Cancer Research

UNLABELLED: Clinical management of melanomas with NRAS mutations is challenging. Targeting MAPK signaling is only beneficial to a small subset of patients due to resistance that arises through genetic, transcriptional, and metabolic adaptation. Identification of targetable vulnerabilities in NRAS-mutated melanoma could help improve patient treatment. Here, we used multiomics analyses to reveal that NRAS-mutated melanoma cells adopt a mesenchymal phenotype with a quiescent metabolic program to resist cellular stress induced by MEK inhibition...

Extensive studies have focused on the misregulation of individual miRNAs in cancer. More recently, mutations in the miRNA biogenesis and processing machinery have been implicated in several malignancies. Such mutations can lead to global miRNA misregulation, which may promote many of the well-known hallmarks of cancer. Interestingly, recent evidence also suggests that oncogenic KRAS mutations act in part by modulating the activity of members of the miRNA regulatory pathway. Here, we highlight the vital role mutations in the miRNA core machinery play in promoting malignant transformation...

Alternative RNA splicing is an essential mechanism linking genetic variation to human diseases. While the signals from genome-wide association studies(GWAS) have been linked to expression quantitative trait loci(eQTLs) in previous studies,further work is needed to better elucidate the relationship to other genetic regulatory mechanisms,such as splicing QTLs(sQTLs). Here,we performed a genome-wide sQTL analysis to identify variants that might affect RNA splicing in 1,010 non-small cell lung cancer(NSCLC) samples from The Cancer Genome Atlas(TCGA)...

Cancer stem-like cells (CSCs) play pivotal roles in both chemoresistance and recurrence of many cancer types, including urothelial bladder cancer (UBC). In addition to intrinsic signaling pathways, extracellular cues from the tumor microenvironment (TME) are indispensable for the maintenance of CSCs. To better understand the mechanisms involved in TME-mediated generation and support of UBC CSCs, we focused on the role of cancer-associated fibroblasts (CAFs) in this study. Overexpression of miR-146a-5p in CAFs promoted CAF-to-UBC cell interactions, cancer stemness, and chemoresistance to treatment with gemcitabine and cisplatin...

N6-Methyladenosine (m6A) is the most prevalent internal modification among mammalian mRNAs. Recent studies show that m6A methyltransferases, METTL3 and METTL14, play important roles in bladder carcinoma (BLCA). However, the impact of YTHDF2, a crucial m6A reader, has yet to be investigated. Here, we found that YTHDF2 is frequently up-regulated at both the RNA and protein level in bladder cancers. Functionally, YTHDF2 promotes the proliferation and tumor growth of BLCA cells in vitro and in vivo, respectively...

The DAB2IP tumor suppressor encodes a RAS GTPase-activating protein (RASGAP). Accordingly, DAB2IP has been shown to be mutated or suppressed in tumor types that typically lack RAS mutations. However, here we report that DAB2IP is mutated or selectively silenced in the vast majority of KRAS and BRAF mutant CRCs. In this setting, DAB2IP loss promoted tumor development by activating wild-type H- and NRAS proteins, which was surprisingly required to achieve robust activation of RAS effector pathways in KRAS-mutant tumors...

Pancreatic neuroendocrine tumors (PanNETs) are a group of rare sporadic malignant tumors in the pancreas. MEN1 is the most frequently mutated gene in PanNETs. The MEN1-encoded protein is a typical tumor suppressor that forms a complex with epigenetic and transcription factors and is an attractive target for therapeutic interventions for PanNET patients. A better understanding of the regulation of MEN1 protein expression in PanNETs could identify strategies for targeting MEN1. Here, we found that the neddylation pathway and DCAF7-mediated ubiquitination regulated MEN1 protein expression...

Epitranscriptomic RNA modifications constitute a critical gene regulatory component that can affect cancer progression. Among these, the RNA N4-acetylcytidine (ac4C) modification, which is mediated by the ac4C writer N-acetyltransferase 10 (NAT10), regulates the stabilization of mRNA. Here, we identified that the ac4C modification is induced upon cisplatin treatment and correlates with chemoresistance in bladder cancer (BCa). Both in vitro and in vivo, NAT10 promoted cisplatin chemoresistance in BCa cells by enhancing DNA damage repair...

Fluorescence-guided surgery is set to play a pivotal role in the intraoperative management of pediatric tumors. Short-wave infrared imaging (SWIR) has advantages over conventional near-infrared I (NIR-I) imaging with reduced tissue scattering and autofluorescence. Here, two NIR-I dyes (IRDye800CW and IR12), with long tails emitting in the SWIR range, were conjugated with a clinical-grade anti-GD2 monoclonal antibody (Dinutuximab-beta) to compare NIR-I and SWIR imaging for neuroblastoma surgery. A first-of-its-kind multispectral NIR-I/SWIR fluorescence imaging device was constructed to allow an objective comparison between the two imaging windows...

Sex-driven immune differences can affect tumor progression and the landscape of the tumor microenvironment. Deeper understanding of these differences in males and females can inform patient selection to improve sex-optimized immunotherapy treatments. In this study, single-cell RNA-sequencing and protein analyses uncovered a subpopulation of myeloid cells in pancreatic lesions associated with an immune-excluded tumor phenotype and effector T-cell exhaustion exclusively in females. This myeloid subpopulation was positively correlated with poor survival and genetic signatures of M2-like macrophages and T-cell exhaustion in females...

Cancer-associated fibroblasts (CAFs) are a major cell type in the stroma of solid tumors and can exert both tumor-promoting and tumor-restraining functions. CAF heterogeneity is frequently observed in pancreatic ductal adenocarcinoma (PDAC), a tumor characterized by a dense and hypoxic stroma that features myofibroblastic CAFs (myCAFs) and inflammatory CAFs (iCAFs) that are thought to have opposing roles in tumor progression. While CAF heterogeneity can be driven in part by tumor cell-produced cytokines, other determinants shaping CAF identity and function are largely unknown...

Tumor metastasis is a complex process. A better understanding of the mechanistic underpinnings of the metastatic cascade could uncover approaches to better prevent and target metastases. Here, we integrated transcriptomic profiling in primary esophageal squamous cell carcinoma (ESCC) and matched lymph node metastatic tissues and genome-wide CRISPR/Cas9 functional screening to identify the key drivers of cancer metastasis. Anoctamin 1 (ANO1) expression was found to be elevated in primary tumors and further increased in metastatic tissues...

Induction of ferroptosis, a recently defined form of nonapoptotic cell death caused by iron-dependent lipid peroxidation, has emerged as an anti-cancer strategy. Erastin is a ferroptosis activator that promotes cell death that not only depends on the depletion of cellular cysteine but also relies on mitochondrial oxidative metabolism of glutamine. Here, we demonstrate that ASS1, a key enzyme involved in the urea cycle, plays a crucial role in ferroptosis resistance. Loss of ASS1 increased the sensitivity of non-small cell lung cancer (NSCLC) cells to erastin in vitro and decreased tumor growth in vivo...

Quiescent cancer stem cells (CSCs) are resistant to conventional anti-cancer treatments and have been shown to contribute to disease relapse after therapy in some cancer types. The identification and characterization of quiescent CSCs could facilitate the development of strategies to target this cell population and block recurrence. Here, we established a syngeneic orthotopic transplantation model in mice based on intestinal cancer organoids to profile quiescent CSCs. Single-cell transcriptomic analysis of the primary tumors formed in vivo revealed that conventional Lgr5high intestinal CSCs comprise both actively and slowly cycling subpopulations, the latter of which specifically expresses the cyclin-dependent kinase inhibitor p57...

The ubiquitin-proteasome system (UPS) is responsible for up to 90% of intracellular protein degradation. Alterations in UPS are extensively involved in the development and advancement of malignant pathologies. Thus, the components of the UPS can become potential targets for cancer therapeutics. KPC1 is an E3 ubiquitin ligase component of the UPS that regulates key pathways and processes in cancer. KPC1 sustains the ubiquitination of cytoplasmic p27, determining its elimination and transition between cell cycle phases...

The lysine demethylase LSD1 (also called KDM1A) plays important roles in promoting multiple malignancies including both hematologic cancers and solid tumors. LSD1 targets histone and non-histone proteins and can function as a transcriptional corepressor and coactivator. LSD1 has been reported to act as a coactivator of androgen receptor (AR) in prostate cancer (PCa) and to regulate the AR cistrome via demethylation of its pioneer factor FOXA1. A deeper understanding of the key oncogenic programs targeted by LSD1 could help stratify PCa patients for treatment with LSD1 inhibitors, which are currently under clinical investigation...

The tumor microenvironment is necessary for recapitulating the intratumoral heterogeneity and cell state plasticity found in human primary glioblastoma (GBM). Conventional models do not accurately recapitulate the spectrum of GBM cellular states, hindering elucidation of the underlying transcriptional regulation of these states. Using our Glioblastoma Cerebral Organoid (GLICO) model, we profiled the chromatin accessibility of 28,040 single cells in five patient-derived glioma stem cell lines. Integration of paired epigenomes and transcriptomes within the context of tumor-normal host cell interactions was used to probe the gene-regulatory networks underlying individual GBM cellular states in a way not readily possible in other in vitro models...

Nucleophosmin (NPM1) is frequently mutated in acute myeloid leukemia, and NPM1 expression is elevated in several cancer types. NPM1 is a multifunctional oligomeric protein involved in numerous cellular functions that include participating in liquid-liquid phase separation, ribosome biogenesis, chaperoning of histones, and modulation of transcription. In this review, we discuss the underappreciated role of NPM1 in DNA damage repair, specifically Polη-mediated translesion synthesis, base excision, and homologous recombination and highlight the therapeutic potential of NPM1 targeting in cancer treatment...

Cysteine plays critical roles in cellular biosynthesis, enzyme catalysis, and redox metabolism. The intracellular cysteine pool can be sustained by cystine uptake or de novo synthesis from serine and homocysteine. Demand for cysteine is increased during tumorigenesis for generating glutathione to deal with oxidative stress. While cultured cells have been shown to be highly dependent on exogenous cystine for proliferation and survival, how diverse tissues obtain and use cysteine in vivo has not been characterized...

In lung adenocarcinoma (LUAD), loss-of-function mutations in the splicing factor RBM10 frequently co-occur with oncogenic EGFR mutations. A detailed understanding of the functional consequences and therapeutic impact of RBM10 loss in EGFR-mutant LUAD could help identify more effective treatment strategies. Here, analysis of LUAD datasets indicated that RBM10 mutations are mutually exclusive with mutations in the tumor suppressor gene TP53. In an EGFR-driven LUAD mouse model, lung-specific ablation of either Rbm10 or Trp53 similarly promoted tumor development, leading to overlapping gene expression changes enriched in cancer-related pathways...