Inverted-repeat Alu elements are the main source of drug-induced immunogenic double-stranded RNAs, which are destabilized by the RNA deaminase ADAR1, thereby limiting activation of the immune response.
Cancer at Nature Research
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Depletion of transforming growth factor-β receptor 2 (TGFBR2) in CD4+ T cells results in IL-4-dependent vascular remodelling, stopping tumour growth in a transgenic mouse model of breast cancer, suggesting that type 2 immunity could be targeted for cancer treatments.
4T-Trap, a bispecific molecule designed to recognize CD4 and bind TGF-β, blocks TGF-β signalling in T helper cells, causing interleukin-4-dependent vascular reorganization and cancer cell death in a mouse model of breast cancer.
Vestigial-like 1 is a shared targetable cancer-placenta antigen expressed by pancreatic and basal-like breast cancers
Cytotoxic T lymphocyte (CTL)-based immunotherapies can induce tumor regressions by targeting HLA class I-bound tumor-associated peptides. Here, the authors identified a peptide derived from Vestigial-like 1 (VGLL1) as a shared, potentially therapeutic CTL target expressed by multiple cancer types.
Sinha et al. demonstrate that overexpression of centrosomal protein Cep55 in mice is sufficient to cause a wide-spectrum of cancer via multiple mechanisms including hyperactivation of the Pi3k/Akt pathway, stabilized microtubules and a defective replication checkpoint response. These findings are relevant to human cancers as high CEP55 expression is associated with worse prognosis across multiple cancer types.
The relative enrichment of cancer stem cells after treatment results in tumour recurrence. Here, the authors show a mechanism where p53 induces WNT3, which increases the number of colorectal cancer stem cells following treatment of 5-fluorouracil.
Immunotherapy may exploit alternative vulnerabilities of drug resistant cells. Here, the authors show that the HLA peptide presentation landscape is heterogeneous even within one individual, hinting that a multi-peptide vaccination approach against highly conserved tumor suppressors may be needed.
Understanding the evolutionary trajectory of cancer samples may enable understanding resistance to treatment. Here, the authors used single cell sequencing of a cohort of acute myeloid leukemia tumours and identify features of linear and branching evolution in tumours.
Telomerase enzymes add telomeric repeats to the end of linear chromosomes. Here the authors reveal mechanisms by which oxidized dNTPs and therapeutic dNTPs inhibit telomerase-mediated telomere elongation.
Yubero et al. report a close connection between energy metabolism and cell stiffness in breast cancer cells, finding that healthy cell stiffness is based on ATP-driven actin polymerization, whereas in metastatic cells it is based on ATP-driven myosin II activity. They show that noninvasive cancerous cells exhibit an anomalous behavior, as their stiffness is little affected by the lack of nutrients and energy.
Amoeboid cells are associated with melanoma invasive capacity. Here, the authors show that the WNT11-FZD7-DAAM1 pathway regulates tumour-initiating potential, invasion and metastasis lead by amoeboid cells in the invasive front of melanoma tumours.
Tumor-secreted midkine modulates immune tolerance in the melanoma tumor microenvironment and determines resistance to immune checkpoint blockade.
Saliakoura et al. find that PLCγ1 is suppressed in hypoxic KRAS-mutant lung cancer cells, which impairs Ca2+ entry into the mitochondria and promotes glycolysis to enhance tumour progression.
ER-resident oxidoreductases are glycosylated and trafficked to the cell surface to promote matrix degradation by tumour cells
Ros et al. show that the ER-resident chaperone calnexin (Cnx) and its partner ERp57 are trafficked to cell surface invadosomes and induce ECM degradation, promoting tumour invasiveness.
Mutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia
Ferrando and colleagues analyze matched diagnostic and relapsed acute lymphocytic leukemia by whole-genome sequencing, and perform in vitro genome-wide CRISPR screens, to examine alterations associated with chemotherapy resistance.
Oncogenic cell growth and proliferation rely on aberrant activation of metabolic pathways, such as glucose fermentation, resulting in elevated cytosolic pH. Koch et al. implicate increased cytosolic pH as a driver for cell proliferation through the transcriptional activation of cyclin D1.
Triple-negative breast cancer is inhibited by depleting mitochondrial copper in mice.
Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA
Circulating DNA detected in plasma can be used for diagnostic purposes. Here, the authors show that the 5-hydroxymethyl cytosine biomarker from plasma-derived cell free DNA can be used to detect early stage pancreatic cancer.
A MYC and RAS co-activation signature in localized prostate cancer drives bone metastasis and castration resistance
Using lineage tracing and molecular profiling, Abate-Shen and colleagues identify a Ras and Myc co-activation signature that predicts metastasis and castration resistance in localized prostate cancer.
Yukiko Inagaki-Kawata et al. report an analysis of germline variants in breast cancer susceptibility genes in 1,995 Japanese breast cancer patients. They find that 5.1% of the patients carry germline variants in cancer-linked genes and investigate the characteristics of patients with germline mutations in BRCA1/2.
Acral melanoma occurs on the soles of the feet, palms of the hands and in nail beds. Here, the authors reports the genomic landscape of 87 acral melanomas and find that some tumors harbor a UV signature and that the tumors are diverse at the levels of mutational signatures, structural aberrations and copy number signatures.
EGFR mutations are common in non-small cell lung cancer and patients with these mutations are treated with tyrosine kinase inhibitors. Here, the authors show that EGFR mutation status can be predicted from 18F-FDG-PET/CT images, which may enable the stratification of patients for treatment.
Focal adhesion ribonucleoprotein complex proteins are major humoral cancer antigens and targets in autoimmune diseases
Atsumi et al. identify antigens to B-cell receptors isolated from gastric tumour samples. They find that focal adhesion-related protein complexes, several of which are also targets for autoimmune disease, are major humoral cancer antigens. These findings provide insights into humoral immunity in tumor environments.
Depending on the cell cycle stage, cells can repair their genome via different pathways. Here the authors reveal mechanistic insights into repair of double strand breaks induced during G1 in an error-prone manner by Pol θ-dependent and PARP1-independent alt NHEJ during the SG2/M phases of the cell cycle
Standardization and harmonization of distributed multi-center proteotype analysis supporting precision medicine studies
Distributed multi-omic digitization of clinical specimen across multiple sites is a prerequisite for turning molecular precision medicine into reality. Here, the authors show that coordinated proteotype data acquisition is feasible using standardized MS data acquisition and analysis strategies.
Manon Penco-Campillo, Yannick Comoglio et al. show that VEGFC decreases the proliferation and migration of medulloblastoma cells, as well as their ability to form pseudo vessels. Cells expressing high levels of VEGFC also form smaller tumors when subcutaneously injected into the flank of nude mice, thus highlighting a negative regulatory role for VEGFC on tumor growth.
Cryopreservation is standard protocol prior to using NK cells in immunotherapy. Here the authors show that cryopreservation substantially reduces the clinical utility of these cells owing to a defect in their motility, an effect that might account for failure to treat some cancers with NK cell immunotherapy.
Exploiting oxidative phosphorylation to promote the stem and immunoevasive properties of pancreatic cancer stem cells
Long-term cultures of pancreatic cancer stem cells (PaCSCs) are difficult to obtain. Here, the authors present a 2D culture method, based on the use of galactose, to establish cell cultures from pancreatic ductal adenocarcinoma xenotransplants enriched in PaCSCs.
Th17-inducing autologous dendritic cell vaccination promotes antigen-specific cellular and humoral immunity in ovarian cancer patients
The folate receptor alpha (FRα) is overexpressed in the majority of high-grade serous ovarian cancers and has been proposed as a candidate vaccine antigen. Here the authors report the safety and immunogenicity of Th17-inducing dendritic cells pulsed with FRα-derived epitopes in an early phase I clinical trial with ovarian cancer patients.
Genomic analysis of neuroblastoma has revealed important disease etiology. In this study, the authors assembled whole genome, exome and transcriptome data from over 700 neuroblastomas and identified molecular signatures correlated with age, and rare, potentially targetable variants overlooked in smaller cohorts.
Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation
Mutations in TP53 and hyperactivation of the PI3K/AKT pathway are the two most frequent drivers of cancer progression across multiple human tumour types. Here, the authors identify two TAp63 regulated long non-coding RNAs, TROLL-2 and TROLL-3, that connect these oncogenic pathways, thus promoting tumour and metastasis formation in a wide variety of cancer types.
This Review discusses how altered processing or activity of coding and non-coding RNAs contributes to cancer, introducing the regulation of gene expression by coding and non-coding RNA and discussing both established and emerging roles for RNAs in cancer.
The majority of individuals with cancer, notably those with breast or prostate cancer, will develop bone metastases. In this Primer, Coleman and colleagues discuss the epidemiology, pathophysiology and diagnosis of metastatic bone disease and highlight the specific treatment strategies to prevent disease progression and to manage skeletal morbidities.
In this Review, Blum et al. summarize the current knowledge on sarcomatoid renal cell carcinoma, a diagnosis characterized by the presence of sarcomatoid dedifferentiation and a poor prognosis. They discuss the origin, presentation, molecular biology and treatment of this disease.
Emerging data have revealed that nonalcoholic steatohepatitis (NASH) and fibrosis are associated with the reactivation of developmental pathways in the liver injury response. This Review describes the role of these pathways in liver development and in the pathogenesis of NASH and fibrosis.
Despite the introduction of novel therapies, lung cancer remains the leading cause of cancer-related mortality worldwide. Randomized controlled trials of low-dose CT-based lung cancer screening in high-risk populations have shown a reduction in mortality. The authors of this Review discuss these studies and present the Screening Planning and Implementation RAtionale for Lung cancer (SPIRAL), a framework to define the scope of future implementation research on lung cancer screening.
This Review summarizes current knowledge of the main gene fusions in genitourinary malignancies, discusses their growing importance in the understanding of the biology of tumours, and highlights their potential use as targets for precision medicine approaches.
Tumors are more than cancer cells — the extracellular matrix is a protein structure that organizes all tissues and is altered in cancer. Here, the authors review recent progress in understanding how the cancer cells and tumor-associated stroma cells remodel the extracellular matrix to drive tumor growth and metastasis.
This Perspective discusses how therapeutic resistance is not only driven by genetic evolution but often involves non-genetic adaptive mechanisms that are intimately linked. Acknowledging these adaptive processes will enable the development of innovative strategies to monitor and counteract non-genetic therapy resistance as well as provide novel therapeutic avenues.
Metastatic dissemination can occur early during cancer progression, yet clinically overt metastases are often not detected for many years after surgical removal of the primary tumour. In this Perspective, Klein argues that understanding the ‘invisible’ phase of metastatic colonization is necessary to explain this phenomenon and develop better therapies to prevent metastasis.
Anticancer therapies that target the HIF oxygen-sensing pathways are moving into the clinic, in particular in kidney cancer.
Deep resequencing has revealed extreme genetic variation in mitochondrial genomes at multiple levels. This heterogeneity has implications for the origins of human mitochondrial DNA mutations as well as their impact on rare and common human diseases, including cancer.
Despite several major therapeutic advances, multiple myeloma (MM) remains largely incurable, indicating a need for novel therapies. Thus, considerable research interest exists in chimeric antigen receptor (CAR) T cells targeting BCMA, which is almost universally expressed on MM cells. In this Review, the authors describe the clinical experience with anti-BCMA CAR T cells and discuss several new directions of future research that might prolong the responses of patients receiving these therapies.
Technological advances have enabled the analysis of whole genomes, leading to the identification of causal factors that present new opportunities to prevent cancer. The authors of this Review discuss relevant findings in cancer genetics and genomics from the perspective of global cancer prevention and present a conceptual framework for the translation of such findings into clinical practice and evidence-based policies.
This Review describes the interplay between host genetics, host immunity and the gut microbiome in the modulation of colorectal cancer, and discusses the role of specific bacterial species and metabolites alongside technological advances that will facilitate more in-depth investigation of the microbiome in disease.
This Review discusses the potential use of cancer-derived extracellular vesicles for cancer biomarkers and novel therapeutics, with a focus on evolving translational applications, and their roles during cancer progression.
News & Commentary
In situ metabolic labelling and targeted modulation of dendritic cells has been achieved using a hydrogel system in combination with covalent capture of antigens and adjuvants, facilitating improved tumour-specific immune response.
Mitochondrial DNA damage, metabolic disruption and aging have all been associated with cancer. These three threads are now woven together to show that aging-associated somatic mutations to mitochondrial DNA alter mitochondrial serine metabolism to support cell transformation and colon-cancer development.
The Zero Childhood Cancer Program’s multi-platform sequencing approach identified molecular alterations in 94% of a cohort of 247 pediatric patients with high-risk cancers, which has enabled more-precise diagnoses and alternative therapeutic recommendations.
Targeted small-molecule inhibition of BRAFV600E faces seemingly insurmountable obstacles in the clinic, such as rapid emergence of drug resistance. A recent study illustrates the potential of an alternative therapeutic strategy via PROTAC-mediated degradation of the oncogenic BRAF.
Cell culture media are typically selected on the basis of common laboratory practices but have major effects on the validity, reproducibility and physiological relevance of the scientific findings. We provide arguments and quantitative examples of why choosing an appropriate cell culture medium matters, particularly in metabolic studies.
Effective methods for treating retinoblastoma while preserving vision are an unmet clinical need. Subretinal delivery of a hydrogel containing T cells that secrete the cytokine IL-15 and express a chimeric antigen receptor directed at the ganglioside protein GD2 completely controls retinoblastoma in immunocompromised mice, with no obvious damage to the surrounding retina.
Cancer sequencing studies have revealed that urothelial carcinomas harbour recurrent mutations in multiple genes that control epigenetics. A major challenge for basic and clinical researchers is to convert this genetic information into biological and pathological insights, as well as to tailor novel therapeutic modalities for individual patients with bladder cancer.
An article in Advanced Healthcare Materials reports a tumour-on-a-chip platform for the high throughput-screening of cancer drugs.
Cancer has found a formidable foil in COVID-19, and this has brought to the fore the early concerns that COVID-19 could have a deeper impact on oncology patients. Two studies now provide insights into the enigma surrounding the determinants of the worsening of COVID-19 symptoms in patients with cancer.
Plastics have an integral role in our daily lives but at a considerable cost to the environment and, as we are now learning, to human health. Increased plastic exposure has been linked to compromised endocrine function, reproductive health and semen quality and, potentially, urological cancers. However, the long-term consequences of plastic exposure remain to be seen.
Melanoma Patient Network Europe has a lot of experience in connecting researchers with patients, including organizing patient-led conferences. The group’s founder explains how productive interaction can be transformative to research.
Sequencing the genomes of individual skin cells called melanocytes has revealed a rich landscape of DNA changes. These insights shed light on the origins of melanoma, an aggressive type of cancer.
Methods & Protocols
Reference-free deconvolution, visualization and interpretation of complex DNA methylation data using DecompPipeline, MeDeCom and FactorViz
This protocol describes a comprehensive computational pipeline for reference-free deconvolution of bulk DNA methylation data, including data preprocessing, confounder adjustment, feature selection, and visualization and interpretation of the results.
This protocol summarizes the various approaches available to derive organoids from cancer patients and use these for screening of possible treatments. An optimized protocol for using head and neck cancer organoids is also described.
This protocol describes how to engraft human cancer cells in immunocompromised adult zebrafish. The fish are first adapted to 37 °C, followed by intraperitoneal or periocular muscle transplantation of xenograft cells and fluorescence imaging.
Formalin fixation and paraffin embedding (FFPE) of human tissue is a central strategy for preserving pathological specimens. This protocol describes how to process these specimens for spatially resolved LC-MS by laser-capture microdissection.
This protocol describes the isolation and 3D culture of organoids from fresh murine or human primary and metastatic tumor tissue and provides instructions for real-time imaging, genetic and microenvironmental manipulation and molecular analysis.
This protocol describes how to build and implant an in vivo compression device that simulates the solid mechanical forces exerted on the mouse brain by a growing tumor. Standard transparent cranial windows are adapted to include a turnable screw for controlled compression/decompression.
Encapsulation and release of living tumor cells using hydrogels with the hybridization chain reaction
An aptamer-trigger-clamped hybridization chain reaction (atcHCR) captures tumor cells in a protective, porous, 3D DNA hydrogel. Subsequent addition of ATP facilitates release of the tumor cells for use in downstream assays.
In this protocol, mice are inoculated with two separate tumors derived from the same cell line. One tumor is removed and assessed before treatment; the other is used to assess the effect of treatment.
Here, the authors present standardized computational pipelines tailored specifically to the analysis of cancer genome sequencing data from mice. The protocol enables detection of single-nucleotide variants, indels, copy-number variations, loss of heterozygosity and complex rearrangements such as those of chromothripsis.
Circulating cell-free DNA (cfDNA) is shed in the bloodstream by normal and tumor cells and is a valuable liquid biopsy tool. This protocol describes a low-input approach to enrich methylated DNA fragments from cfDNA and prepare sequencing libraries.
A marker-independent lineage-tracing system to quantify clonal dynamics and stem cell functionality in cancer tissue
Here, the authors describe a marker-independent, unbiased lineage-tracing method to quantitatively assess stem cell function and tumor growth dynamics in unperturbed tumor tissue.
The percentage of cancer neoantigens that are spontaneously recognized by T cells is generally very low. This protocol describes how CD8+ T cells from healthy donors can be used for enhanced targeting of these neoantigens.