Poonam Tewary, Alan D Brooks, Ya-Ming Xu, E M Kithsiri Wijeratne, Ashley L Babyak, Timothy C Back, Raj Chari, Christine N Evans, Curtis J Henrich, Thomas J Meyer, Elijah F Edmondson, Maria T Prudente de Aquino, Thanigaivelan Kanagasabai, Anil Shanker, A A Leslie Gunatilaka, Thomas J Sayers
Screening for sensitizers of cancer cells to TRAIL-mediated apoptosis identified a natural product (NP) of the 17β-hydroxywithanolide (17-BHW) class, physachenolide C (PCC), as a promising hit. In this study, we show that PCC was also able to sensitize melanoma and renal carcinoma cells to apoptosis in response not only to TRAIL, but also to the synthetic polynucleotide poly I:C, a viral mimetic and immune activator, by reducing levels of anti-apoptotic proteins cFLIP and Livin. Both death receptor and TLR3 signaling elicited subsequent increased assembly of a pro-apoptotic ripoptosome signaling complex...
April 9, 2021: Cancer Research
Yu Saida, Jeffrey R Brender, Kazutoshi Yamamoto, James B Mitchell, Murali C Krishna, Shun Kishimoto
Immune checkpoint blockade (ICB) has become a standard therapy for several cancers; however, the response to ICB is inconsistent and a method for non-invasive assessment has not been established to date. To investigate the capability of multi-modal imaging to evaluate treatment response to ICB therapy, hyperpolarized 13C MRI using [1-13C] pyruvate and [1,4-13C2] fumarate and dynamic contrast enhanced (DCE) MRI were evaluated to detect early changes in tumor glycolysis, necrosis, and intratumor perfusion/permeability, respectively...
April 9, 2021: Cancer Research
Shu-Chen Liu, Ngan-Ming Tsang, Po-Ju Lee, Yun-Hua Sui, Chen-Han Huang, Tzu-Tung Liu
The most frequent location of metastatic EBV+ nasopharyngeal carcinoma (NPC) is the bone marrow, an adipocyte-dominant region. Several EBV-associated lymphoepithelioma-like carcinoma (LELC) types also grow in the anatomical vicinity of fat tissues. Here we show that in an adipose tissue-rich tumor setting, EBV targets adipocytes and remodels the tumor microenvironment. Positive immunoreactivity for EBV-encoded early antigen D was detected in adipose tissue near tumor beds of bone marrow metastatic NPC. EBV was capable of infecting primary human adipocytes in vitro, triggering expression of multiple EBV-encoded mRNA and proteins...
April 6, 2021: Cancer Research
Annamil Alvarez-Trotta, William Guerrant, Luisana Astudillo, Mohini Lahiry, Giulia Diluvio, Elena Shersher, Hugo Kaneku, David J Robbins, Darren Orton, Anthony J Capobianco
In many human cancers, deregulation of the Notch pathway has been shown to play a role in the initiation and maintenance of the neoplastic phenotype. Aberrant Notch activity also plays a central role in the maintenance and survival of cancer stem cells, which underlie metastasis and resistance to therapy. For these reasons, inhibition of Notch signaling has become an exceedingly attractive target for cancer therapeutic development. However, attempts to develop Notch pathway specific drugs have largely failed in the clinic, in part due to intestinal toxicity...
April 5, 2021: Cancer Research
Barbara J Fuhrman, Steven C Moore, Celia Byrne, Issam Makhoul, Cari M Kitahara, Amy Berrington de González, Martha S Linet, Elisabete Weiderpass, Hans-Olov Adami, Neal D Freedman, Linda M Liao, Charles E Matthews, Rachael Z Stolzenberg-Solomon, Mia M Gaudet, Alpa V Patel, I-Min Lee, Julie E Buring, Alicja Wolk, Susanna C Larsson, Anna E Prizment, Kim Robien, Michael Spriggs, David P Check, Neil Murphy, Marc J Gunter, Harold L Van Dusen, Regina G Ziegler, Robert N Hoover
The average age at menarche declined in European and U.S. populations during the 19th and 20th centuries. The timing of pubertal events may have broad implications for chronic disease risks in aging women. Here we tested for associations of recalled menarcheal age with risks of 19 cancers in 536,450 women [median age, 60 years (range, 31-39 years)] in nine prospective U.S. and European cohorts that enrolled participants from 1981 to 1998. Cox regression estimated multivariable-adjusted HRs and 95% confidence intervals (CI) for associations of the age at menarche with risk of each cancer in each cohort and random-effects meta-analysis was used to generate summary estimates for each cancer...
April 5, 2021: Cancer Research
Bin Wei, Lingyan Xu, Wenjie Guo, Yuanyuan Wang, Jingjing Wu, Xiaofei Li, Xiaomin Cai, Jinbo Hu, Meijing Wang, Qiang Xu, Wen Liu, Yanhong Gu
As a cytoplasmic sensor of double-stranded DNA (dsDNA), the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays an important role in anti-tumor immunity. In this study, we investigated the effect of Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) on tumor cell-intrinsic STING pathway activity and DNA repair in colon cancer. SHP2 interacted with and dephosphorylated poly ADP-ribose polymerase (PARP1) after DNA damage. PARP1 inhibition by SHP2 resulted in reduced DNA repair and accumulation of dsDNA in cells, thus promoting hyperactivation of the STING pathway...
April 5, 2021: Cancer Research
Feng Chen, Zhuojia Chen, Tao Guan, Yan Zhou, Lichen Ge, Haisheng Zhang, Yingmin Wu, Guan-Min Jiang, Weiling He, Jiexin Li, Hongsheng Wang
The roles of RNA modification during organ metastasis of cancer cells are not known. Here we established breast cancer (BC) lung metastasis cells by three rounds of selection of lung metastatic subpopulations in vivo and designated them BCLMF3 cells. In these cells, mRNA N6-methyladenosine (m6A) and methyltransferase METTL3 were increased, while the demethylase FTO was decreased. Epi-transcriptome and transcriptome analyses together with functional studies identified keratin 7 (KRT7) as a key effector for m6A-induced BC lung metastasis...
April 1, 2021: Cancer Research
Esther Schoutrop, Ibrahim El-Serafi, Thomas Poiret, Ying Zhao, Okan Gultekin, Rui He, Lidia Moyano-Galceran, Joseph W Carlson, Kaisa Lehti, Moustapha Hassan, Isabelle Magalhaes, Jonas Mattsson
New therapeutic options for patients with ovarian cancer are urgently needed. Therefore, we evaluated the efficacy of two second-generation mesothelin (MSLN)-directed CAR T cells in orthotopic mouse models of ovarian cancer. Treatment with CAR T cells expressing an MSLN CAR construct including the CD28 domain (M28z) significantly prolonged survival, but no persistent tumor control was observed. Despite lower response rates, MSLN-4-1BB (MBBz) CAR T cells induced long-term remission in some SKOV-3-bearing mice...
April 1, 2021: Cancer Research
Qi-Nian Wu, Xiao-Jing Luo, Jia Liu, Yun-Xin Lu, Yun Wang, Jingjing Qi, Ze-Xian Liu, Qitao Huang, Zekun Liu, Jiabin Lu, Ying Jin, Heng-Ying Pu, Pei-Shan Hu, Jia-Bo Zheng, Zhao-Lei Zeng, Huai-Qiang Ju, Dan Xie, Qi Zhao, Rui-Hua Xu
Long noncoding RNAs (lncRNA) are involved in tumorigenesis and drug resistance. However, the roles and underlying mechanisms of lncRNAs in colorectal cancer (CRC) are still unknown. In this work, through transcriptomic profiling analysis of 21 paired tumor and normal samples, we identified a novel colorectal cancer-related lncRNA, MNX1-AS1. MNX1-AS1 expression was significantly upregulated in colorectal cancer and associated with poor prognosis. In vitro and in vivo gain- and loss-of-function experiments showed that MNX1-AS1 promotes the proliferation of CRC cells...
March 29, 2021: Cancer Research
Ali Jalali, Kwanha Yu, Vivek Beechar, Navish Bosquez Huerta, Anthony Grichuk, Deepika Mehra, Brittney Lozzi, Kathleen Kong, Kenneth L Scott, Ganesh Rao, Matthew N Bainbridge, Melissa L Bondy, Benjamin Deneen
Germline POT1 mutations are found in a spectrum of cancers and confer increased risk. Recently, we identified a series of novel germline POT1 mutations that predispose carrier families to the development of glioma. Despite these strong associations, how these glioma-associated POT1 mutations contribute to glioma tumorigenesis remains undefined. Here we show that POT1-G95C increases proliferation in glioma-initiating cells in vitro and in progenitor populations in the developing brain. In a native mouse model of glioma, loss of Pot1a/b resulted in decreased survival in females compared to males...
March 29, 2021: Cancer Research
Francisco Gonzalez-Romero, Daniela Mestre, Igor Aurrekoetxea, Colm J O'Rourke, Jesper B Andersen, Ashwin Woodhoo, Miguel Tamayo-Caro, Marta Varela Rey, Marta Palomo-Irigoyen, Beatriz Gómez-Santos, Diego Sáenz de Urturi, Maitane Núñez-García, Juan L García-Rodríguez, Larraitz Fernández-Ares, Xabier Buqué, Ainhoa Iglesias-Ara, Irantzu Bernales, Virginia Gutierrez De Juan, Teresa C Delgado, Naroa Goikoetxea-Usandizaga, Richard Lee, Sanjay Bhanot, Igotz Delgado, Maria J Perugorria, Gaizka Errazti, Lorena Mosteiro, Sonia Gaztambide, Idoia Martinez de la Piscina, Paula Iruzubieta, Javier Crespo, Jesus M Banales, María L Martínez-Chantar, Luis Castaño, Ana M Zubiaga, Patricia Aspichueta
Lipid metabolism rearrangements in nonalcoholic fatty-liver disease (NAFLD) contribute to disease progression. NAFLD has emerged as a major risk for hepatocarcinogenesis (HCC), where metabolic reprogramming is a hallmark. Identification of metabolic drivers might reveal therapeutic targets to improve HCC treatment. Here we investigated the contribution of transcription factors E2F1 and E2F2 to NAFLD-related HCC and their involvement in metabolic rewiring during disease progression. In mice receiving a high-fat diet (HFD) and diethylnitrosamine (DEN) administration, E2f1 and E2f2 expression was increased in NAFLD-related HCC...
March 26, 2021: Cancer Research
Yali Wang, Weimin Zhang, Wenzhong Liu, Lijie Huang, Yan Wang, Dan Li, Guangchao Wang, Zitong Zhao, Xinming Chi, Yu Xue, Yongmei Song, Xuefeng Liu, Qimin Zhan
Lymph node (LN) metastasis is one of the most malignant clinical features in patients with esophageal squamous cell carcinoma (ESCC). Understanding the mechanism of LN metastasis will provide treatment strategies for ESCC patients. Long noncoding RNAs (lncRNA) play a critical role in the development and progression of human cancers. However, the role and mechanism of lncRNAs in LN metastasis remain largely unknown. Here we show that VEGF-C mRNA stability-associated long noncoding RNA (VESTAR) is involved in LN metastasis of ESCC...
March 26, 2021: Cancer Research
Hsin-Fang Tu, Chun-Jung Ko, Ching-Tai Lee, Cheng-Fan Lee, Shao-Wei Lan, Hsin-Hsien Lin, Hsin-Ying Lin, Chia-Chi Ku, Der-Yen Lee, I-Chun Chen, Ya-Hui Chuang, Francisco Del Caño-Ochoa, Santiago Ramón-Maiques, Chao-Chi Ho, Ming-Shyue Lee, Geen-Dong Chang
Current clinical trials of combined EGFR-tyrosine kinase inhibitors (TKIs) and immune checkpoint blockade (ICB) therapies show no additional effect. This raises questions regarding whether EGFR-TKIs attenuate ICB-enhanced CD8+ T lymphocyte function. Here we show that the EGFR-TKI afatinib suppresses CD8+ T lymphocyte proliferation, and we identify CAD, a key enzyme of de novo pyrimidine biosynthesis, to be a novel afatinib target. Afatinib reduced tumor-infiltrating lymphocyte numbers in Lewis lung carcinoma (LLC)-bearing mice...
March 26, 2021: Cancer Research
Ki Hyun Yoo, Jason J Tang, Mohammad Abdur Rashid, Chang Hoon Cho, Ana Corujo-Ramirez, Jonghoon Choi, Mun Gyeong Bae, Danielle Brogren, John R Hawse, Xiaonan Hou, S John Weroha, Alfredo Oliveros, Lindsey A Kirkeby, Joseph A Baur, Mi-Hyeon Jang
Chemotherapy-induced cognitive impairment (CICI) is often reported as a neurotoxic side effect of chemotherapy. Although CICI has emerged as a significant medical problem, meaningful treatments are not currently available due to a lack of mechanistic understanding underlying CICI pathophysiology. Using the platinum-based chemotherapy cisplatin as a model for CICI, we show here that cisplatin suppresses nicotinamide adenine dinucleotide (NAD+) levels in the adult female mouse brain in vivo and in human cortical neurons derived from induced pluripotent stem cells in vitro...
March 26, 2021: Cancer Research
Francesco De Logu, Matilde Marini, Lorenzo Landini, Daniel Souza Monteiro de Araujo, Niccolò Bartalucci, Gabriela Trevisan, Gennaro Bruno, Martina Marangoni, Brian Lee Schmidt, Nigel W Bunnett, Pierangelo Geppetti, Romina Nassini
Although macrophages (MΦ) are known to play a central role in neuropathic pain, their contribution to cancer pain has not been established. Here we report that depletion of sciatic nerve resident MΦs (rMΦ) in mice attenuates mechanical/cold hypersensitivity and spontaneous pain evoked by intraplantar injection of melanoma or lung carcinoma cells. MΦ-colony stimulating factor (M-CSF) was upregulated in the sciatic nerve trunk and mediated cancer-evoked pain via rMΦ expansion, transient receptor potential ankyrin 1 (TRPA1) activation, and oxidative stress...
March 26, 2021: Cancer Research
David de Semir, Vladimir Bezrookove, Mehdi Nosrati, Altaf A Dar, James R Miller, Stanley P Leong, Kevin B Kim, Wilson Liao, Liliana Soroceanu, Sean McAllister, Robert J Debs, Dirk Schadendorf, Sancy A Leachman, James E Cleaver, Mohammed Kashani-Sabet
Melanoma occurs as a consequence of inherited susceptibility to the disease and exposure to ultraviolet radiation (UVR) and is characterized by uncontrolled cellular proliferation and a high mutational load. The precise mechanisms by which UVR contributes to the development of melanoma remain poorly understood. Here we show that activation of nuclear receptor coactivator 3 (NCOA3) promotes melanomagenesis through regulation of UVR sensitivity, cell cycle progression, and circumvention of the DNA damage response (DDR)...
March 25, 2021: Cancer Research
Daniela V Carreño, Néstor B Corro, Javier F Cerda-Infante, Carolina E Echeverría, Catalina A Asencio-Barría, Verónica A Torres-Estay, Gonzalo A Mayorga-Weber, Pablo A Rojas, Loreto P Véliz, Pedro A Cisternas, Viviana P Montecinos, Ignacio F San Francisco, Manuel A Varas-Godoy, Paula C Sotomayor, Maite A Castro, Francisco J Nualart, Nibaldo C Inestrosa, Alejandro S Godoy
Clinical localization of primary tumors and sites of metastasis by positron emission tomography (PET) is based on the enhanced cellular uptake of 2-deoxy-2-[18F]-fluoro-D-glucose (FDG). In prostate cancer (PCa), however, PET-FDG imaging has shown limited clinical applicability, suggesting that PCa cells may utilize hexoses other than glucose, such as fructose, as the preferred energy source. Our previous studies suggested that PCa cells overexpress fructose transporters but not glucose transporters compared to benign cells...
March 24, 2021: Cancer Research
Matteo Lulli, Laura Del Coco, Tommaso Mello, Caecilia Sukowati, Stefania Madiai, Laura Gragnani, Paolo Forte, Francesco Paolo Fanizzi, Antonio Mazzocca, Krista Rombouts, Andrea Galli, Vinicio Carloni
Defective mitosis with chromosome missegregation can have a dramatic effect on genome integrity by causing DNA damage, activation of the DNA damage response (DDR), and chromosomal instability. Although this is an energy-dependent process, mechanisms linking DDR to cellular metabolism are unknown. Here we show that checkpoint kinase 2 (CHK2), a central effector of DDR, regulates cellular energy production by affecting glycolysis and mitochondrial functions. Patients with hepatocellular carcinoma (HCC) had increased CHK2 mRNA in blood, which was associated with elevated tricarboxylic acid cycle (TCA) metabolites...
March 24, 2021: Cancer Research
Yang Liu, Chunzhang Yang
Oncometabolites are pathognomonic hallmarks in human cancers, including glioma, leukemia, neuroendocrine tumors, and renal cancer. Oncometabolites are aberrantly accumulated from disrupted Krebs cycle and affect the catalytic activity of α-ketoglutarate-dependent dioxygenases. Oncometabolites indicate distinct cancer-related patterns ranging from oncogenesis and metabolism to therapeutic resistance. Here we discuss the current understanding of oncometabolites as well as the controversies and challenges associated with oncometabolite-driven cancers...
March 24, 2021: Cancer Research
Lei Shi, Yuqian Yan, Yundong He, Binyuan Yan, Yunqian Pan, Jacob J Orme, Jun Zhang, Wanhai Xu, Jun Pang, Haojie Huang
Molecular mechanisms underlying intratumoral androgenesis and aberrant androgen receptor (AR) activation in prostate cancer (PCa) remain poorly understood. Here we demonstrate that ectopic expression of the E3 ubiquitin ligase adaptor speckle-type poxvirus and zinc finger domain protein (SPOP) stabilizes 17βHSD4. SPOP bound a functional substrate-binding consensus (SBC) motif 315RATST319 in 17βHSD4 and promoted non-degradable K27- and K29-linked poly-ubiquitination of 17βHSD4. The effect of SPOP was antagonized by serum- and glucocorticoid kinase-3 (SGK3)-mediated phosphorylation of serine 318 (S318) in the SBC and S318 phosphorylation-dependent binding of SKP2 E3 ligase and subsequent K48-linked poly-ubiquitination and proteasomal degradation of 17βHSD4...
March 24, 2021: Cancer Research
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