Meng Zhu, Tianpei Wang, Yanqian Huang, Xiaoyu Zhao, Yuqing Ding, Mengyi Zhu, Mengmeng Ji, Cheng Wang, Juncheng Dai, Rong Yin, Lin Xu, Hongxia Ma, Qingyi Wei, Guangfu Jin, Zhibin Hu, Hongbing Shen
Cancer site-specific polygenic risk scores (PRS) effectively identify individuals at high risk of individual cancers, but the effectiveness of PRS on overall cancer risk assessment and the extent to which a high genetic risk of overall cancer can be offset by a healthy lifestyle remain unclear. Here, we constructed an incidence-weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific PRSs. Lifestyle was determined according to smoking, alcohol consumption, physical activity, body mass index, and diet...
July 28, 2021: Cancer Research
Anastasia Velalopoulou, Ilias V Karagounis, Gwendolyn M Cramer, Michele M Kim, Giorgos Skoufos, Denisa Goia, Sarah Hagan, Ioannis I Verginadis, Khayrullo Shoniyozov, June Chiango, Michelle Cerullo, Kelley Varner, Lutian Yao, Ling Qin, Artemis G Hatzigeorgiou, Andy J Minn, Mary Putt, Matthew Lanza, Charles-Antoine Assenmacher, Enrico Radaelli, Jennifer Huck, Eric Diffenderfer, Lei Dong, James Metz, Constantinos Koumenis, Keith A Cengel, Amit Maity, Theresa M Busch
In studies of electron and proton radiotherapy, ultrahigh dose rates of FLASH radiation therapy appear to produce fewer toxicities than standard dose rates while maintaining local tumor control. FLASH-proton radiotherapy (F-PRT) brings the spatial advantages of PRT to FLASH dose rates (>40 Gy/sec), making it important to understand if and how F-PRT spares normal tissues while providing anti-tumor efficacy that is equivalent to standard-proton radiotherapy (S-PRT). Here we studied PRT damage to skin and mesenchymal tissues of muscle and bone and found that F-PRT of the C57BL/6 murine hind leg produced fewer severe toxicities leading to death or requiring euthanasia than S-PRT of the same dose...
July 28, 2021: Cancer Research
Junshang Ge, Jie Wang, Fang Xiong, Xianjie Jiang, Kunjie Zhu, Yian Wang, Yongzhen Mo, Zhaojian Gong, Shanshan Zhang, Yi He, Xiayu Li, Lei Shi, Can Guo, Fuyan Wang, Ming Zhou, Bo Xiang, Yong Li, Guiyuan Li, Wei Xiong, Zhaoyang Zeng
Epstein-Barr virus (EBV) infection is an established cause of nasopharyngeal carcinoma (NPC) and is involved in a variety of malignant phenotypes, including tumor immune escape. EBV can encode a variety of circular RNAs; however, little is known regarding the biological functions of these circRNAs in NPC. In this study, EBV-encoded circBART2.2 was found to be highly expressed in NPC where it upregulated PD-L1 expression and inhibited T cell function in vitro and in vivo. circBART2.2 promoted transcription of PD-L1 by binding the helicase domain of RIG-I and activating transcription factors IRF3 and NF-κB, resulting in tumor immune escape...
July 28, 2021: Cancer Research
Juan P Unfried, Mikel Marín-Baquero, Ángel Rivera-Calzada, Nerea Razquin, Eva M Martín-Cuevas, Sara de Bragança, Clara Aicart-Ramos, Christopher McCoy, Laura Prats-Mari, Raquel Arribas-Bosacoma, Linda Lee, Stefano Caruso, Jessica Zucman-Rossi, Bruno Sangro, Gareth Williams, Fernando Moreno-Herrero, Oscar Llorca, Susan P Lees-Miller, Puri Fortes
Long noncoding RNAs (lncRNAs) are emerging as key players in cancer as parts of poorly understood molecular mechanisms. Here, we investigated lncRNAs that play a role in hepatocellular carcinoma (HCC) and identified NIHCOLE, a novel lncRNA induced in HCC with oncogenic potential and a role in the ligation efficiency of DNA double-stranded breaks (DSB). NIHCOLE expression was associated with poor prognosis and survival of HCC patients. Depletion of NIHCOLE from HCC cells led to impaired proliferation and increased apoptosis...
July 28, 2021: Cancer Research
Liat Goldberg, Vijay Negi, Yang Jo Chung, Masahiro Onozawa, Yuelin J Zhu, Robert L Walker, Rachel Pierce, Daxesh P Patel, Kristopher W Krausz, Frank J Gonzalez, Margaret A Goodell, Benjamin At Rodriguez, Paul S Meltzer, Peter D Aplan
Mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes are frequently observed in a wide variety of hematologic malignancies, including myeloid and T-cell leukemias. In this study, we generated Idh2R140Q transgenic mice to examine the role of the Idh2R140Q mutation in leukemia. No leukemia developed in Idh2R140Q transgenic mice, suggesting a need for additional genetic events for leukemia development. Since myeloid cells from NUP98-HOXD13 fusion (NHD13) transgenic mice frequently acquire somatic Idh mutations when they transform to AML, we generated Idh2R140Q/NHD13 double transgenic mice...
July 28, 2021: Cancer Research
Ksenija Nesic, Olga Kondrashova, Rachel M Hurley, Cordelia D McGehee, Cassandra J Vandenberg, Gwo-Yaw Ho, Elizabeth Lieschke, Genevieve Dall, Nirashaa Bound, Kristy Shield-Artin, Marc Radke, Ashan Musafer, Zi Qing Chai, Mohammad Reza Eftekhariyan Ghamsari, Maria I Harrell, Damien Kee, Inger Olesen, Orla McNally, Nadia Traficante, Australian Ovarian Cancer Study, Anna DeFazio, David D L Bowtell, Elizabeth M Swisher, S John Weroha, Katia Nones, Nicola Waddell, Scott H Kaufmann, Alexander Dobrovic, Matthew J Wakefield, Clare L Scott
In high-grade serous ovarian carcinoma (HGSC), deleterious mutations in DNA repair gene RAD51C are established drivers of defective homologous recombination and are emerging biomarkers of PARP inhibitor (PARPi) sensitivity. RAD51C promoter methylation (meRAD51C) is detected at similar frequencies to mutations, yet its effects on PARPi responses remain unresolved. In this study, three HGSC patient-derived xenograft (PDX) models with methylation at most or all examined CpG sites in the RAD51C promoter show responses to PARPi...
July 28, 2021: Cancer Research
Huijuan Liu, Jiahuan Yang, Yang Zhang, Jingxia Han, Yuyan Yang, Zihan Zhao, Xintong Dai, Hongqi Wang, Xiujuan Ding, Yanrong Liu, Weilong Zhong, Wenqing Gao, Tao Sun
Although it is established that the sustained psychological stress conditions under which tumor patients often reside accelerates malignant progression of tumors, the molecular mechanism behind this association is unclear. In this work, the effect of psychological stress on tumor progression was verified using a stress-stimulated tumor-bearing mouse model (Str-tumor). Both D2 dopamine receptor (DRD2) and hypoxia-inducible factor 1-alpha (HIF-1α) were highly expressed in the nucleus of stress-stimulated tumors...
July 28, 2021: Cancer Research
Mark P Labrecque, Lisha G Brown, Ilsa M Coleman, Bryce Lakely, Nicholas J Brady, John K Lee, Holly M Nguyen, Dapei Li, Brian Hanratty, Michael C Haffner, David S Rickman, Lawrence D True, Daniel W Lin, Hung-Ming Lam, Joshi J Alumkal, Eva Corey, Peter S Nelson, Colm Morrissey
Neuroendocrine (NE) differentiation in metastatic castration-resistant prostate cancer (mCRPC) is an increasingly common clinical feature arising from cellular plasticity. We recently characterized two mCRPC phenotypes with NE features: androgen receptor (AR)-positive NE-positive amphicrine prostate cancer (AMPC) and AR-negative small cell or neuroendocrine prostate cancer (SCNPC). Here, we interrogated the regulation of RE1-silencing transcription factor (REST), a transcriptional repressor of neuronal genes, and elucidated molecular programs driving AMPC and SCNPC biology...
July 26, 2021: Cancer Research
Lee-Ann Van de Velde, E Kaitlynn Allen, Jeremy Chase Crawford, Taylor L Wilson, Clifford S Guy, Marion Russier, Leonie Zeitler, Armita Bahrami, David Finkelstein, Stephane Pelletier, Stacey Schultz-Cherry, Paul G Thomas, Peter J Murray
Immune cells regulate tumor growth by mirroring their function as tissue repair organizers in normal tissues. To understand the different facets of immune-tumor collaboration through genetics, spatial transcriptomics, and immunological manipulation with non-invasive, longitudinal imaging, we generated a penetrant double oncogene-driven autochthonous model of neuroblastoma. Spatial transcriptomic analysis showed that CD4+ and myeloid populations co-localized within the tumor parenchyma, while CD8+ T cells and B cells were peripherally dispersed...
July 23, 2021: Cancer Research
Tzeh K Foo, Gabrele Vincelli, Eric Huselid, Joonyoung Her, Haiyan Zheng, Srilatha Simhadri, Meiling Wang, Yanying Huo, Tao Li, Xiaochun Yu, Hong Li, Weixing Zhao, Samuel F Bunting, Bing Xia
BRCA1 maintains genome integrity and suppresses tumorigenesis by promoting homologous recombination (HR)-mediated repair of DNA double strand breaks (DSB) and DNA damage-induced cell cycle checkpoints. Phosphorylation of BRCA1 by ATM, ATR, CHK2, CDK, and PLK1 kinases has been reported to regulate its functions. Here we show that ATR and ATM-mediated phosphorylation of BRCA1 on T1394, a highly conserved but functionally uncharacterized site, is a key modification for its function in the DNA damage response. Following DNA damage, T1394 phosphorylation ensured faithful repair of DSBs by promoting HR and preventing single strand annealing, a deletion-generating repair process...
July 23, 2021: Cancer Research
Xinyao Qiu, Shuai Yang, Shan Wang, Jianmin Wu, Bo Zheng, Kaiting Wang, Siyun Shen, Seogsong Jeong, Zhixuan Li, Yanjing Zhu, Tong Wu, Xuan Wu, Rui Wu, Weiwei Liu, Hong-Yang Wang, Lei Chen
N6-methyladenosine (m6A) has been reported as an important mechanism of post-transcriptional regulation. Programmed death-ligand 1 (PD-L1) is a primary immune inhibitory molecule expressed on tumor cells that promotes immune evasion. Here we report ALKBH5 as an important m6A demethylase that orchestrates PD-L1 expression in intrahepatic cholangiocarcinoma (ICC). Regulation of PD-L1 expression by ALKBH5 was confirmed in human ICC cell lines. Sequencing of the m6A methylome identified PD-L1 mRNA as a direct target of m6A modification whose levels were regulated by ALKBH5...
July 23, 2021: Cancer Research
Katie Teng, Matthew J Ford, Keerthana Harwalkar, YuQi Li, Alain Sarabia Pacis, David Farnell, Nobuko Yamanaka, Yu-Chang Wang, Dunarel Badescu, Tuyet Nhung Ton Nu, Jiannis Ragoussis, David G Huntsman, Jocelyne Arseneau, Yojiro Yamanaka
Ovarian cancer is the most lethal gynecological cancer. High-grade serous ovarian carcinoma (HGSOC) accounts for most ovarian cancer cases, and it is most frequently diagnosed at advanced stages. Here we developed a novel strategy to generate somatic ovarian cancer mouse models using a combination of in vivo electroporation and CRISPR-Cas9-mediated genome editing. Mutation of tumour suppressor genes associated with HGSOC in two different combinations (Brca1, Tp53, Pten with and without Lkb1) resulted in successfully generation of HGSOC, albeit with different latencies and pathophysiology...
July 23, 2021: Cancer Research
Hieu-Huy Nguyen-Tran, Thi-Ngoc Nguyen, Chen-Yun Chen, Tien Hsu
Clear-cell renal cell carcinoma (ccRCC) is the most prevalent subtype of RCC, and its progression has been linked to chronic inflammation. About 70% of the ccRCC cases are associated with inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. However, it is still not clear how mutations in VHL, encoding the substrate-recognition subunit of an E3 ubiquitin ligase that targets the alpha subunit of hypoxia-inducible factor (HIF-α), can coordinate tissue inflammation and tumorigenesis. We previously generated mice with conditional Vhlh knockout in kidney tubules, which resulted in severe inflammation and fibrosis in addition to hyperplasia and the appearance of transformed clear cells...
July 23, 2021: Cancer Research
Asmaa El-Kenawi, William Dominguez-Viqueira, Min Liu, Shivanshu Awasthi, Julieta Abraham-Miranda, Aysenur Keske, KayLee K Steiner, Leenil Noel, Amparo N Serna, Jasreman Dhillon, Robert J Gillies, Xiaoqing Yu, John M Koomen, Kosj Yamoah, Robert A Gatenby, Brian Ruffell
Castration-resistant prostate cancer (CRPC) is a lethal stage of disease in which androgen receptor (AR) signaling is persistent despite androgen deprivation therapy (ADT). Most studies have focused on investigating cell-autonomous alterations in CRPC, while the contributions of the tumor microenvironment are less well understood. Here we sought to determine the role of tumor-associated macrophages in CRPC, based upon their role in cancer progression and therapeutic resistance. In a syngeneic model that reflected the mutational landscape of CRPC, macrophage depletion resulted in a reduced transcriptional signature for steroid and bile acid synthesis, indicating potential perturbation of cholesterol metabolism...
July 23, 2021: Cancer Research
Paul Yenerall, Rahul K Kollipara, Kimberley Avila, Michael Peyton, Christopher A Eide, Daniel Bottomly, Shannon K McWeeney, Yan Liu, Kenneth D Westover, Brian J Druker, John D Minna, Ralf Kittler
Identifying resistance mutations in a drug target provides crucial information. Lentiviral transduction creates multiple types of mutations due to the error-prone nature of the HIV-1 reverse transcriptase (RT). Here we optimized and leveraged this property to identify drug resistance mutations, developing a technique we term LentiMutate. This technique was validated by identifying clinically relevant EGFR resistance mutations, then applied to two additional clinical anti-cancer drugs: imatinib, a BCR-ABL inhibitor, and AMG 510, a KRAS G12C inhibitor...
July 23, 2021: Cancer Research
Lei Zhu, Zhen Chen, Hongjing Zang, Songqing Fan, Jiajia Gu, Guojing Zhang, Kevin D-Y Sun, Qiming Wang, Yong He, Taofeek K Owonikoko, Suresh S Ramalingam, Shi-Yong Sun
Osimertinib (AZD9291 or TAGRISSOTM) is a promising and approved third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for treating patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations or the resistant T790M mutation. However, the inevitable emergence of acquired resistance limits its long-term efficacy. A fuller understanding of the mechanism of action of osimertinib and its linkage to acquired resistance will enable the development of more efficacious therapeutic strategies...
July 21, 2021: Cancer Research
Ryo Sato, Kosuke Imamura, Takashi Semba, Yusuke Tomita, Sho Saeki, Koei Ikeda, Yoshihiro Komohara, Makoto Suzuki, Takuro Sakagami, Hideyuki Saya, Yoshimi Arima
Invasive lung adenocarcinoma (LADC) can be classified histologically as lepidic, acinar, papillary, micropapillary, or solid. Most LADC tumors manifest several of these histological subtypes, with heterogeneity being related to therapeutic resistance. We report here that in immunodeficient mice, human LADC cells form tumors with distinct histological features, MUC5AC-expressing solid-type or cytokeratin 7 (CK7)-expressing acinar-type tumors, depending on the site of development, and that a solid-to-acinar transition (SAT) could be induced by the tumor microenvironment...
July 21, 2021: Cancer Research
Dominique C Hinshaw, Ann Hanna, Tshering Lama-Sherpa, Brandon Metge, Sarah C Kammerud, Gloria A Benavides, Atul Kumar, Heba Allah Alsheikh, Mateus Mota, Dongquan Chen, Scott W Ballinger, Jeffrey C Rathmell, Selvarangan Ponnazhagan, Victor Darley-Usmar, Rajeev S Samant, Lalita A Shevde
Elevated infiltration of immunosuppressive alternatively polarized (M2) macrophages is associated with poor prognosis in cancer patients. The tumor microenvironment remarkably orchestrates molecular mechanisms that program these macrophages. Here we identify a novel role for oncogenic Hedgehog (Hh) signaling in programming signature metabolic circuitries that regulate alternative polarization of tumor-associated macrophages. Two immunocompetent orthotopic mouse models of mammary tumors were used to test the effect of inhibiting Hh signaling on tumor-associated macrophages...
July 21, 2021: Cancer Research
Feifei Xu, Zining Wang, Hongxia Zhang, Jiemin Chen, Xiaojuan Wang, Lei Cui, Chunyuan Xie, Mengyun Li, Fang Wang, Penghui Zhou, Jinyun Liu, Peng Huang, Xiaodong Xia, Xiaojun Xia
Hyperactive mevalonate (MVA) metabolic activity is often observed in cancer cells, and blockade of this pathway inhibits tumor cell lipid synthesis and cell growth and enhances tumor immunogenicity. How tumor cell MVA metabolic blockade promotes antitumor immune responses, however, remains unclear. Here we show that inhibition of the MVA metabolic pathway in tumor cells elicits type 1 classical dendritic cells (cDC1)-mediated tumor recognition and antigen cross-presentation for antitumor immunity. Mechanistically, MVA blockade disrupted prenylation of the small GTPase Rac1 and induced cancer cell actin filament exposure, which was recognized by CLEC9A, a C-lectin receptor specifically expressed on cDC1s, in turn activating antitumor T cells...
July 15, 2021: Cancer Research
Marta Falcinelli, Premal H Thaker, Susan K Lutgendorf, Suzanne D Conzen, Renée L Flaherty, Melanie S Flint
The hypothesis that the physiological response to psychological stress influences the initiation of cancer is highly controversial. The link between initiating stressors, the psychological stress response, and disease is plausible considering that the stress response is associated with defined physiological outcomes and molecular mechanisms. In light of this, we review the clinical relevance of psychological stress on the risk of cancer, and we propose potential molecular pathways that may link the stress response to early stages of malignant cell transformation...
July 15, 2021: Cancer Research
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