William F Forrest, Bruno Alicke, Oleg Mayba, Magdalena Osinska, Michal Jakubczak, Pawel Piatkowski, Lech Choniawko, Alice Starr, Stephen E Gould
Scientists working in translational oncology regularly conduct multi-group studies of mice with serially measured tumors. Longitudinal data collected can feature mid-study dropouts and complex nonlinear temporal response patterns. Parametric statistical models such as ones assuming exponential growth are useful for summarizing tumor volume over ranges for which the growth model holds, with the advantage that the model's parameter estimates can be used to summarize between-group differences in tumor volume growth with statistical measures of uncertainty...
September 25, 2020: Cancer Research
Hao-Nien Chen, Kang-Hao Liang, Jun-Kai Lai, Chun-Hsin Lan, Mei-Ying Liao, Shao-Hsi Hung, Yi-Ting Chuang, Kai-Chi Chen, William Wei-Fu Tsuei, Han-Chung Wu
Although EpCAM has previously been shown to promote tumor progression, the underlying mechanisms remain largely unknown. Here we report that the EGF-like domain I within the extracellular domain of EpCAM (EpEX) binds EGFR, activating both AKT and MAPK signaling to inhibit FOXO3a function and stabilize PD-L1 protein, respectively. Treatment with the EpCAM-neutralizing antibody EpAb2-6 inhibited AKT and FOXO3a phosphorylation, increased FOXO3a nuclear translocation, and upregulated HtrA2 expression to promote apoptosis while decreasing PD-L1 protein levels to enhance the cytotoxic activity of CD8+ T cells...
September 25, 2020: Cancer Research
Marie-Lisa Eich, James E Ferguson, Sooryanarayana Varambally
Next-generation genomic sequencing has identified multiple novel molecular alterations in cancer. Since the identification of DNA methylation and histone modification, it has become evident that genes encoding epigenetic modifiers that locally and globally regulate gene expression play a crucial role in normal development and cancer progression. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is the enzymatic catalytic subunit of the polycomb repressive complex 2 (PRC2) that can alter gene expression by trimethylating lysine 27 on histone 3 (H3K27)...
September 25, 2020: Cancer Research
Emily B Harrison, Alessandro Porrello, Brittany M Bowman, Adam R Belanger, Gabriella Yacovone, Salma H Azam, Ian A Windham, Subrata K Ghosh, Menglin Wang, Nick McKenzie, Trent A Waugh, Amanda E D Van Swearingen, Stephanie M Cohen, Devon G Allen, Tyler J Goodwin, Teresa Mascenik, James E Bear, Sarah Cohen, Scott H Randell, Pierre P Massion, Michael B Major, Leaf Huang, Chad V Pecot
Lung squamous carcinoma (LUSC) is a highly metastatic disease with a poor prognosis. Using an integrated screening approach, we found that miR-671-5p reduces LUSC metastasis by inhibiting a circular RNA (circRNA), CDR1as. Although the putative function of circRNA is through miRNA sponging, we found that miR-671-5p more potently silenced an axis of CDR1as and its antisense transcript, cerebellar degeneration related protein 1 (CDR1). Silencing of CDR1as or CDR1 significantly inhibited LUSC metastases and CDR1 was sufficient to promote migration and metastases...
September 25, 2020: Cancer Research
Michiel Bolkestein, John K L Wong, Verena Thewes, Verena Körber, Mario Hlevnjak, Shaymaa Elgaafary, Markus Schulze, Felix K F Kommoss, Hans-Peter Sinn, Tobias Anzeneder, Steffen Hirsch, Frauke Devens, Petra Schröter, Thomas Höfer, Andreas Schneeweiss, Peter Lichter, Marc Zapatka, Aurélie Ernst
Chromothripsis is a form of genome instability by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosomes. Widely assumed to be an early event in tumor development, this phenomenon plays a prominent role in tumor onset. In this study, an analysis of chromothripsis in 252 human breast cancers from two patient cohorts (149 metastatic breast cancers, 63 untreated primary tumors, 29 local relapses, 11 longitudinal pairs) using whole-genome and whole-exome sequencing reveals that chromothripsis affects a substantial proportion of human breast cancers, with a prevalence over 60% in a cohort of metastatic cases and 25% in a cohort comprising predominantly luminal breast cancers...
September 24, 2020: Cancer Research
Kee-Beom Kim, Youngchul Kim, Christopher J Rivard, Dong-Wook Kim, Kwon-Sik Park
Small cell lung cancer (SCLC) remains a recalcitrant disease where limited therapeutic options have not improved overall survival and approved targeted therapies are lacking. Amplification of the tyrosine kinase receptor FGFR1 (fibroblast growth factor receptor 1) is one of the few actionable alterations found in the SCLC genome. However, efforts to develop targeted therapies for FGFR1-amplified SCLC are hindered by critical gaps in knowledge around the molecular origins and mediators of FGFR1-driven signalling as well as the physiological impact of targeting FGFR1...
September 24, 2020: Cancer Research
Hiroshi Sootome, Hidenori Fujita, Kenjiro Ito, Hiroaki Ochiiwa, Yayoi Fujioka, Kimihiro Ito, Akihiro Miura, Takeshi Sagara, Satoru Ito, Hirokazu Ohsawa, Sachie Otsuki, Kaoru Funabashi, Masakazu Yashiro, Kenichi Matsuo, Kazuhiko Yonekura, Hiroshi Hirai
Fibroblast growth factor receptor (FGFR) signaling is deregulated in many human cancers and FGFR is considered a valid target in FGFR-deregulated tumors. Here we examine the preclinical profile of futibatinib (TAS-120; 1-[(3S)-[4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d] pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one), a structurally novel, irreversible FGFR1-4 inhibitor. Among a panel of 296 human kinases, futibatinib selectively inhibited FGFR1-4 with half-maximal inhibitory concentration (IC50) values of 1...
September 24, 2020: Cancer Research
Ga-Young Jeong, Mi Kyung Park, Hee-Joo Choi, Hee Woon An, Young-Un Park, Hyung-Jun Choi, Jin Park, Hyung-Yong Kim, Taekwon Son, Ho Lee, Kyueng-Whan Min, Young-Ha Oh, Jeong-Yeon Lee, Gu Kong
Histone methyltransferase NSD3 is frequently dysregulated in human cancers, yet the epigenetic role of NSD3 during cancer development remains elusive. Here we report that NSD3-induced methylation of H3K36 is crucial for breast tumor initiation and metastasis. In breast cancer patients, elevated expression of NSD3 was associated with recurrence, distant metastasis, and poor survival. In vivo, NSD3 promoted malignant transformation of mammary epithelial cells, a function comparable to that of HRAS. Furthermore, NSD3 expanded breast cancer-initiating cells and promoted epithelial-mesenchymal transition to trigger tumor invasion and metastasis...
September 23, 2020: Cancer Research
Nicola Manfrini, Marilena Mancino, Annarita Miluzio, Stefania Oliveto, Matteo Balestra, Piera Calamita, Roberta Alfieri, Riccardo L Rossi, Marco Sassoè-Pognetto, Chiara Salio, Alessandro Cuomo, Tiziana Bonaldi, Marcello Manfredi, Emilio Marengo, Elia Ranzato, Simona Martinotti, Davide Cittaro, Giovanni Tonon, Stefano Biffo
Multiple myeloma (MM) is a plasma cell neoplasm characterized by the production of unfolded immunoglobulins which cause endoplasmic reticulum (ER) stress and sensitivity to proteasome inhibition. The genomic landscape of MM is characterized by the loss of several genes rarely mutated in other cancers that may underline specific weaknesses of MM cells. One of these is FAM46C that is lost in more than 10% of MM patients. We show here that FAM46C is part of a new complex containing the ER-associated protein FNDC3A which regulates trafficking and secretion and, by impairing autophagy, exacerbates proteostatic stress...
September 22, 2020: Cancer Research
Surya Murty, Louai Labanieh, Tara Murty, Gayatri Gowrishankar, Tom Haywood, Israt S Alam, Corinne Beinat, Elise Robinson, Amin Aalipour, Dorota D Klysz, Jennifer R Cochran, Robbie G Majzner, Crystal L Mackall, Sanjiv S Gambhir
Imaging strategies to monitor chimeric antigen receptor (CAR) T-cell biodistribution and proliferation harbor the potential to facilitate clinical translation for the treatment of both liquid and solid tumors. Additionally, the potential adverse effects of CAR T-cells highlight the need for mechanisms to modulate CAR T-cell activity. The herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene has previously been translated as a positron emission tomography (PET) reporter gene for imaging of T-cell trafficking in brain tumor patients...
September 21, 2020: Cancer Research
Hui Liu, Kangdong Liu, Zigang Dong
Cyclin dependent kinase 12 (CDK12) is a member of the CDK family of proteins (CDK) and is critical for cancer development. Years of study into CDK12 have generated much information regarding the intricacy of its function and mechanism as well as inhibitors against it for oncological research. However, there remains a lack of understanding regarding the role of CDK12 in carcinogenesis and cancer prevention. An exhaustive comprehension of CDK12 will highly stimulate the development of new strategies for treating and preventing cancer...
September 21, 2020: Cancer Research
Elavarasan Subramani, Marina Radoul, Chloe Najac, Georgios Batsios, Abigail R Molloy, Donghyun Hong, Anne Marie Gillespie, Romelyn Delos Santos, Pavithra Viswanath, Joseph F Costello, Russell O Pieper, Sabrina M Ronen
Although lower-grade gliomas are driven by mutations in the isocitrate dehydrogenase 1 (IDH1) gene and are less aggressive than primary glioblastoma, they nonetheless generally recur. IDH1 mutant patients are increasingly being treated with temozolomide (TMZ), but early detection of response remains a challenge and there is a need for complementary imaging methods to assess response to therapy prior to tumor shrinkage. The goal of this study was to determine the value of magnetic resonance spectroscopy (MRS)-based metabolic changes for detection of response to TMZ in both genetically engineered and patient-derived mutant IDH1 models...
September 21, 2020: Cancer Research
Justin M Drerup, Yilun Deng, Sri Lakshmi Pandeswara, Álvaro S Padrón, Ryan M Reyes, Xinyue Zhang, Jenny Mendez, Aijie Liu, Curtis A Clark, Wanjiao Chen, José R Conejo-Garcia, Vincent Hurez, Harshita Gupta, Tyler J Curiel
The IL-2 receptor (IL-2R) is an attractive cancer immunotherapy target that controls immunosuppressive T regulatory cells (Tregs) and anti-tumor T cells. Here we used IL-2Rβ-selective IL-2/anti-IL-2 complexes (IL-2c) to stimulate effector T cells preferentially in the orthotopic mouse ID8agg ovarian cancer (OC) model. Despite strong tumor rejection, IL-2c unexpectedly lowered the tumor microenvironmental CD8+/Treg ratio. IL-2c reduced tumor microenvironmental Treg suppression and induced a fragile Treg phenotype, helping explain improved efficacy despite numerically increased Tregs without affecting Treg in draining lymph nodes...
September 18, 2020: Cancer Research
Cai Bowen, Maho Shibata, Hailan Zhang, Sarah K Bergren, Michael M Shen, Edward P Gelmann
NKX3.1 is the most commonly deleted gene in prostate cancer and is a gatekeeper suppressor. NKX3.1 is haploinsufficient, and pathogenic reduction in protein levels may result from genetic loss, decreased transcription, and increased protein degradation caused by inflammation or PTEN loss. NKX3.1 acts by retarding proliferation, activating antioxidants, and enhancing DNA repair. DYRK1B-mediated phosphorylation at serine 185 of NKX3.1 leads to its polyubiquitination and proteasomal degradation. Because NKX3.1 protein levels are reduced but never entirely lost in prostate adenocarcinoma, enhancement of NKX3...
September 17, 2020: Cancer Research
Melissa A Galati, Karl P Hodel, Miki S Gams, Sumedha Sudhaman, Taylor Bridge, Walter J Zahurancik, Nathan A Ungerleider, Vivian S Park, Ayse B Ercan, Lazar Joksimovic, Iram Siddiqui, Robert Siddaway, Melissa Edwards, Richard de Borja, Dana Elshaer, Jiil Chung, Victoria J Forster, Nuno M Nunes, Melyssa Aronson, Xia Wang, Jagadeesh Ramdas, Andrea Seeley, Tomasz Sarosiek, Gavin P Dunn, Jonathan N Byrd, Oz Mordechai, Carol Durno, Alberto Martin, Adam Shlien, Eric Bouffet, Zucai Suo, James G Jackson, Cynthia E Hawkins, Cynthia J Guidos, Zachary F Pursell, Uri Tabori
POLE mutations are a major cause of hypermutant cancers, yet questions remain regarding mechanisms of tumorigenesis, genotype-phenotype correlation, and therapeutic considerations. In this study, we establish mouse models harboring cancer-associated POLE mutations P286R and S459F, which cause rapid albeit distinct time to cancer initiation in vivo independent of their exonuclease activity. Mouse and human correlates enabled novel stratification of POLE mutations into 3 groups based on clinical phenotype and mutagenicity...
September 16, 2020: Cancer Research
Gregory J Kimmel, Mark Dane, Laura M Heiser, Philipp M Altrock, Noemi Andor
Breast cancer progresses in a multistep process from primary tumor growth and stroma invasion to metastasis. Nutrient-limiting environments promote chemotaxis with aggressive morphologies characteristic of invasion. It is unknown how co-existing cells differ in their response to nutrient limitations and how this impacts invasion of the metapopulation as a whole. In this study, we integrate mathematical modeling with microenvironmental perturbation data to investigate invasion in nutrient-limiting environments inhabited by one or two cancer cell subpopulations...
September 16, 2020: Cancer Research
Neel Shah, Nikolas Kesten, Alba Font-Tello, Matthew E K Chang, Raga Vadhi, Klothilda Lim, Mark R Flory, Paloma Cejas, Hisham Mohammed, Henry W Long, Myles Brown
The TMPRSS2-ERG fusion is the most common genomic rearrangement in human prostate cancer. However, in established adenocarcinoma, it is unknown how the ERG oncogene promotes a cancerous phenotype and maintains downstream androgen receptor (AR) signaling pathways. In this study, we utilized a murine prostate organoid system to explore the effects of ERG on tumorigenesis and determined the mechanism underlying prostate cancer dependence on ERG. Prostate organoids lacking PTEN and overexpressing ERG (Pten-/- R26-ERG) faithfully recapitulated distinct stages of prostate cancer disease progression...
September 15, 2020: Cancer Research
Derek S Park, Kimberly A Luddy, Mark Robertson-Tessi, Cliona O'Farrelly, Robert A Gatenby, Alexander R A Anderson
Deaths from cancer are mostly due to metastatic disease that becomes resistant to therapy. A mainstay treatment for many cancers is chemotherapy for which the dosing strategy is primarily limited by patient toxicity. While this Maximum Tolerated Dose (MTD) approach builds upon the intuitively appealing principle that maximum therapeutic benefit is achieved by killing the largest possible number of cancer cells, there is increasing evidence that moderation might allow host-specific features to contribute to success...
September 15, 2020: Cancer Research
Poornima Bhat-Nakshatri, Brijesh Kumar, Ed Simpson, Kandice K Ludwig, Mary L Cox, Hongyu Gao, Yunlong Liu, Harikrishna Nakshatri
Radiologic techniques remain the main method for early detection for breast cancer and are critical to achieve a favorable outcome from cancer. However, more sensitive detection methods to complement radiologic techniques are needed to enhance early detection and treatment strategies. Using our recently established culturing method that allows propagation of normal and cancerous breast epithelial cells of luminal origin, flow cytometry characterization, and genomic sequencing, we show that cancer cells can be detected in breast milk...
September 15, 2020: Cancer Research
Elizabeth Lenkiewicz, Smriti Malasi, Tara L Hogenson, Luis F Flores, Whitney Barham, William J Phillips, Alexander S Roesler, Kendall R Chambers, Nirakar Rajbhandari, Akimasa Hayashi, Paul M Grandgenett, Michael A Hollingsworth, Derek Cridebring, Yuning Xiong, Jeong-Heon Lee, Zhenqing Ye, Huihuang Yan, Matthew C Hernandez, Jennifer L Leiting, Tamas Ordog, Mark J Truty, Mitesh J Borad, Tannishtha Reya, Daniel D Von Hoff, Martin E Fernandez-Zapico, Michael T Barrett
Adenosquamous cancer of the pancreas (ASCP) is a subtype of pancreatic cancer that has a worse prognosis and greater metastatic potential than the more common pancreatic ductal adenocarcinoma (PDAC) subtype. To distinguish the genomic landscape of ASCP and identify actionable targets for this lethal cancer, we applied DNA content flow cytometry to a series of 15 tumor samples including five patient-derived xenografts (PDX). We interrogated purified sorted tumor fractions from these samples with whole-genome copy-number variant (CNV), whole-exome sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analyses...
September 14, 2020: Cancer Research
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