeloid differentiation. Consistent with these observations, p53-null leukemias were insensitive to Csnk1a1 knockdown. We further evaluated whether D4476, a casein kinase 1 inhibitor, would exhibit selective antileukemic effects. Treatment of leukemia stem cells (LSCs) with D4476 showed highly selective killing of LSCs over normal HSPCs. In summary, these findings demonstrate that Csnk1a1 inhibition causes reduced Rps6 phosphorylation and activation of p53, resulting in selective elimination of leukemia cells, revealing Csnk1a1 as a potential therapeutic target for the treatment of AML.
FBXW7 is one of the most frequently mutated tumor suppressors, deficiency of which has been associated with resistance to some anticancer therapies. Through bioinformatics and genome‐wide CRISPR ...screens, we here reveal that FBXW7 deficiency leads to multidrug resistance (MDR). Proteomic analyses found an upregulation of mitochondrial factors as a hallmark of FBXW7 deficiency, which has been previously linked to chemotherapy resistance. Despite this increased expression of mitochondrial factors, functional analyses revealed that mitochondria are under stress, and genetic or chemical targeting of mitochondria is preferentially toxic for FBXW7‐deficient cells. Mechanistically, the toxicity of therapies targeting mitochondrial translation such as the antibiotic tigecycline relates to the activation of the integrated stress response (ISR) in a GCN2 kinase‐dependent manner. Furthermore, the discovery of additional drugs that are toxic for FBXW7‐deficient cells showed that all of them unexpectedly activate a GCN2‐dependent ISR regardless of their accepted mechanism of action. Our study reveals that while one of the most frequent mutations in cancer reduces the sensitivity to the vast majority of available therapies, it renders cells vulnerable to ISR‐activating drugs.
Synopsis
FBXW7 mutations are among the most frequent in cancer. This study reveals that while FBXW7 deficiency renders cells resistant to most chemotherapies, it also leads to mitochondrial stress and renders cancer cells vulnerable to drugs activating the Integrated Stress Response (ISR).
FBXW7 deficiency leads to a broad multidrug resistant (MDR) phenotype.
Loss of FBXW7 increases mitochondrial factors expression, yet functional analyses reveal that these mitochondria are under stress.
Genetically or chemically targeting mitochondria is toxic for FBXW7 deficient cells.
Despite the broad MDR associated to FBXW7 deficiency, FBXW7 loss sensitizes cancer cells to drugs activating the ISR through GCN2.
Several kinase inhibitors used in the clinic exert toxicity through activation of a GCN2‐dependent ISR.
FBXW7 mutations are among the most frequent in cancer. This study reveals that while FBXW7 deficiency renders cells resistant to most chemotherapies, it also leads to mitochondrial stress and renders cancer cells vulnerable to drugs activating the integrated stress response (ISR).
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