Explore the vast range of titles available.

Mammalian hosts constantly interact with diverse exogenous microbes, but only a subset of the microbes manage to colonize due to selective colonization resistance exerted by host genetic factors as well as the native microbiota of the host. An important question in microbial ecology and medical science is if such colonization resistance can discriminate closely related microbial species, or even closely related strains of the same species. Using human-mouse fecal microbiota transplantation and metagenomic shotgun sequencing, we reconstructed colonization patterns of human fecal microbes in mice with different genotypes (C57BL6/J vs. NSG) and with or without an intact gut microbiota. We found that mouse genotypes and the native mouse gut microbiota both exerted different selective pressures on exogenous colonizers: human fecal Bacteroides successfully established in the mice gut, however, different species of Bacteroides selectively enriched under different gut conditions, potentially due to a multitude of functional differences, ranging from versatility in nutrient acquisition to stress responses. Additionally, different clades of Bacteroides cellulosilyticus strains were selectively enriched in different gut conditions, suggesting that the fitness of conspecific microbial strains in a novel host environment could differ.

Malignant pleural mesothelioma (MPM) has relatively ineffective first/second-line therapy for advanced disease and only 18% five-year survival for early disease. Drug-induced mitochondrial priming measured by dynamic BH3 profiling identifies efficacious drugs in multiple disease settings. We use high throughput dynamic BH3 profiling (HTDBP) to identify drug combinations that prime primary MPM cells derived from patient tumors, which also prime patient derived xenograft (PDX) models. A navitoclax (BCL-xL/BCL-2/BCL-w antagonist) and AZD8055 (mTORC1/2 inhibitor) combination demonstrates efficacy in vivo in an MPM PDX model, validating HTDBP as an approach to identify efficacious drug combinations. Mechanistic investigation reveals AZD8055 treatment decreases MCL-1 protein levels, increases BIM protein levels, and increases MPM mitochondrial dependence on BCL-xL, which is exploited by navitoclax. Navitoclax treatment increases dependency on MCL-1 and increases BIM protein levels. These findings demonstrate that HTDBP can be used as a functional precision medicine tool to rationally construct combination drug regimens in MPM and other cancers. Malignant pleural mesothelioma (MPM) is an aggressive malignancy with few effective treatment options available. Here, the authors use dynamic BH3 profiling to measure drug-induced mitochondrial priming and identify AZD8055 and navitoclax as a pro-apoptotic drug combination in ex vivo and preclinical MPM models.

Epithelial-to-mesenchymal transition (EMT) is associated with tumor initiation, metastasis, and drug resistance. However, the mechanisms underlying these associations are largely unknown. We studied several tumor types to identify the source of EMT gene expression signals and a potential mechanism of resistance to immuno-oncology treatment. Across tumor types, EMT-related gene expression was strongly associated with expression of stroma-related genes. Based on RNA sequencing of multiple patient-derived xenograft models, EMT-related gene expression was enriched in the stroma versus parenchyma. EMT-related markers were predominantly expressed by cancer-associated fibroblasts (CAFs), cells of mesenchymal origin which produce a variety of matrix proteins and growth factors. Scores derived from a 3-gene CAF transcriptional signature ( COL1A1 , COL1A2 , COL3A1 ) were sufficient to reproduce association between EMT-related markers and disease prognosis. Our results suggest that CAFs are the primary source of EMT signaling and have potential roles as biomarkers and targets for immuno-oncology therapies.

How cancer cells adapt to evade the therapeutic effects of drugs targeting oncogenic drivers is poorly understood. Here we report an epigenetic mechanism leading to the adaptive resistance of triple-negative breast cancer (TNBC) to fibroblast growth factor receptor (FGFR) inhibitors. Prolonged FGFR inhibition suppresses the function of BRG1-dependent chromatin remodelling, leading to an epigenetic state that derepresses YAP-associated enhancers. These chromatin changes induce the expression of several amino acid transporters, resulting in increased intracellular levels of specific amino acids that reactivate mTORC1. Consistent with this mechanism, addition of mTORC1 or YAP inhibitors to FGFR blockade synergistically attenuated the growth of TNBC patient-derived xenograft models. Collectively, these findings reveal a feedback loop involving an epigenetic state transition and metabolic reprogramming that leads to adaptive therapeutic resistance and provides potential therapeutic strategies to overcome this mechanism of resistance. Li et al. define an adaptive resistance mechanism against FGFR inhibitor treatment in breast cancer attributed to loss of BRG1 chromatin recruitment, reactivation of YAP-dependent enhancers and upregulation of amino acid-induced mTORC1 activity.

Key Points Nuclear morphology is often altered in cancer. Irregularity in nuclear contours is a feature used by pathologists in diagnostic cytology. The nuclear envelope provides a specialized microenvironment within the nucleus. It is also the site where a series of protein–protein interactions take place to connect the cytoskeleton to the interior of the nucleus. Constituents of the nuclear envelope — lamins, nuclear pore complexes and lipid membranes — have key roles in several processes that affect tumour cell biology and response to therapy. Changes in the abundance or the function of components of the nuclear envelope in tumour cells can cause the occurrence of dysmorphic nuclei and can deregulate cell migration, intracellular signalling, DNA repair, cell division and gene expression. Tracking the abundance of molecular components of the nuclear envelope environment and enhanced methods to visualize changes at the nuclear envelope could potentially be used for the prognostic assessment of cancer patients. Aberrant nuclear morphology is already used as a diagnostic criterion for cancer, but why is the nucleus deformed in cancer cells? This Review discusses how components of the nuclear envelope and the adjoining lamina are deregulated in cancer cells and the consequences of this change in cell morphology. Because of the association between aberrant nuclear structure and tumour grade, nuclear morphology is an indispensible criterion in the current pathological assessment of cancer. Components of the nuclear envelope environment have central roles in many aspects of cell function that affect tumour development and progression. As the roles of the nuclear envelope components, including nuclear pore complexes and nuclear lamina, are being deciphered in molecular detail there are opportunities to harness this knowledge for cancer therapeutics and biomarker development. In this Review, we summarize the progress that has been made in our understanding of the nuclear envelope and the implications of changes in this environment for cancer biology.

Drug tolerance is an acute defence response preceding a fully drug-resistant state and tumour relapse; however, there are few therapeutic agents targeting drug tolerance in the clinic. Here we show that miR-147b initiates a reversible state of tolerance to the epidermal growth factor receptor (EGFR) inhibitor osimertinib in non-small-cell lung cancer. With miRNA-seq analysis, we find that miR-147b is the most upregulated microRNA in osimertinib-tolerant and EGFR -mutated lung cancer cells. Whole-transcriptome analysis of single-cell-derived clones reveals a link between osimertinib tolerance and pseudohypoxia responses irrespective of oxygen levels. Further metabolomics and genetic studies demonstrate that osimertinib tolerance is driven by miR-147b-mediated repression of VHL and succinate dehydrogenase, which are linked to the tricarboxylic acid cycle and pseudohypoxia pathways. Finally, pretreatment with a miR-147b inhibitor delays osimertinib-associated drug tolerance in patient-derived 3D structures. This link between miR-147b and the tricarboxylic acid cycle may provide promising targets for preventing tumour relapse. Relapsed disease after conventional cancer treatments is an obstacle in epidermal growth factor receptor (EGFR)-based targeted therapy. Here the authors show that tolerance to the EGFR inhibitor osimertinib in non-small-cell lung cancer is mediated by the effects of miR-147b on the tricarboxylic acid cycle and pseudohypoxia pathways, which can be manipulated with a miR-147b inhibitor.

Collateral lethality occurs when loss of a gene/protein renders cancer cells dependent on its remaining paralog. Combining genome-scale CRISPR/Cas9 loss-of-function screens with RNA sequencing in over 900 cancer cell lines, we found that cancers of nervous system lineage, including adult and pediatric gliomas and neuroblastomas, required the nuclear kinase vaccinia-related kinase 1 (VRK1) for their survival in vivo. VRK1 dependency was inversely correlated with expression of its paralog VRK2. VRK2 knockout sensitized cells to VRK1 loss, and conversely, VRK2 overexpression increased cell fitness in the setting of VRK1 loss. DNA methylation of the VRK2 promoter was associated with low VRK2 expression in human neuroblastomas and adult and pediatric gliomas. Mechanistically, depletion of VRK1 reduced barrier-to-autointegration factor phosphorylation during mitosis, resulting in DNA damage and apoptosis. Together, these studies identify VRK1 as a synthetic lethal target in VRK2 promoter-methylated adult and pediatric gliomas and neuroblastomas.

DNA lesions that block replication are a primary cause of rearrangements, mutations, and lethality in all cells. After ultraviolet (UV)-induced DNA damage in Escherichia coli, replication recovery requires RecA and several other recF pathway proteins. To characterize the mechanism by which lesion-blocked replication forks recover, we used two-dimensional agarose gel electrophoresis to show that replication-blocking DNA lesions induce a transient reversal of the replication fork in vivo. The reversed replication fork intermediate is stabilized by RecA and RecF and is degraded by the RecQ-RecJ helicase-nuclease when these proteins are absent. We propose that fork regression allows repair enzymes to gain access to the replication-blocking lesion, allowing processive replication to resume once the blocking lesion is removed.

DNA lesions that arrest replication can lead to rearrangements, mutations, or lethality when not processed accurately. After UV-induced DNA damage in Escherichia coli, RecA and several recF pathway proteins are thought to process arrested replication forks and ensure that replication resumes accurately. Here, we show that the RecJ nuclease and RecQ helicase, which partially degrade the nascent DNA at blocked replication forks, are required for the rapid recovery of DNA synthesis and prevent the potentially mutagenic bypass of UV lesions. In the absence of RecJ, or to a lesser extent RecQ, the recovery of replication is significantly delayed, and both the recovery and cell survival become dependent on translesion synthesis by polymerase V. The RecJ-mediated processing is proposed to restore the region containing the lesion to a form that allows repair enzymes to remove the blocking lesion and DNA synthesis to resume. In the absence of nascent DNA processing, polymerase V can synthesize past the lesion to prevent lethality, although this occurs with slower kinetics and a higher frequency of mutagenesis.

Uterine carcinoma (UC) is the most common gynecologic malignancy in the United States. TP53 mutant UCs cause a disproportionate number of deaths due to limited therapies for these tumors and the lack of mechanistic understanding of their fundamental vulnerabilities. Here we sought to understand the functional and therapeutic relevance of TP53 mutations in UC. We functionally profiled targetable TP53 dependent DNA damage repair and cell cycle control pathways in a panel of TP53 mutant UC cell lines and patient-derived organoids. There were no consistent defects in DNA damage repair pathways. Rather, most models demonstrated dependence on defective G2/M cell cycle checkpoints and subsequent upregulation of Aurora kinase-LKB1-p53-AKT signaling in the setting of baseline mitotic defects. This combination makes them sensitive to Aurora kinase inhibition. Resistant lines demonstrated an intact G2/M checkpoint, and combining Aurora kinase and WEE1 inhibitors, which then push these cells through mitosis with Aurora kinase inhibitor-induced spindle defects, led to apoptosis in these cases. Overall, this work presents Aurora kinase inhibitors alone or in combination with WEE1 inhibitors as relevant mechanism driven therapies for TP53 mutant UCs. Context specific functional assessment of the G2/M checkpoint may serve as a biomarker in identifying Aurora kinase inhibitor sensitive tumors.