journal
https://read.qxmd.com/read/36449563/single-cell-analysis-in-lung-adenocarcinoma-implicates-rna-editing-in-cancer-innate-immunity-and-patient-prognosis
#1
JOURNAL ARTICLE
Tracey W Chan, Jack P Dodson, Jaron Arbet, Paul C Boutros, Xinshu Xiao
RNA editing modifies single nucleotides of RNAs, regulating primary protein structure and protein abundance. In recent years, the diversity of proteins and complexity of gene regulation associated with RNA editing dysregulation has been increasingly appreciated in oncology. Large-scale shifts in editing have been observed in bulk tumors across various cancer types. However, RNA editing in single cells and individual cell types within tumors has not been explored. By profiling editing in single cells from lung adenocarcinoma biopsies, we found that the increased editing trend of bulk lung tumors was unique to cancer cells...
November 30, 2022: Cancer Research
https://read.qxmd.com/read/36449018/a-pro-regenerative-environment-triggers-premalignant-to-malignant-transformation-of-senescent-hepatocytes
#2
JOURNAL ARTICLE
Anna Wuestefeld, Viktoriia Iakovleva, Shirlyn Xue Ling Yap, Agnes Bee Leng Ong, Daniel Q Huang, Timothy Wai Ho Shuen, Han Chong Toh, Yock Young Dan, Lars Zender, Torsten Wuestefeld
Unfortunately, available liver cancer treatments are associated with modest survival advantage. The biggest factor improving survival is early detection, but the current understanding of early transformation events is limited. Therefore, we set up a model to study these early events and investigated the relationship of premalignant, senescent hepatocytes, a regenerative environment, and the influence of secreted factors on liver tumorigenesis. Oncogene-induced senescence (OIS) was triggered in a subset of mouse hepatocytes, which under normal conditions, are eliminated by immunosurveillance...
November 30, 2022: Cancer Research
https://read.qxmd.com/read/36413141/plk1-inhibitors-and-abiraterone-synergistically-disrupt-mitosis-and-kill-cancer-cells-of-disparate-origin-independently-of-androgen-receptor-signaling
#3
JOURNAL ARTICLE
Jesse C Patterson, Andreas Varkaris, Peter J P Croucher, Maya Ridinger, Susan Dalrymple, Mannan Nouri, Fang Xie, Shohreh Varmeh, Oliver Jonas, Matthew A Whitman, Sen Chen, Saleh Rashed, Lovemore Makusha, Jun Luo, John T Isaacs, Mark G Erlander, David J Einstein, Steven P Balk, Michael B Yaffe
Abiraterone is a standard treatment for metastatic castrate-resistant prostate cancer (mCRPC) that slows disease progression by abrogating androgen synthesis and antagonizing the androgen receptor (AR). Here we report that inhibitors of the mitotic regulator polo-like kinase-1 (Plk1), including the clinically active third-generation Plk1 inhibitor onvansertib, synergizes with abiraterone in vitro and in vivo to kill a subset of cancer cells from a wide variety of tumor types in an androgen-independent manner...
November 22, 2022: Cancer Research
https://read.qxmd.com/read/36409827/loss-of-nf1-in-melanoma-confers-sensitivity-to-syk-kinase-inhibition
#4
JOURNAL ARTICLE
Cara Abecunas, Christopher E Whitehead, Elizabeth K Ziemke, Douglas G Baumann, Christy L Frankowski-McGregor, Judith S Sebolt-Leopold, Mohammad Fallahi-Sichani
NF1 loss of function (LoF) mutations are frequent in melanoma and drive hyperactivated RAS and tumor growth. NF1-LoF melanoma cells, however, do not show consistent sensitivity to individual MEK, ERK, or PI3K/mTOR inhibitors. To identify more effective therapeutic strategies for treating NF1-LoF melanoma, we performed a targeted kinase inhibitor screen. A tool compound named MTX-216 was highly effective in blocking NF1LoF melanoma growth in vitro and in vivo. Single cell analysis indicated that drug-induced cytotoxicity was linked to effective co-suppression of proliferation marker Ki-67 and ribosomal protein S6 phosphorylation...
November 21, 2022: Cancer Research
https://read.qxmd.com/read/36409826/aberrant-l-fucose-accumulation-and-increased-core-fucosylation-are-metabolic-liabilities-in-mesenchymal-glioblastoma
#5
JOURNAL ARTICLE
Valentina Pieri, Alberto L Gallotti, Denise Drago, Manuela Cominelli, Ilaria Pagano, Valentina Conti, Silvia Valtorta, Angela Coliva, Sara Lago, Daniela Michelatti, Luca Massimino, Federica Ungaro, Laura Perani, Antonello Spinelli, Antonella Castellano, Andrea Falini, Alessio Zippo, Pietro L Poliani, Rosa Maria Moresco, Annapaola Andolfo, Rossella Galli
Glioblastoma (GBM) is a common and deadly form of brain tumor in adults. Dysregulated metabolism in GBM offers an opportunity to deploy metabolic interventions as precise therapeutic strategies. To identify the molecular drivers and the modalities by which different molecular subgroups of GBM exploit metabolic rewiring to sustain tumor progression, we interrogated the transcriptome, the metabolome, and the glycoproteome of human subgroup-specific GBM sphere-forming cells (GSCs). L-fucose abundance and core fucosylation activation were elevated in mesenchymal (MES) compared to proneural (PN) GSCs; this pattern was retained in subgroup-specific xenografts and in subgroup-affiliated human patient samples...
November 21, 2022: Cancer Research
https://read.qxmd.com/read/36409824/jak-stat-signaling-in-inflammatory-breast-cancer-enables-chemotherapy-resistant-cell-states
#6
JOURNAL ARTICLE
Laura E Stevens, Guillermo Peluffo, Xintao Qiu, Daniel Temko, Anne Fassl, Zheqi Li, Anne Trinh, Marco Seehawer, Bojana Jovanovic, Masa Aleckovic, Callahan M Wilde, Renee C Geck, Shaokun Shu, Natalie L Kingston, Nicholas W Harper, Vanessa Almendro, Alanna L Pyke, Shawn B Egri, Malvina Papanastasiou, Kendell Clement, Ningxuan Zhou, Sarah Walker, Jacqueline Salas, So Yeon Park, David A Frank, Alexander Meissner, Jacob D Jaffe, Piotr Sicinski, Alex Toker, Franziska Michor, Henry W Long, Beth A Overmoyer, Kornelia Polyak
Inflammatory breast cancer (IBC) is a difficult-to-treat disease with poor clinical outcomes due to high risk of metastasis and resistance to treatment. In breast cancer, CD44+CD24- cells possess stem cell-like features and contribute to disease progression, and we previously described a CD44+CD24-pSTAT3+ breast cancer cell subpopulation that is dependent on JAK2/STAT3 signaling. Here we report that CD44+CD24- cells are the most frequent cell-type in IBC and are commonly pSTAT3+. Combination of JAK2/STAT3 inhibition with paclitaxel decreased IBC xenograft growth more than either agent alone...
November 21, 2022: Cancer Research
https://read.qxmd.com/read/36409821/the-oncogenic-foxl2-c134w-mutation-is-a-key-driver-of-granulosa-cell-tumors
#7
JOURNAL ARTICLE
Elena Llano, Anne Laure Todeschini, Natalia Felipe-Medina, María D Corte-Torres, Yazmine B Condezo, Manuel Sanchez-Martin, Sara López-Tamargo, Aurora Astudillo, Xose S Puente, Alberto M Pendas, Reiner A Veitia
Adult-type granulosa cell tumors (AGCTs) are the most common type of malignant ovarian sex cord-stromal tumors. Most AGCTs carry the somatic variant c.402C>G (p.C134W) affecting the transcription factor FOXL2. Germline dominant variants in FOXL2 are responsible for blepharophimosis syndrome, which is characterized by underdevelopment of the eyelid. In this work, we generated a mouse model harboring the C134W variant of FOXL2 to evaluate in vivo the poorly understood oncogenic role of FOXL2. The mutation was dominant regarding eyelid hypoplasia, reminiscent of blepharophimosis syndrome...
November 21, 2022: Cancer Research
https://read.qxmd.com/read/36398965/transcriptional-antagonism-by-cdk8-inhibition-improves-therapeutic-efficacy-of-mek-inhibitors
#8
JOURNAL ARTICLE
Clare F Malone, Minjee Kim, Gabriela Alexe, Kathleen Engel, Alexandra B Forman, Amanda Robichaud, Amy Saur Conway, Amy Goodale, Ashleigh Meyer, Delan Khalid, Allen Thayakumar, John M Hatcher, Nathanael S Gray, Federica Piccioni, Kimberly Stegmaier
Aberrant RAS/MAPK signaling is a common driver of oncogenesis that can be therapeutically targeted with clinically approved MEK inhibitors. Disease progression on single agent MEK inhibitors is common, however, and combination therapies are typically required to achieve significant clinical benefit in advanced cancers. Here we focused on identifying MEK inhibitor-based combination therapies in neuroblastoma with mutations that activate the RAS/MAPK signaling pathway, which are rare at diagnosis but frequent in relapsed neuroblastoma...
November 18, 2022: Cancer Research
https://read.qxmd.com/read/36378845/immunogenetic-determinants-of-susceptibility-to-head-and-neck-cancer-in-the-million-veteran-program-cohort
#9
JOURNAL ARTICLE
Yanhong Liu, Jennifer R Kramer, Vlad C Sandulache, Robert Yu, Guojun Li, Liang Chen, Zenab I Yusuf, Yunling Shi, Saiju Pyarajan, Spyros Tsavachidis, Li Jiao, Michelle L Mierzwa, Elizabeth Chiao, Yvonne M Mowery, Andrew Shuman, Sanjay Shete, Andrew G Sikora, Donna L White
Increasing rates of human papillomavirus (HPV)-driven oropharyngeal cancer (OPC) have largely offset declines in tobacco-associated head and neck squamous cell carcinoma (HNSCC) at non-OPC sites. Host immunity is an important modulator of HPV infection, persistence, and clearance, and also of immune evasion in both virally- and non-virally-driven cancers. However, the association between collective known cancer-related immune gene variants and HNSCC susceptibility has not been fully characterized. Here, we conducted a genetic association study in the multi-ethnic Veterans Affairs Million Veteran Program cohort, evaluating 16,050 variants in 1,576 immune genes in 4,012 HNSCC cases (OPC=1,823, Non-OPC=2,189) and 16,048 matched controls...
November 15, 2022: Cancer Research
https://read.qxmd.com/read/36354374/mex3a-mediates-p53-degradation-to-suppress-ferroptosis-and-facilitate-ovarian-cancer-tumorigenesis
#10
JOURNAL ARTICLE
Cheng-Kai Wang, Tzu-Jou Chen, Grace Y T Tan, Fang-Pei Chang, Samyuktha Sridharan, Chen-Hsin Albert Yu, Yen-Hou Chang, Yi-Jen Chen, Li-Tzu Cheng, Wendy W Hwang-Verslues
Epithelial ovarian cancer (OC) is a highly heterogeneous and malignant female cancer with an overall low survival rate. Mutations in p53 are prevalent in the major OC histotype, high-grade serous ovarian carcinoma (HGSOC), while p53 mutations are much less frequent in other OC subtypes, particularly in ovarian clear cell carcinoma (OCCC). Advanced stage OCCC with wildtype (WT) p53 has a worse prognosis and increased drug resistance, metastasis, and recurrence than HGSOC. The mechanisms responsible for driving the aggressiveness of WT p53-expressing OC remain poorly understood...
November 10, 2022: Cancer Research
https://read.qxmd.com/read/36354368/genome-wide-analysis-of-rare-haplotypes-associated-with-breast-cancer-risk
#11
JOURNAL ARTICLE
Fan Wang, Wonjong Moon, William Letsou, Yadav Sapkota, Zhaoming Wang, Cindy Im, Jessica L Baedke, Leslie Robison, Yutaka Yasui
Numerous common genetic variants have been linked to breast cancer (BCa) risk, but they only partially explain the total BCa heritability. Inference from Nordic population-based twin data indicates rare high-risk loci as the chief determinant of BCa risk. Here, we use haplotypes, rather than single variants, to identify rare high-risk loci for BCa. With computationally-phased genotypes from 181,034 white British women in the UK Biobank, a genome-wide haplotype-BCa association analysis was conducted using sliding windows of 5-500 consecutive array-genotyped variants...
November 10, 2022: Cancer Research
https://read.qxmd.com/read/36353752/atm-regulates-differentiation-of-myofibroblastic-cancer-associated-fibroblasts-and-can-be-targeted-to-overcome-immunotherapy-resistance
#12
JOURNAL ARTICLE
Massimiliano Mellone, Klaudia Piotrowska, Giulia Venturi, Lija James, Aleksandra Bzura, Maria A Lopez, Sonya James, Chuan Wang, Matthew J Ellis, Christopher J Hanley, Josephine F Buckingham, Kerry L Cox, Gareth Hughes, Viia Valge-Archer, Emma V King, Stephen A Beers, Vincent Jaquet, George D D Jones, Natalia Savelyeva, Emre Sayan, Jason L Parsons, Stephen Durant, Gareth J Thomas
Myofibroblastic cancer-associated fibroblast (myoCAF)-rich tumors generally contain few T cells and respond poorly to immune-checkpoint blockade. Although myoCAFs are associated with poor outcome in most solid tumors, the molecular mechanisms regulating myoCAF accumulation remain unclear, limiting the potential for therapeutic intervention. Here, we identify ataxia-telangiectasia mutated (ATM) as a central regulator of the myoCAF phenotype. Differentiating myofibroblasts in vitro and myoCAFs cultured ex vivo display activated ATM signaling, and targeting ATM genetically or pharmacologically could suppress and reverse differentiation...
November 10, 2022: Cancer Research
https://read.qxmd.com/read/36351074/genetic-ancestry-inference-from-cancer-derived-molecular-data-across-genomic-and-transcriptomic-platforms
#13
JOURNAL ARTICLE
Pascal Belleau, Astrid Deschênes, Nyasha Chambwe, David A Tuveson, Alexander Krasnitz
Genetic ancestry-oriented cancer research requires the ability to perform accurate and robust genetic ancestry inference from existing cancer-derived data, including whole exome sequencing, transcriptome sequencing, and targeted gene panels, very often in the absence of matching cancer-free genomic data. Here we examined the feasibility and accuracy of computational inference of genetic ancestry relying exclusively on cancer-derived data. A data synthesis framework was developed to optimize and assess the performance of the ancestry inference for any given input cancer-derived molecular profile...
November 9, 2022: Cancer Research
https://read.qxmd.com/read/36351060/immunotherapeutic-targeting-and-pet-imaging-of-dll3-in-small-cell-neuroendocrine-prostate-cancer
#14
JOURNAL ARTICLE
Jonathan Chou, Emily A Egusa, Sinan Wang, Michelle L Badura, Fei Lee, Anil P Bidkar, Jun Zhu, Tanushree Shenoy, Kai Trepka, Troy M Robinson, Veronica Steri, Jiaoti Huang, Yuzhuo Wang, Eric J Small, Emily Chan, Bradley A Stohr, Alan Ashworth, Brant Delafontaine, Sylvie Rottey, Keegan S Cooke, Nooshin Hashemi Sadraei, Brian Yu, Mark Salvati, Julie M Bailis, Felix Y Feng, Robert R Flavell, Rahul Aggarwal
Effective treatments for de novo and treatment-emergent small cell/neuroendocrine (t-SCNC) prostate cancer represent an unmet need for this disease. Using metastatic biopsies from advanced cancer patients, we demonstrate that delta-like ligand 3 (DLL3) is expressed in de novo and t-SCNC and is associated with reduced survival. We develop a positron-emission tomography (PET) agent, [89Zr]-DFO-DLL3-scFv, that detects DLL3 levels in mouse SCNC models. In multiple patient-derived xenograft models, AMG 757 (tarlatamab), a half-life-extended bispecific T cell engager (BiTE®) immunotherapy that redirects CD3-positive T cells to kill DLL3-expressing cells, exhibited potent and durable anti-tumor activity...
November 9, 2022: Cancer Research
https://read.qxmd.com/read/36346366/combination-therapies-with-cdk4-6-inhibitors-to-treat-kras-mutant-pancreatic-cancer
#15
JOURNAL ARTICLE
Craig M Goodwin, Andrew M Waters, Jennifer E Klomp, Sehrish Javaid, Kirsten L Bryant, Clint A Stalnecker, Kristina Drizyte-Miller, Bjoern Papke, Runying Yang, Amber M Amparo, Irem Ozkan-Dagliyan, Elisa Baldelli, Valerie Calvert, Mariaelena Pierobon, Jessica A Sorrentino, Andrew P Beelen, Natalie Bublitz, Mareen Lüthen, Kris C Wood, Emanuel F Petricoin, Christine Sers, Autumn J McRee, Adrienne D Cox, Channing J Der
Mutational loss of CDKN2A (encoding p16INK4A) tumor suppressor function is a key genetic step that complements activation of KRAS in promoting the development and malignant growth of pancreatic ductal adenocarcinoma (PDAC). However, pharmacologic restoration of p16INK4A function with inhibitors of CDK4 and CDK6 (CDK4/6) has shown limited clinical efficacy in PDAC. Here, we found that concurrent treatment with both a CDK4/6 inhibitor (CDK4/6i) and an ERK MAPK inhibitor (ERKi) synergistically suppresses the growth of PDAC cell lines and organoids by cooperatively blocking CDK4/6i-induced compensatory upregulation of ERK, PI3K, anti-apoptotic signaling, and MYC expression...
November 8, 2022: Cancer Research
https://read.qxmd.com/read/36318118/mitochondrial-uncoupling-induces-epigenome-remodeling-and-promotes-differentiation-in-neuroblastoma
#16
JOURNAL ARTICLE
Haowen Jiang, Rachel L Greathouse, Sarah Jane Tiche, Man Zhao, Bo He, Yang Li, Albert M Li, Balint Forgo, Michaela Yip, Allison Li, Moriah Shih, Selene Banuelos, Meng-Ning Zhou, Joshua J Gruber, Erinn B Rankin, Zhen Hu, Hiroyuki Shimada, Bill Chiu, Jiangbin Ye
The Warburg effect is the major metabolic hallmark of cancer. According to Warburg himself, the consequence of the Warburg effect is cell dedifferentiation. Therefore, reversing the Warburg effect might be an approach to restore cell differentiation in cancer. In this study, we used a mitochondrial uncoupler, niclosamide ethanolamine (NEN), to activate mitochondrial respiration, which induced neural differentiation in neuroblastoma cells. NEN treatment increased the nicotinamide adenine dinucleotide (NAD)+/NADH and pyruvate/lactate ratios and also the α-ketoglutarate (α-KG)/2- hydroxyglutarate (2-HG) ratio...
November 1, 2022: Cancer Research
https://read.qxmd.com/read/36318117/gene-fusion-detection-and-characterization-in-long-read-cancer-transcriptome-sequencing-data-with-fusionseeker
#17
JOURNAL ARTICLE
Yu Chen, Yiqing Wang, Weisheng Chen, Zhengzhi Tan, Yuwei Song, N/A Human Genome Structural Variation Consortium, Herbert Chen, Zechen Chong
Gene fusions are prevalent in a wide array of cancer types with different frequencies. Long-read transcriptome sequencing technologies, such as PacBio, Iso-Seq, and Nanopore direct RNA sequencing, provide full-length transcript sequencing reads, which could facilitate detection of gene fusions. In this work, we developed a method, FusionSeeker, to comprehensively characterize gene fusions in long-read cancer transcriptome data and reconstruct accurate fused transcripts from raw reads. FusionSeeker identified gene fusions in both exonic and intronic regions, allowing comprehensive characterization of gene fusions in cancer transcriptomes...
November 1, 2022: Cancer Research
https://read.qxmd.com/read/36318106/atf3-reprograms-the-bone-marrow-niche-in-response-to-early-breast-cancer-transformation
#18
JOURNAL ARTICLE
Milena Perrone, Claudia Chiodoni, Mara Lecchi, Laura Botti, Barbara Bassani, Annamaria Piva, Elena Jachetti, Matteo Milani, Daniele Lecis, Elda Tagliabue, Paolo Verderio, Sabina Sangaletti, Mario P Colombo
Cancer is a systemic disease able to reprogram the bone marrow (BM) niche towards a pro-tumorigenic state. The impact of cancer on specific BM subpopulations can qualitatively differ according the signals released by the tumor, which can vary based on the tissue of origin. Using a spontaneous model of mammary carcinoma, we identified BM mesenchymal stem cells (MSCs) as the first sensors of distal cancer cells and key mediators of BM reprogramming. Through the release of IL1B, BM MSCs induced transcriptional up-regulation and nuclear translocation of the activating transcription factor 3 (ATF3) in hematopoietic stem cells...
November 1, 2022: Cancer Research
https://read.qxmd.com/read/36306422/kdm6a-loss-recruits-tumor-associated-neutrophils-and-promotes-neutrophil-extracellular-trap-formation-in-pancreatic-cancer
#19
JOURNAL ARTICLE
Jing Yang, Lin Jin, Hong Sun Kim, Feng Tian, Zhujun Yi, Karan Bedi, Mats Ljungman, Marina Pasca di Magliano, Howard Crawford, Jiaqi Shi
Lysine (K)-specific demethylase 6A (KDM6A) is a frequently mutated tumor suppressor gene in pancreatic ductal adenocarcinoma (PDAC). However, the impact of KDM6A loss on the PDAC tumor immune microenvironment is not known. This study used a genetically engineered, pancreas-specific Kdm6a knockout (KO) PDAC mouse model and human PDAC tissue samples to demonstrate that KDM6A loss correlates with increased tumor-associated neutrophils and neutrophil extracellular traps (NET) formation, which are known to contribute to PDAC progression...
October 28, 2022: Cancer Research
https://read.qxmd.com/read/36287637/global-dna-methylation-analysis-of-cancer-associated-fibroblasts-reveals-extensive-epigenetic-rewiring-linked-with-runx1-upregulation-in-breast-cancer-stroma
#20
JOURNAL ARTICLE
Coral Halperin, Joschka Hey, Dieter Weichenhan, Yaniv Stein, Shimrit Mayer, Pavlo Lutsik, Christoph Plass, Ruth Scherz-Shouval
Cancer cells recruit and rewire normal fibroblasts in their microenvironment to become protumorigenic cancer-associated fibroblasts (CAF). These CAFs are genomically stable, yet their transcriptional programs are distinct from those of their normal counterparts. Transcriptional regulation plays a major role in this reprogramming, but the extent to which epigenetic modifications of DNA also contribute to the rewiring of CAF transcription is not clear. Here we address this question by dissecting the epigenetic landscape of breast CAFs...
October 26, 2022: Cancer Research
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