ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage
Pancreatic ductal adenocarcinomas (PDAC) harbor recurrent functional mutations of the master DNA damage response kinase ATM, which has been shown to accelerate tumorigenesis and epithelial–mesenchymal transition. To study how ATM deficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional Atm deletion in a mouse model of PDAC. ATM deficiency was associated with increased mitotic defects, recurrent genomic rearrangements, and deregulated DNA integrity checkpoints, reminiscent of human PDAC. We hypothesized that altered genome integrity might allow synthetic lethali...
Source: Cancer Research - October 15, 2017 Category: Cancer & Oncology Authors: Lukas Perkhofer, Anna Schmitt, Maria Carolina Romero Carrasco, Michaela Ihle, Stephanie Hampp, Dietrich Alexander Ruess, Elisabeth Hessmann, Ronan Russell, Andre Lechel, Ninel Azoitei, Qiong Lin, Stefan Liebau, Meike Hohwieler, Hanibal Bohnenberger, Marin Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer
Resistance invariably develops to antiandrogen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here, we report that the transcriptional coactivator CBP/p300 is required to maintain the growth of castration-resistant prostate cancer. To exploit this vulnerability, we developed a novel small-molecule inhibitor of the CBP/p300 bromodomain that blocks prostate cancer growth in vitro and in vivo. Molecular dissection of the consequences of drug treatment revealed a critical role for CBP/p300 in histone acetylation required for the transcriptiona...
Source: Cancer Research - October 15, 2017 Category: Cancer & Oncology Authors: Lingyan Jin, Jesse Garcia, Emily Chan, Cecile de la Cruz, Ehud Segal, Mark Merchant, Samir Kharbanda, Ryan Raisner, Peter M. Haverty, Zora Modrusan, Justin Ly, Edna Choo, Susan Kaufman, Maureen H. Beresini, F. Anthony Romero, Steven Magnuson, Karen E. Gas Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
Adaptation to TKI Treatment Reactivates ERK Signaling in Tyrosine Kinase-Driven Leukemias and Other Malignancies
FMS-like tyrosine kinase-3 (FLT3) tyrosine kinase inhibitors (TKI) have been tested extensively to limited benefit in acute myeloid leukemia (AML). We hypothesized that FLT3/internal tandem duplication (ITD) leukemia cells exhibit mechanisms of intrinsic signaling adaptation to TKI treatment that are associated with an incomplete response. Here, we identified reactivation of ERK signaling within hours following treatment of FLT3/ITD AML cells with selective inhibitors of FLT3. When these cells were treated with inhibitors of both FLT3 and MEK in combination, ERK reactivation was abrogated and anti-leukemia effects were mor...
Source: Cancer Research - October 15, 2017 Category: Cancer & Oncology Authors: J. Kyle Bruner, Hayley S. Ma, Li Li, Alice Can Ran Qin, Michelle A. Rudek, Richard J. Jones, Mark J. Levis, Keith W. Pratz, Christine A. Pratilas, Donald Small Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
Shrimp miR-S8 Suppresses the Stemness of Human Melanoma Stem-like Cells by Targeting the Transcription Factor YB-1
In this study, we report a novel approach to ablate melanoma stem-like cells by targeting the transcription factor YB-1, which is significantly and selectively upregulated in these cells in melanoma. Silencing YB-1 expression was sufficient to significantly inhibit the stemness of melanoma stem-like cells. In exploring YB-1 targeting, we discovered that the shrimp microRNA miR-S8 could suppress human YB-1 expression in melanoma stem-like cells. Mechanistic investigations revealed that miR-S8 recognized the 3′UTR of YB-1 mRNA and mediated its degradation. In tumor cell and xenograft experiments, miR-S8 suppressed the tumo...
Source: Cancer Research - October 15, 2017 Category: Cancer & Oncology Authors: Fan Yang, Jun Wei, Song Zhang, Xiaobo Zhang Tags: Tumor and Stem Cell Biology Source Type: research
Loss of Tumor Suppressor STAG2 Promotes Telomere Recombination and Extends the Replicative Lifespan of Normal Human Cells
Sister chromatids are held together by cohesin, a tripartite ring with a peripheral SA1/2 subunit, where SA1 is required for telomere cohesion and SA2 for centromere cohesion. The STAG2 gene encoding SA2 is often inactivated in human cancer, but not in in a manner associated with aneuploidy. Thus, how these tumors maintain chromosomal cohesion and how STAG2 loss contributes to tumorigenesis remain open questions. Here we show that, despite a loss in centromere cohesion, sister chromatids in STAG2 mutant tumor cells maintain cohesion in mitosis at chromosome arms and telomeres. Telomere maintenance in STAG2 mutant tumor cel...
Source: Cancer Research - October 15, 2017 Category: Cancer & Oncology Authors: Zharko Daniloski, Susan Smith Tags: Tumor and Stem Cell Biology Source Type: research
Sensitivity to BUB1B Inhibition Defines an Alternative Classification of Glioblastoma
In this study, we develop evidence that the mitotic spindle checkpoint molecule BUB1B may offer a predictive marker for aggressiveness and effective drug response. A subset of GBM tumor isolates requires BUB1B to suppress lethal kinetochore–microtubule attachment defects. Using gene expression data from GBM stem-like cells, astrocytes, and neural progenitor cells that are sensitive or resistant to BUB1B inhibition, we created a computational framework to predict sensitivity to BUB1B inhibition. Applying this framework to tumor expression data from patients, we stratified tumors into BUB1B-sensitive (BUB1BS) or BUB1B-resi...
Source: Cancer Research - October 15, 2017 Category: Cancer & Oncology Authors: Eunjee Lee, Margaret Pain, Huaien Wang, Jacob A. Herman, Chad M. Toledo, Jennifer G. DeLuca, Raymund L. Yong, Patrick Paddison, Jun Zhu Tags: Tumor and Stem Cell Biology Source Type: research
De Novo Lipid Synthesis Facilitates Gemcitabine Resistance through Endoplasmic Reticulum Stress in Pancreatic Cancer
Pancreatic adenocarcinoma is moderately responsive to gemcitabine-based chemotherapy, the most widely used single-agent therapy for pancreatic cancer. Although the prognosis in pancreatic cancer remains grim in part due to poor response to therapy, previous attempts at identifying and targeting the resistance mechanisms have not been very successful. By leveraging The Cancer Genome Atlas dataset, we identified lipid metabolism as the metabolic pathway that most significantly correlated with poor gemcitabine response in pancreatic cancer patients. Furthermore, we investigated the relationship between alterations in lipogene...
Source: Cancer Research - October 15, 2017 Category: Cancer & Oncology Authors: Saber Tadros, Surendra K. Shukla, Ryan J. King, Venugopal Gunda, Enza Vernucci, Jaime Abrego, Nina V. Chaika, Fang Yu, Audrey J. Lazenby, Lyudmyla Berim, Jean Grem, Aaron R. Sasson, Pankaj K. Singh Tags: Tumor and Stem Cell Biology Source Type: research
Human Pluripotent Stem Cell-Derived TSC2-Haploinsufficient Smooth Muscle Cells Recapitulate Features of Lymphangioleiomyomatosis
Lymphangioleiomyomatosis (LAM) is a progressive destructive neoplasm of the lung associated with inactivating mutations in the TSC1 or TSC2 tumor suppressor genes. Cell or animal models that accurately reflect the pathology of LAM have been challenging to develop. Here, we generated a robust human cell model of LAM by reprogramming TSC2 mutation–bearing fibroblasts from a patient with both tuberous sclerosis complex (TSC) and LAM (TSC-LAM) into induced pluripotent stem cells (iPSC), followed by selection of cells that resemble those found in LAM tumors by unbiased in vivo differentiation. We established expandable cell l...
Source: Cancer Research - October 15, 2017 Category: Cancer & Oncology Authors: Lisa M. Julian, Sean P. Delaney, Ying Wang, Alexander A. Goldberg, Carole Dore, Julien Yockell–Lelievre, Roger Y. Tam, Krinio Giannikou, Fiona McMurray, Molly S. Shoichet, Mary–Ellen Harper, Elizabeth P. Henske, David J. Kwiatkowski, Thomas N. Tags: Molecular and Cellular Pathobiology Source Type: research
LSD1-Mediated Epigenetic Reprogramming Drives CENPE Expression and Prostate Cancer Progression
Androgen receptor (AR) signaling is a key driver of prostate cancer, and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant prostate cancer (CRPC). Here, we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell-cycle genes, including CENPE, a centromere binding protein and mitotic kinesin. CENPE was regulated by the co-binding of LSD1 and ...
Source: Cancer Research - October 15, 2017 Category: Cancer & Oncology Authors: Yi Liang, Musaddeque Ahmed, Haiyang Guo, Fraser Soares, Junjie T. Hua, Shuai Gao, Catherine Lu, Christine Poon, Wanting Han, Jens Langstein, Muhammad B. Ekram, Brian Li, Elai Davicioni, Mandeep Takhar, Nicholas Erho, R. Jeffrey Karnes, Dianne Chadwick, Th Tags: Molecular and Cellular Pathobiology Source Type: research
STRAP Promotes Stemness of Human Colorectal Cancer via Epigenetic Regulation of the NOTCH Pathway
NOTCH signaling exerts essential roles in normal and malignant intestinal physiology and the homeostasis of cancer stem-like cells (CSC), but the basis for this latter role remains obscure. The signaling scaffold protein STRAP is upregulated in several cancers, where it promotes tumorigenicity and metastasis. Here we report a novel oncogenic function for STRAP in maintaining CSC subpopulations in a heterogeneous mixture by antagonizing formation of the chromatin modifier PRC2 and by epigenetically activating NOTCH signals in human colorectal cancer. Silencing STRAP sensitized colorectal cancer cells to chemotherapeutic dru...
Source: Cancer Research - October 15, 2017 Category: Cancer & Oncology Authors: Lin Jin, Trung Vu, Guandou Yuan, Pran K. Datta Tags: Molecular and Cellular Pathobiology Source Type: research
HIF-2{alpha} Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1
Disease progression and relapse in multiple myeloma is dependent on the ability of the multiple myeloma plasma cells (PC) to reenter the circulation and disseminate throughout the bone marrow. Increased bone marrow hypoxia is associated with increased recirculation of multiple myeloma PCs. Accordingly, we hypothesized that during chronic hypoxia, activation of HIF-2α may overcome the bone marrow retention signal provided by stromal-derived CXCL12, thereby enabling dissemination of multiple myeloma PCs. Here we demonstrate that HIF-2α upregulates multiple myeloma PC CXCL12 expression, decreasing migration toward CXCL12 an...
Source: Cancer Research - October 15, 2017 Category: Cancer & Oncology Authors: Kate Vandyke, Mara N. Zeissig, Duncan R. Hewett, Sally K. Martin, Krzysztof M. Mrozik, Chee Man Cheong, Peter Diamond, L. Bik To, Stan Gronthos, Daniel J. Peet, Peter I. Croucher, Andrew C.W. Zannettino Tags: Molecular and Cellular Pathobiology Source Type: research
The Rac GTPase in Cancer: From Old Concepts to New Paradigms
Rho family GTPases are critical regulators of cellular functions that play important roles in cancer progression. Aberrant activity of Rho small G-proteins, particularly Rac1 and their regulators, is a hallmark of cancer and contributes to the tumorigenic and metastatic phenotypes of cancer cells. This review examines the multiple mechanisms leading to Rac1 hyperactivation, particularly focusing on emerging paradigms that involve gain-of-function mutations in Rac and guanine nucleotide exchange factors, defects in Rac1 degradation, and mislocalization of Rac signaling components. The unexpected pro-oncogenic functions of R...
Source: Cancer Research - October 15, 2017 Category: Cancer & Oncology Authors: Marcelo G. Kazanietz, Maria J. Caloca Tags: Reviews Source Type: research
Cancer Self-Defense: An Immune Stealth
The hurdles in realizing successful cancer immunotherapy stem from the fact that cancer patients are either refractory to immune response and/or develop resistance. Here, we propose that these phenomena are due, in part, to the deployment/secretion of a “decoy flare,” for example, anomalous cancer-associated antigens by the tumor cells. The cancer secretome, which resembles the parent cell make-up, is composed of soluble macromolecules (proteins, glycans, lipids, DNAs, RNAs, etc.) and insoluble vesicles (exosomes), thus hindering cancer detection/recognition by immunotherapeutic agents, resulting in a “cancer-stealth...
Source: Cancer Research - October 15, 2017 Category: Cancer & Oncology Authors: Kosei Nakajima, Pratima Nangia-Makker, Victor Hogan, Avraham Raz Tags: Reviews Source Type: research
Highlights from Recent Cancer Literature
(Source: Cancer Research)
Source: Cancer Research - October 15, 2017 Category: Cancer & Oncology Tags: Breaking Advances Source Type: research
Evolution of Cancer Stem-like Cells in Endocrine-Resistant Metastatic Breast Cancers Is Mediated by Stromal Microvesicles
(Source: Cancer Research)
Source: Cancer Research - October 1, 2017 Category: Cancer & Oncology Tags: Correction Source Type: research
