journal
https://read.qxmd.com/read/38885312/single-stranded-dna-gap-accumulation-is-a-functional-biomarker-for-usp1-inhibitor-sensitivity
#21
JOURNAL ARTICLE
Alexandre André B A da Costa, Ozge Somuncu, Ramya Ravindranathan, Sirisha Mukkavalli, David B Martignetti, Huy Nguyen, Yuqing Jiao, Benjamin P Lamarre, Golbahar Sadatrezaei, Lisa Moreau, Joyce Liu, Divya R Iyer, Jean-Bernard Lazaro, Geoffrey I Shapiro, Kalindi Parmar, Alan D D'Andrea
Recent studies suggest that PARP inhibitors and POLQ inhibitors confer synthetic lethality in BRCA1-deficient tumors by accumulation of single-stranded DNA (ssDNA) gaps at replication forks. Loss of USP1, a deubiquitinating enzyme, is also synthetic lethal with BRCA1 deficiency, and USP1 inhibitors are now undergoing clinical development for these cancers. Here, we show that USP1 inhibitors also promote the accumulation of ssDNA gaps during replication in BRCA1-deficient cells, and this phenotype correlates with the drug sensitivity...
June 17, 2024: Cancer Research
https://read.qxmd.com/read/38885294/transient-differentiation-state-plasticity-occurs-during-acute-lymphoblastic-leukemia-initiation
#22
JOURNAL ARTICLE
Vera M Poort, Rico Hagelaar, Markus J van Roosmalen, Laurianne Trabut, Jessica G C A M Buijs-Gladdines, Bram van Wijk, Jules Meijerink, Ruben van Boxtel
Leukemia is characterized by oncogenic lesions that result in a block of differentiation while phenotypic plasticity is retained. A better understanding of how these two phenomena arise during leukemogenesis in humans could help inform diagnosis and treatment strategies. Here, we leveraged the well-defined differentiation states during T-cell development to pinpoint the initiation of T-cell acute lymphoblastic leukemia (T-ALL), an aggressive form of childhood leukemia, and study the emergence of phenotypic plasticity...
June 17, 2024: Cancer Research
https://read.qxmd.com/read/38885087/a-multimodal-drug-diet-immunotherapy-combination-restrains-melanoma-progression-and-metastasis
#23
JOURNAL ARTICLE
Nicole Oatman, Mruniya V Gawali, Sunny Congrove, Roman Caceres, Abitha Sukumaran, Nishtha Gupta, Narmadha Murugesan, Priyanka Arora, Sri Vidhya Subramanian, Kwangmin Choi, Zalfa Abdel-Malek, Julie A Reisz, Daniel Stephenson, Ravi Amaravadi, Pankaj Desai, Angelo D'Alessandro, Kakajan Komurov, Biplab Dasgupta
The genetic landscape of cancer cells can lead to specific metabolic dependencies for tumor growth. Dietary interventions represent an attractive strategy to restrict the availability of key nutrients to tumors. In this study, we identified that growth of a subset of melanoma was severely restricted by a rationally designed combination therapy of a stearoyl-CoA desaturase (SCD) inhibitor with an isocaloric low-oleic acid diet. Despite its importance in oncogenesis, SCD underwent monoallelic co-deletion along with PTEN on chromosome 10q in about 47...
June 17, 2024: Cancer Research
https://read.qxmd.com/read/38862269/ku70-binding-to-yap-alters-parp1-ubiquitination-to-regulate-genome-stability-and-tumorigenesis
#24
JOURNAL ARTICLE
Yinyin Shu, Xiaoni Jin, Mintao Ji, Zhisen Zhang, Xiuxiu Wang, Haisheng Liang, Shuangshuang Lu, Shuai Dong, Yiping Lin, Yuhan Guo, Qiuyu Zhuang, Yuhong Wang, Zhe Lei, Lingchuan Guo, Xuanyu Meng, Guangming Zhou, Wensheng Zhang, Lei Chang
YAP is a central player in cancer development with functions extending beyond its recognized role in cell growth regulation. Recent work has identified a link between YAP/TAZ and the DNA damage response. Here, we investigated the mechanistic underpinnings of the crosstalk between DNA damage repair and YAP activity. Ku70, a key component of the non-homologous end joining pathway to repair DNA damage, engaged in a dynamic competition with TEAD4 for binding to YAP, limiting the transcriptional activity of YAP...
June 11, 2024: Cancer Research
https://read.qxmd.com/read/38861367/serine-depletion-promotes-anti-tumor-immunity-by-activating-mitochondrial-dna-mediated-cgas-sting-signaling
#25
JOURNAL ARTICLE
Suchandrima Saha, Monisankar Ghosh, Jinyu Li, Asher Wen, Lorenzo Galluzzi, Luis A Martinez, David C Montrose
Serine is critical for supporting cancer metabolism, and depriving malignant cells of this non-essential amino acid exerts anti-neoplastic effects, in large part, through disrupting metabolic pathways. Given the intricate relationship between cancer metabolism and the immune system, the metabolic defects imposed by serine deprivation might impact tumor-targeting immunity. Here, we demonstrated that restricting endogenous and exogenous sources of serine in colorectal cancer (CRC) cells results in mitochondrial dysfunction, leading to mitochondrial DNA (mtDNA) accumulation in the cytosol and consequent cGAS-STING1-driven type I interferon (IFN) secretion...
June 11, 2024: Cancer Research
https://read.qxmd.com/read/38861365/integration-of-clinical-trial-spatial-multi-omics-analysis-and-virtual-clinical-trials-enables-immunotherapy-response-prediction-and-biomarker-discovery
#26
JOURNAL ARTICLE
Shuming Zhang, Atul Deshpande, Babita K Verma, Hanwen Wang, Haoyang Mi, Long Yuan, Won Jin Ho, Elizabeth M Jaffee, Qingfeng Zhu, Robert A Anders, Mark Yarchoan, Luciane T Kagohara, Elana J Fertig, Aleksander S Popel
Computational methods that simulate tumors mathematically to describe cellular and molecular interactions are emerging as promising tools to simulate the impact of therapy entirely in silico, potentially greatly accelerating the delivery of new therapeutics to patients. To facilitate the design of dosing regimens and identification of potential biomarkers for immunotherapy, we developed a new computational model to track tumor progression at the organ scale while capturing the spatial heterogeneity of the tumor in HCC...
June 11, 2024: Cancer Research
https://read.qxmd.com/read/38861363/comprehensive-proteogenomic-profiling-reveals-the-molecular-characteristics-of-colorectal-cancer-at-distinct-stages-of-progression
#27
JOURNAL ARTICLE
Lingling Li, Dongxian Jiang, Hui Liu, Chunmei Guo, Qiao Zhang, Xuedong Li, Xiaojian Chen, Zheqi Chen, Jinwen Feng, Subei Tan, Wen Huang, Jie Huang, Chen Xu, Chen-Ying Liu, Wei Yu, Yingyong Hou, Chen Ding
Colorectal cancer (CRC) is the second most common malignant tumor world-wide. Analysis of the changes that occur during CRC progression could provide insights into the molecular mechanisms driving CRC development and identify improved treatment strategies. Here, we performed an integrated multi-omics analysis of 435 trace-tumor-samples from 148 colorectal cancer (CRC) patients, covering non-tumor (NT), intraepithelial neoplasia (IEN), infiltration (IFT), and advanced-stage CRC (A-CRC) phases. Proteogenomics analyses demonstrated that KRAS and BRAF mutations were mutually exclusive and elevated oxidation phosphorylation in the IEN phase...
June 11, 2024: Cancer Research
https://read.qxmd.com/read/38861362/cdk4-6-alters-tbk1-phosphorylation-to-inhibit-the-sting-signaling-pathway-in-prostate-cancer
#28
JOURNAL ARTICLE
Wei Li, Feng Guo, Ruijiang Zeng, Huaiyuan Liang, Yinhuai Wang, Wei Xiong, Heshui Wu, Chunguang Yang, Xin Jin
The efficacy of immunotherapy in prostate cancer patients is limited due to the "cold" tumor microenvironment and the paucity of neoantigens. The STING-TBK1-IRF3 signaling axis is involved in innate immunity and has been increasingly recognized as a candidate target for cancer immunotherapy. Here, we found that treatment with CDK4/6 inhibitors stimulates the STING pathway and enhances the antitumor effect of STING agonists in prostate cancer. Mechanistically, CDK4/6 phosphorylated TBK1 at S527 to inactivate the STING signaling pathway independent of RB1 in prostate cancer cells...
June 11, 2024: Cancer Research
https://read.qxmd.com/read/38861359/hts384-nci60-the-next-phase-of-the-nci60-screen
#29
JOURNAL ARTICLE
Mark W Kunkel, Nathan P Coussens, Joel Morris, Ronald C Taylor, Thomas S Dexheimer, Eric M Jones, James H Doroshow, Beverly A Teicher
The NCI60 human tumor cell line screen has been in operation as a service to the cancer research community for over 30 years. The screen operated with 96-well plates, a 2-day exposure period to test agents, and, following cell fixation, a visible absorbance endpoint by the protein-staining dye sulforhodamine B. Here, we describe the next phase of this important cancer research tool, the HTS384 NCI60 screen. While the cell lines remain the same, the updated screen is performed with 384-well plates, a 3-day exposure period to test agents, and a luminescent endpoint to measure cell viability based upon cellular ATP content...
June 11, 2024: Cancer Research
https://read.qxmd.com/read/38843355/idh1-inhibition-potentiates-chemotherapy-efficacy-in-pancreatic-cancer
#30
JOURNAL ARTICLE
Mehrdad Zarei, Omid Hajihassani, Jonathan J Hue, Alexander W Loftus, Hallie J Graor, Faith Nakazzi, Parnian Naji, Christina S Boutros, Vinayak Uppin, Ali Vaziri-Gohar, Akram Shalaby, John M Asara, Luke D Rothermel, Jonathan R Brody, Jordan M Winter
Pancreatic ductal adenocarcinoma (PDAC) is associated with a five-year overall survival rate of just 13%, and development of chemotherapy resistance is nearly universal. PDAC cells overexpress wild-type IDH1 that can enable them to overcome metabolic stress, suggesting it could represent a therapeutic target in PDAC. Here, we found that anti-IDH1 therapy enhanced the efficacy of conventional chemotherapeutics. Chemotherapy treatment induced ROS and increased TCA cycle activity in PDAC cells, along with the induction of wild-type IDH1 expression as a key resistance factor...
June 6, 2024: Cancer Research
https://read.qxmd.com/read/38833522/comprehensive-target-engagement-by-the-ezh2-inhibitor-tulmimetostat-allows-for-targeting-of-arid1a-mutant-cancers
#31
JOURNAL ARTICLE
Patricia J Keller, Elizabeth J Adams, Rentian Wu, Alexandre Côté, Shilpi Arora, Nico Cantone, Rosana Meyer, Jennifer A Mertz, Victor Gehling, Jike Cui, Jacob I Stuckey, Avinash Khanna, Feng Zhao, Zehua Chen, Ziyang Yu, Richard Cummings, Mohammed Taimi, Nehal J Lakhani, Drew W Rasco, Martin Gutierrez, Linda Duska, Michael Devitt, Ronda Rippley, Julian Levell, Jennifer Truong, Jing Wang, Kaiming Sun, Patrick Trojer
Recurrent somatic mutations in the BAF chromatin remodeling complex subunit ARID1A occur frequently in advanced urothelial carcinoma, endometrial cancers, and ovarian clear cell carcinoma, creating an alternative chromatin state that may be exploited therapeutically. The histone methyltransferase EZH2 has previously been identified as targetable vulnerability in the context of ARID1A mutations. Here, we describe the discovery of tulmimetostat, an orally available, clinical stage EZH2 inhibitor and elucidate its therapeutic potential for treating ARID1A mutant tumors...
June 4, 2024: Cancer Research
https://read.qxmd.com/read/38832939/cenp-e-inhibition-induces-chromosomal-instability-and-synergizes-with-diverse-microtubule-targeting-agents-in-breast-cancer
#32
JOURNAL ARTICLE
John B Tucker, Caleb L Carlsen, Christina M Scribano, Srishrika M Pattaswamy, Mark E Burkard, Beth A Weaver
Drugs that perturb microtubules are commonly used to treat breast cancers of all subtypes in both early stage and metastatic disease, but they are only effective in approximately 50% of patients. High concentrations of microtubule-targeting agents can elicit mitotic arrest in cell culture models; however, recent evidence from primary and metastatic breast cancers revealed that they only accumulate at intratumoral levels capable of inducing abnormal multipolar mitotic spindles, not mitotic arrest. While maintenance of multipolar spindles can generate cytotoxic rates of chromosomal instability (CIN), focusing of aberrant multipolar spindles into normal bipolar spindles dramatically reduces CIN and confers resistance to microtubule poisons...
June 4, 2024: Cancer Research
https://read.qxmd.com/read/38832931/the-dna-methyltransferase-inhibitor-5-aza-4-thio-2-deoxycytidine-induces-c-g-transversions-and-acute-lymphoid-leukemia-development
#33
JOURNAL ARTICLE
Ryan M Bertoli, Yang Jo Chung, Michael J Difilippantonio, Anthony Wokasch, Madison R B Marasco, Haley Klimaszewski, Susannah Gammell, Yuelin J Zhu, Robert L Walker, Dengchao Cao, Ajay Khanna, Matthew J Walter, James H Doroshow, Paul S Meltzer, Peter D Aplan
DNA methyltransferase inhibitors (DNMTi), most commonly cytidine analogs, are compounds that decrease 5'-cytosine methylation. DNMTi are used clinically based on the hypothesis that cytosine demethylation will lead to re-expression of tumor suppressor genes. 5-Aza-4'-thio-2'-deoxycytidine (Aza TdCyd or ATC) is a recently described thiol substituted DNMTi that has been shown to have anti-tumor activity in solid tumor models. Here, we investigated the therapeutic potential of ATC in a murine transplantation model of myelodysplastic syndrome...
June 4, 2024: Cancer Research
https://read.qxmd.com/read/38832928/case-case-genome-wide-analyses-identify-subtype-informative-variants-that-confer-risk-for-breast-cancer
#34
JOURNAL ARTICLE
Xiaohui Sun, Shiv Prakash Verma, Guochong Jia, Xinjun Wang, Jie Ping, Xingyi Guo, Xiao-Ou Shu, Jianhong Chen, Andriy Derkach, Qiuyin Cai, Xiaolin Liang, Jirong Long, Kenneth Offit, Jung Hun Oh, Anne S Reiner, Gordon P Watt, Meghan Woods, Yaohua Yang, Christine B Ambrosone, Stefan Ambs, Yu Chen, Patrick Concannon, Montserrat Garcia-Closas, Jian Gu, Christopher A Haiman, Jennifer J Hu, Dezheng Huo, Esther M John, Julia A Knight, Christopher I Li, Charles F Lynch, Lene Mellemkjaer, Katherine L Nathanson, Barbara Nemesure, Olufunmilayo I Olopade, Andrew F Olshan, Tuya Pal, Julie R Palmer, Michael F Press, Maureen Sanderson, Dale P Sandler, Melissa A Troester, Wei Zheng, Jonine L Bernstein, Matthew F Buas, Xiang Shu
Breast cancer includes several subtypes with distinct characteristic biological, pathological, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate development of improved prevention and treatment approaches. Here, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case GWAS (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer...
June 4, 2024: Cancer Research
https://read.qxmd.com/read/38832925/dietary-commensal-wrestles-iron-from-tumor-microenvironment-to-activate-antitumoral-macrophages
#35
JOURNAL ARTICLE
Amanda H Lee, Simran K Randhawa, Marlies Meisel
The microbiome dictates the response to cancer immunotherapy efficacy. However, the mechanisms of how the microbiota impacts on therapy efficacy remains still poorly understood. In a recent issue of Nature Immunology, Sharma and colleagues elucidate a multifaceted, macrophage-driven mechanism exerted by a specific strain of fermented food commensal Lactiplantibacillus plantarum, LpIMB19. LpIMB19 activates tumor macrophages, resulting in the enhancement of cytotoxic CD8 T cells. LpIMB19 administration led to an expansion of tumor-infiltrating CD8 T cells and improved the efficacy of anti-PD-L1 therapy...
June 4, 2024: Cancer Research
https://read.qxmd.com/read/38819641/human-3d-ovarian-cancer-models-reveal-malignant-cell-intrinsic-and-extrinsic-factors-that-influence-car-t-cell-activity
#36
JOURNAL ARTICLE
Joash D Joy, Beatrice Malacrida, Florian Laforets, Panoraia Kotantaki, Eleni Maniati, Ranjit Manchanda, Alessandro Annibaldi, Sarah Hopkins, Ianire Garrobo-Calleja, Julien Gautrot, Frances R Balkwill
In vitro preclinical testing of chimeric antigen receptor (CAR) T cells is mostly carried out in monolayer cell cultures. However, alternative strategies are needed to take into account the complexity and the effects of the tumor microenvironment (TME). Here, we describe the modulation of CAR T cell activity by malignant cells and fibroblasts in human 3D in vitro cell models of increasing complexity. In models combining mucin-1 (MUC1) and TnMUC1 CAR T cells with human high-grade serous ovarian cancer (HGSOC) cell spheroids, malignant cell-intrinsic resistance to CAR T cell killing was due to defective death receptor signaling involving TNFα...
May 31, 2024: Cancer Research
https://read.qxmd.com/read/38809694/vpac2-receptor-signaling-promotes-growth-and-immunosuppression-in-pancreatic-cancer
#37
JOURNAL ARTICLE
Tenzin Passang, Shuhua Wang, Hanwen Zhang, Fanyuan Zeng, Po-Chih Hsu, Wenxi Wang, Jian-Ming Li, Yuan Liu, Sruthi Ravindranathan, Gregory B Lesinski, Edmund K Waller
Pancreatic cancer (PDAC) harbors a complex tumor microenvironment (TME), and crosstalk between cells in the TME can contribute to drug resistance and relapse. Vasoactive intestinal peptide (VIP) is overexpressed in PDAC, and VIP receptors expressed on T cells are a targetable pathway that sensitizes PDAC to immunotherapy. In this study, we showed that pancreatic cancer cells engage in autocrine VIP signaling through VIP receptor 2 (VPAC2). High co-expression of VIP with VPAC2 correlated with reduced relapse-free survival in PDAC patients...
May 29, 2024: Cancer Research
https://read.qxmd.com/read/38781455/physical-activity-decreases-inflammation-and-delays-development-of-obesity-associated-pancreatic-ductal-adenocarcinoma
#38
JOURNAL ARTICLE
Valentina Pita-Grisanti, Ericka Vélez-Bonet, Kaylin Chasser, Zachary Hurst, Alexus Liette, Grace Vulic, Kelly Dubay, Ali Lahooti, Niharika Badi, Olivia Ueltschi, Kristyn Gumpper-Fedus, Hsiang-Yin Hsueh, Ila Lahooti, Myrriah Chavez-Tomar, Samantha Terhorst, Sue E Knoblaugh, Lei Cao, Wei Huang, Christopher C Coss, Thomas A Mace, Fouad Choueiry, Alice Hinton, Stacey Culp, Jennifer M Mitchell, Rosemarie Schmandt, Michaela Onstad Grinsfelder, Karen Basen-Engquist, Zobeida Cruz-Monserrate
Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), a deadly disease with limited preventive strategies. Lifestyle interventions to decrease obesity represent a potential approach to prevent obesity-associated PDAC. Here, we examined whether decreasing obesity through physical activity (PA) and/or dietary changes could decrease inflammation in humans and prevent obesity-associated PDAC in mice. Comparison of circulating inflammatory-associated cytokines in subjects (overweight and obese) before and after a PA intervention revealed PA lowered systemic inflammatory cytokines...
May 22, 2024: Cancer Research
https://read.qxmd.com/read/38775809/targeting-super-enhancer-driven-transcriptional-dependencies-suppresses-aberrant-hedgehog-pathway-activation-and-overcomes-smoothened-inhibitor-resistance
#39
JOURNAL ARTICLE
Yi Sui, Teng Wang, Yanqing Mei, Ying Zhu, Wenyan Jiang, Jiayi Shen, Siyuan Yan, Wenjie Lu, Kewen Zhao, Jialin Mo, Chaochen Wang, Yujie Tang
Aberrant activation of the Hedgehog (Hh) signaling pathway plays important roles in oncogenesis and therapeutic resistance in several types of cancer. The clinical application of FDA-approved Hh-targeted Smoothened inhibitors (SMOi) is hindered by the emergence of primary or acquired drug resistance. Epigenetic and transcriptional targeted therapies represent a promising direction for developing improved anti-Hh therapies. In this study, we integrated epigenetic/transcriptional-targeted small-molecule library screening with CRISPR/Cas9 knockout library screening and identified CDK9 and CDK12, two transcription elongation regulators, as therapeutic targets for antagonizing aberrant Hh activation and overcoming SMOi resistance...
May 22, 2024: Cancer Research
https://read.qxmd.com/read/38775804/fbxo32-stimulates-protein-synthesis-to-drive-pancreatic-cancer-progression-and-metastasis
#40
JOURNAL ARTICLE
Dan Su, Ruobing Wang, Guangyu Chen, Chen Ding, Yueze Liu, JInxin Tao, Yuanyang Wang, Jiangdong Qiu, Wenhao Luo, Guihu Weng, Yang Gang, Taiping Zhang
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide, primarily due to its rapid progression. The current treatment options for PDAC are limited, and a better understanding of the underlying mechanisms responsible for PDAC progression is required to identify improved therapeutic strategies. Here, we identified FBXO32 as an oncogenic driver in PDAC. FBXO32 was aberrantly upregulated in PDAC, and high FBXO32 expression was significantly associated with an unfavorable prognosis in PDAC patients...
May 22, 2024: Cancer Research
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