Cancer Cell

Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality Publication date: Available online 2 May 2019 Source: Cancer Cell Author(s): Jo Ishizawa, Sarah F. Zarabi, R. Eric Davis, Ondrej Halgas, Takenobu Nii, Yulia Jitkova, Ran Zhao, Jonathan St-Germain, Lauren E. Heese, Grace Egan, Vivian R. Ruvolo, Samir H. Barghout, Yuki Nishida, Rose Hurren, Wencai Ma, Marcela Gronda, Todd Link, Keith Wong, Mark Mabanglo, Kensuke Kojima Summary The mitochondrial caseinolytic protease P (ClpP) plays a central role in mitochondrial protein quality control by degrading misfolded proteins. Using genetic and chemical approaches, we showed that hyperactivation of the protease selectively kills cancer cells, independently of p53 status, by selective degradation of its respiratory chain protein substrates and disrupts mitochondrial structure and function, while it does not affect non-malignant cells. We identified imipridones as potent activators of ClpP. Through biochemical studies and crystallography, we show that imipridones bind ClpP non-covalently and induce proteolysis by diverse structural changes. Imipridones are presently in clinical trials. Our findings suggest a general concept of inducing cancer cell lethality through activation of mitochondrial proteolysis.

Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis Publication date: Available online 25 April 2019 Source: Cancer Cell Author(s): Mohamed Elgendy, Marco Cirò, Amir Hosseini, Jakob Weiszmann, Luca Mazzarella, Elisa Ferrari, Riccardo Cazzoli, Giuseppe Curigliano, Andrea DeCensi, Bernardo Bonanni, Alfredo Budillon, Pier Giuseppe Pelicci, Veerle Janssens, Manfred Ogris, Manuela Baccarini, Luisa Lanfrancone, Wolfram Weckwerth, Marco Foiani, Saverio Minucci Summary Tumor cells may adapt to metabolic challenges by alternating between glycolysis and oxidative phosphorylation (OXPHOS). To target this metabolic plasticity, we combined intermittent fasting, a clinically feasible approach to reduce glucose availability, with the OXPHOS inhibitor metformin. In mice exposed to 24-h feeding/fasting cycles, metformin impaired tumor growth only when administered during fasting-induced hypoglycemia. Synergistic anti-neoplastic effects of the metformin/hypoglycemia combination were mediated by glycogen synthase kinase 3β (GSK3β) activation downstream of PP2A, leading to a decline in the pro-survival protein MCL-1, and cell death. Mechanistically, specific activation of the PP2A-GSK3β axis was the sum of metformin-induced inhibition of CIP2A, a PP2A suppressor, and of upregulation of the PP2A regulatory subunit B56δ by low glucose, leading to an active PP2A-B56δ complex with high affinity toward GSK3β. Graphical Abstract

Evolutionary Trajectories of IDHWT Glioblastomas Reveal a Common Path of Early Tumorigenesis Instigated Years ahead of Initial Diagnosis Publication date: 15 April 2019 Source: Cancer Cell, Volume 35, Issue 4 Author(s): Verena Körber, Jing Yang, Pankaj Barah, Yonghe Wu, Damian Stichel, Zuguang Gu, Michael Nai Chung Fletcher, David Jones, Bettina Hentschel, Katrin Lamszus, Jörg Christian Tonn, Gabriele Schackert, Michael Sabel, Jörg Felsberg, Angela Zacher, Kerstin Kaulich, Daniel Hübschmann, Christel Herold-Mende, Andreas von Deimling, Michael Weller Summary We studied how intratumoral genetic heterogeneity shapes tumor growth and therapy response for isocitrate dehydrogenase (IDH)-wild-type glioblastoma, a rapidly regrowing tumor. We inferred the evolutionary trajectories of matched pairs of primary and relapsed tumors based on deep whole-genome-sequencing data. This analysis suggests both a distant origin of de novo glioblastoma, up to 7 years before diagnosis, and a common path of early tumorigenesis, with one or more of chromosome 7 gain, 9p loss, or 10 loss, at tumor initiation. TERT promoter mutations often occurred later as a prerequisite for rapid growth. In contrast to this common early path, relapsed tumors acquired no stereotypical pattern of mutations and typically regrew from oligoclonal origins, suggesting sparse selective pressure by therapeutic measures. Graphical Abstract

Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia Publication date: 15 April 2019 Source: Cancer Cell, Volume 35, Issue 4 Author(s): Yue Huang, Rui Su, Yue Sheng, Lei Dong, Ze Dong, Hongjiao Xu, Tengfeng Ni, Zijie Scott Zhang, Tao Zhang, Chenying Li, Li Han, Zhenyun Zhu, Fulin Lian, Jiangbo Wei, Qiangqiang Deng, Yungui Wang, Mark Wunderlich, Zhiwei Gao, Guoyu Pan, Dafang Zhong Summary FTO, an mRNA N6-methyladenosine (m6A) demethylase, was reported to promote leukemogenesis. Using structure-based rational design, we have developed two promising FTO inhibitors, namely FB23 and FB23-2, which directly bind to FTO and selectively inhibit FTO's m6A demethylase activity. Mimicking FTO depletion, FB23-2 dramatically suppresses proliferation and promotes the differentiation/apoptosis of human acute myeloid leukemia (AML) cell line cells and primary blast AML cells in vitro. Moreover, FB23-2 significantly inhibits the progression of human AML cell lines and primary cells in xeno-transplanted mice. Collectively, our data suggest that FTO is a druggable target and that targeting FTO by small-molecule inhibitors holds potential to treat AML. Graphical Abstract

Synthetic Lethality of Wnt Pathway Activation and Asparaginase in Drug-Resistant Acute Leukemias Publication date: 15 April 2019 Source: Cancer Cell, Volume 35, Issue 4 Author(s): Laura Hinze, Maren Pfirrmann, Salmaan Karim, James Degar, Connor McGuckin, Divya Vinjamur, Joshua Sacher, Kristen E. Stevenson, Donna S. Neuberg, Esteban Orellana, Martin Stanulla, Richard I. Gregory, Daniel E. Bauer, Florence F. Wagner, Kimberly Stegmaier, Alejandro Gutierrez Summary Resistance to asparaginase, an antileukemic enzyme that depletes asparagine, is a common clinical problem. Using a genome-wide CRISPR/Cas9 screen, we found a synthetic lethal interaction between Wnt pathway activation and asparaginase in acute leukemias resistant to this enzyme. Wnt pathway activation induced asparaginase sensitivity in distinct treatment-resistant subtypes of acute leukemia, but not in normal hematopoietic progenitors. Sensitization to asparaginase was mediated by Wnt-dependent stabilization of proteins (Wnt/STOP), which inhibits glycogen synthase kinase 3 (GSK3)-dependent protein ubiquitination and proteasomal degradation, a catabolic source of asparagine. Inhibiting the alpha isoform of GSK3 phenocopied this effect, and pharmacologic GSK3α inhibition profoundly sensitized drug-resistant leukemias to asparaginase. Our findings provide a molecular rationale for activation of Wnt/STOP signaling to improve the therapeutic index of asparaginase. Graphical Abstract

γ-Catenin-Dependent Signals Maintain BCR-ABL1+ B Cell Acute Lymphoblastic Leukemia Publication date: 15 April 2019 Source: Cancer Cell, Volume 35, Issue 4 Author(s): Noemie Luong-Gardiol, Imran Siddiqui, Irene Pizzitola, Beena Jeevan-Raj, Mélanie Charmoy, Yun Huang, Anja Irmisch, Sara Curtet, Georgi S. Angelov, Maxime Danilo, Mélanie Juilland, Beat Bornhauser, Margot Thome, Oliver Hantschel, Yves Chalandon, Gianni Cazzaniga, Jean-Pierre Bourquin, Joerg Huelsken, Werner Held Summary The BCR-ABL1 fusion protein is the cause of chronic myeloid leukemia (CML) and of a significant fraction of adult-onset B cell acute lymphoblastic leukemia (B-ALL) cases. Using mouse models and patient-derived samples, we identified an essential role for γ-catenin in the initiation and maintenance of BCR-ABL1+ B-ALL but not CML. The selectivity was explained by a partial γ-catenin dependence of MYC expression together with the susceptibility of B-ALL, but not CML, to reduced MYC levels. MYC and γ-catenin enabled B-ALL maintenance by augmenting BIRC5 and enforced BIRC5 expression overcame γ-catenin loss. Since γ-catenin was dispensable for normal hematopoiesis, these lineage- and disease-specific features of canonical Wnt signaling identified a potential therapeutic target for the treatment of BCR-ABL1+ B-ALL. Graphical Abstract

Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties Publication date: 15 April 2019 Source: Cancer Cell, Volume 35, Issue 4 Author(s): Xiangqian Kong, Jie Chen, Wenbing Xie, Stephen M. Brown, Yi Cai, Kaichun Wu, Daiming Fan, Yongzhan Nie, Srinivasan Yegnasubramanian, Rochelle L. Tiedemann, Yong Tao, Ray-Whay Chiu Yen, Michael J. Topper, Cynthia A. Zahnow, Hariharan Easwaran, Scott B. Rothbart, Limin Xia, Stephen B. Baylin Summary UHRF1 facilitates the establishment and maintenance of DNA methylation patterns in mammalian cells. The establishment domains are defined, including E3 ligase function, but the maintenance domains are poorly characterized. Here, we demonstrate that UHRF1 histone- and hemimethylated DNA binding functions, but not E3 ligase activity, maintain cancer-specific DNA methylation in human colorectal cancer (CRC) cells. Disrupting either chromatin reader activity reverses DNA hypermethylation, reactivates epigenetically silenced tumor suppressor genes (TSGs), and reduces CRC oncogenic properties. Moreover, an inverse correlation between high UHRF1 and low TSG expression tracks with CRC progression and reduced patient survival. Defining critical UHRF1 domain functions and its relationship with CRC prognosis suggests directions for, and value of, targeting this protein to develop therapeutic DNA demethylating agents. Graphical Abstract

Intraclonal Plasticity in Mammary Tumors Revealed through Large-Scale Single-Cell Resolution 3D Imaging Publication date: 15 April 2019 Source: Cancer Cell, Volume 35, Issue 4 Author(s): Anne C. Rios, Bianca D. Capaldo, François Vaillant, Bhupinder Pal, Ravian van Ineveld, Caleb A. Dawson, Yunshun Chen, Emma Nolan, Nai Yang Fu, 3DTCLSM Group, Felicity C. Jackling, Sapna Devi, David Clouston, Lachlan Whitehead, Gordon K. Smyth, Scott N. Mueller, Geoffrey J. Lindeman, Jane E. Visvader Summary Breast tumors are inherently heterogeneous, but the evolving cellular organization through neoplastic progression is poorly understood. Here we report a rapid, large-scale single-cell resolution 3D imaging protocol based on a one-step clearing agent that allows visualization of normal tissue architecture and entire tumors at cellular resolution. Imaging of multicolor lineage-tracing models of breast cancer targeted to either basal or luminal progenitor cells revealed profound clonal restriction during progression. Expression profiling of clones arising in Pten/Trp53-deficient tumors identified distinct molecular signatures. Strikingly, most clones harbored cells that had undergone an epithelial-to-mesenchymal transition, indicating widespread, inherent plasticity. Hence, an integrative pipeline that combines lineage tracing, 3D imaging, and clonal RNA sequencing technologies offers a comprehensive path for studying mechanisms underlying heterogeneity in whole tumors. Graphical Abstract

CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis Publication date: 15 April 2019 Source: Cancer Cell, Volume 35, Issue 4 Author(s): Michael A. Augello, Deli Liu, Lesa D. Deonarine, Brian D. Robinson, Dennis Huang, Suzan Stelloo, Mirjam Blattner, Ashley S. Doane, Elissa W.P. Wong, Yu Chen, Mark A. Rubin, Himisha Beltran, Olivier Elemento, Andries M. Bergman, Wilbert Zwart, Andrea Sboner, Noah Dephoure, Christopher E. Barbieri Summary Deletion of the gene encoding the chromatin remodeler CHD1 is among the most common alterations in prostate cancer (PCa); however, the tumor-suppressive functions of CHD1 and reasons for its tissue-specific loss remain undefined. We demonstrated that CHD1 occupied prostate-specific enhancers enriched for the androgen receptor (AR) and lineage-specific cofactors. Upon CHD1 loss, the AR cistrome was redistributed in patterns consistent with the oncogenic AR cistrome in PCa samples and drove tumor formation in the murine prostate. Notably, this cistrome shift was associated with a unique AR transcriptional signature enriched for pro-oncogenic pathways unique to this tumor subclass. Collectively, these data credential CHD1 as a tumor suppressor in the prostate that constrains AR binding/function to limit tumor progression. Graphical Abstract

Human Tumor-Associated Macrophage and Monocyte Transcriptional Landscapes Reveal Cancer-Specific Reprogramming, Biomarkers, and Therapeutic Targets Publication date: 15 April 2019 Source: Cancer Cell, Volume 35, Issue 4 Author(s): Luca Cassetta, Stamatina Fragkogianni, Andrew H. Sims, Agnieszka Swierczak, Lesley M. Forrester, Hui Zhang, Daniel Y.H. Soong, Tiziana Cotechini, Pavana Anur, Elaine Y. Lin, Antonella Fidanza, Martha Lopez-Yrigoyen, Michael R. Millar, Alexandra Urman, Zhichao Ai, Paul T. Spellman, E. Shelley Hwang, J. Michael Dixon, Lisa Wiechmann, Lisa M. Coussens Summary The roles of tumor-associated macrophages (TAMs) and circulating monocytes in human cancer are poorly understood. Here, we show that monocyte subpopulation distribution and transcriptomes are significantly altered by the presence of endometrial and breast cancer. Furthermore, TAMs from endometrial and breast cancers are transcriptionally distinct from monocytes and their respective tissue-resident macrophages. We identified a breast TAM signature that is highly enriched in aggressive breast cancer subtypes and associated with shorter disease-specific survival. We also identified an auto-regulatory loop between TAMs and cancer cells driven by tumor necrosis factor alpha involving SIGLEC1 and CCL8, which is self-reinforcing through the production of CSF1. Together these data provide direct evidence that monocyte and macrophage transcriptional landscapes are perturbed by cancer, reflecting patient outcomes. Graphical Abstract