bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Table S4 from SRSF3-Regulated RNA Alternative Splicing Promotes Glioblastoma Tumorigenicity by Affecting Multiple Cellular Processes
Authors: Song Xiao , Wan Xuechao , Huang Tianzhi , Zeng Chang , Sastry Namratha , Wu Bingli , James C. David , Horbinski Craig , Nakano Ichiro , Zhang Wei , Hu Bo , Cheng Shi-Yuan
Published: March 2023

List of SRSF3-affected and -correlated AS events in GSCs
Supplementary Figure 2 from Landscape of Germline and Somatic Mitochondrial DNA Mutations in Pediatric Malignancies
Authors: Triska Petr , Kaneva Kristiyana , Merkurjev Daria , Sohail Noor , Falk Marni J. , Triche Timothy J. , Biegel Jaclyn A. , Gai Xiaowu
Published: March 2023

Supplementary Figure 2 illustrates that individual tumor cells showing the same mtDNA variants at different heteroplasmy levels as exhibited by the bulk tumor samples.
Table S2 from SIX2 Mediates Late-Stage Metastasis via Direct Regulation of SOX2 and Induction of a Cancer Stem Cell Program
Authors: Oliphant Michael U.J. , Vincent Melanie Y. , Galbraith Matthew D. , Pandey Ahwan , Zaberezhnyy Vadym , Rudra Pratyaydipta , Johnson Katherine R. , Costello James C. , Ghosh Debashis , DeGregori James , Espinosa Joaquin M. , Ford Heide L.
Published: March 2023

List of enriched pathways after GSEA Analysis
Supplementary Table S2 from Inactivation of Proprotein Convertases in T Cells Inhibits PD-1 Expression and Creates a Favorable Immune Microenvironment in Colorectal Cancer
Authors: Tomé Mercedes , Pappalardo Angela , Soulet Fabienne , López José Javier , Olaizola Jone , Leger Yannick , Dubreuil Marielle , Mouchard Amandine , Fessart Delphine , Delom Frédéric , Pitard Vincent , Bechade Dominique , Fonck Mariane , Rosado Juan Antonio , Ghiringhelli François , Déchanet-Merville Julie , Soubeyran Isabelle , Siegfried Geraldine , Evrard Serge , Khatib Abdel-Majid
Published: March 2023

Key resources Table
Figure S3 from SIX2 Mediates Late-Stage Metastasis via Direct Regulation of SOX2 and Induction of a Cancer Stem Cell Program
Authors: Oliphant Michael U.J. , Vincent Melanie Y. , Galbraith Matthew D. , Pandey Ahwan , Zaberezhnyy Vadym , Rudra Pratyaydipta , Johnson Katherine R. , Costello James C. , Ghosh Debashis , DeGregori James , Espinosa Joaquin M. , Ford Heide L.
Published: March 2023

Six2 binding is enriched at the promoters of genes previously shown to be critical for normal and cancer stem cell like function.
Figure S2 from Chemotherapy-Induced Extracellular Vesicle miRNAs Promote Breast Cancer Stemness by Targeting ONECUT2
Authors: Shen Meng , Dong Chuan , Ruan Xianhui , Yan Wei , Cao Minghui , Pizzo Donald , Wu Xiwei , Yang Lin , Liu Liang , Ren Xiubao , Wang Shizhen Emily
Published: March 2023

Figure S2 showing strategy to select chemo-EV miRNAs for functional investigation
Supplementary Table S1 from YES1 Is a Targetable Oncogene in Cancers Harboring YES1 Gene Amplification
Authors: Hamanaka Natsuki , Nakanishi Yoshito , Mizuno Takakazu , Horiguchi-Takei Kana , Akiyama Nukinori , Tanimura Hiromi , Hasegawa Masami , Satoh Yasuko , Tachibana Yukako , Fujii Toshihiko , Sakata Kiyoaki , Ogasawara Kiyomoto , Ebiike Hirosato , Koyano Hiroshi , Sato Haruhiko , Ishii Nobuya , Mio Toshiyuki
Published: March 2023

Kinase inhibitory activity of CH6953755, dasatinib and bosutinib against 39 kinases.
Figure S6 from A Microbial Siderophore-Inspired Self-Gelling Hydrogel for Noninvasive Anticancer Phototherapy
Authors: Ko Seungbeom , Park Joo Yeon , Oh Yu-Kyoung
Published: March 2023

Infiltration of inflammatory cells
Supplementary Materials and Methods from Isoflavone ME-344 Disrupts Redox Homeostasis and Mitochondrial Function by Targeting Heme Oxygenase 1
Authors: Zhang Leilei , Zhang Jie , Ye Zhiwei , Manevich Yefim , Ball Lauren E. , Bethard Jennifer R. , Jiang Yu-Lin , Broome Ann-Marie , Dalton Annamarie C. , Wang Gavin Y. , Townsend Danyelle M. , Tew Kenneth D.
Published: March 2023

Antibodies. Primers. Click Chemistry and Affinity Enrichment Mass Spectrometry. Surface Plasmon Resonance - Biacore 3000 Kinetic Determinations. Co-Immunoprecipitation. Transfections with shRNA and plasmids. Plate colony formation assay. References.
Supplementary Figures from A PolH Transcript with a Short 3′UTR Enhances PolH Expression and Mediates Cisplatin Resistance
Authors: Zhang Jin , Sun Wenqiang , Ren Cong , Kong Xiangmudong , Yan Wensheng , Chen Xinbin
Published: March 2023

Supplementary figures to elucidate that the role of APA in PolH-meidated cisplatin resistance in bladder cancer and to elucidate the role of Mir619 in regulating PolH expression via APA.
Supplementary Data S3 from Oncogenic KRAS Sensitizes Lung Adenocarcinoma to GSK-J4–Induced Metabolic and Oxidative Stress
Authors: Hong Beom-Jin , Park Woo-Yong , Kim Hwa-Ryeon , Moon Jin Woo , Lee Ho Yeon , Park Jun Hyung , Kim Seon-Kyu , Oh Youngbin , Roe Jae-Seok , Kim Mi-Young
Published: March 2023

GO analysis of GSK-J4-upregulated genes
Supplementary Figures from Heparanase Accelerates Obesity-Associated Breast Cancer Progression
Authors: Hermano Esther , Goldberg Rachel , Rubinstein Ariel M. , Sonnenblick Amir , Maly Bella , Nahmias Daniela , Li Jin-Ping , Bakker Marinka A.H. , van der Vlag Johan , Vlodavsky Israel , Peretz Tamar , Elkin Michael
Published: March 2023

All supplementary Figures
Figure S1 from Radiosensitivity Is an Acquired Vulnerability of PARPi-Resistant BRCA1-Deficient Tumors
Authors: Barazas Marco , Gasparini Alessia , Huang Yike , Küçükosmanoğlu Asli , Annunziato Stefano , Bouwman Peter , Sol Wendy , Kersbergen Ariena , Proost Natalie , de Korte-Grimmerink Renske , van de Ven Marieke , Jonkers Jos , Borst Gerben R. , Rottenberg Sven
Published: March 2023

Supplementary Figure S1. KB1P-RR tumors have an activated DNA damage response. Related to Figure 1.
Figure S5 from Targeting APLN/APLNR Improves Antiangiogenic Efficiency and Blunts Proinvasive Side Effects of VEGFA/VEGFR2 Blockade in Glioblastoma
Authors: Mastrella Giorgia , Hou Mengzhuo , Li Min , Stoecklein Veit M. , Zdouc Nina , Volmar Marie N.M. , Miletic Hrvoje , Reinhard Sören , Herold-Mende Christel C. , Kleber Susanne , Eisenhut Katharina , Gargiulo Gaetano , Synowitz Michael , Vescovi Angelo L. , Harter Patrick N. , Penninger Josef M. , Wagner Ernst , Mittelbronn Michel , Bjerkvig Rolf , Hambardzumyan Dolores , Schüller Ulrich , Tonn Jörg-Christian , Radke Josefine , Glass Rainer , Kälin Roland E.
Published: March 2023

APLNR is expressed in glioblastoma cells and receptor internalization is activated by apelin peptides specifically.
Supplementary Figure 3 from ICOS Is an Indicator of T-cell–Mediated Response to Cancer Immunotherapy
Authors: Xiao Zunyu , Mayer Aaron T. , Nobashi Tomomi W. , Gambhir Sanjiv S.
Published: March 2023

Figure S3: Ex-vivo biodistribution study of PD-1 i.p and PBS i.p groups (n{greater than or equal to}5) on Day 8 post anti PD-1 treatment: the quantification of TDLN was expressed as %ID, other organs were expressed as %ID/g. All values represent the mean {plus minus} SD unless otherwise specified. Unpaired 2-tailed student's t-test were used for analysis. (*: P<0.05, the data was presented as mean {plus minus} SD)
Supplementary Data from p53-Suppressed Oncogene TET1 Prevents Cellular Aging in Lung Cancer
Authors: Filipczak Piotr T. , Leng Shuguang , Tellez Carmen S. , Do Kieu C. , Grimes Marcie J. , Thomas Cynthia L. , Walton-Filipczak Stephanie R. , Picchi Maria A. , Belinsky Steven A.
Published: March 2023

Fig. S3. Induction of WT p53 protein using temperature regulated expression vector.
Supplementary figure 1 from RIPK3-Induced Inflammation by I-MDSCs Promotes Intestinal Tumors
Authors: Jayakumar Asha , Bothwell Alfred L.M.
Published: March 2023

Gating strategy for MDSCs and sorting purity
Supplementary Table 1 from RUNX1 Is a Driver of Renal Cell Carcinoma Correlating with Clinical Outcome
Authors: Rooney Nicholas , Mason Susan M. , McDonald Laura , Däbritz J. Henry M. , Campbell Kirsteen J. , Hedley Ann , Howard Steven , Athineos Dimitris , Nixon Colin , Clark William , Leach Joshua D.G. , Sansom Owen J. , Edwards Joanne , Cameron Ewan R. , Blyth Karen
Published: March 2023

Supplementary Table 1. The relationship between RUNX2 and clinico-pathological characteristics of kidney cancer in the TMA study.
Supplementary Data from Destablilization of TRAF6 by DRAK1 Suppresses Tumor Growth and Metastasis in Cervical Cancer Cells
Authors: Park Yuna , Pang Kyoungwha , Park Jinah , Hong Eunji , Lee Jihee , Ooshima Akira , Kim Hae-Suk , Cho Jae Hyun , Han Youngjin , Lee Cheol , Song Yong Sang , Park Kyung-Soon , Yang Kyung-Min , Kim Seong-Jin
Published: March 2023

Supplementary Information
Supplementary Video 6 from Pattern of Invasion in Human Pancreatic Cancer Organoids Is Associated with Loss of SMAD4 and Clinical Outcome
Authors: Huang Wenjie , Navarro-Serer Bernat , Jeong Yea Ji , Chianchiano Peter , Xia Limin , Luchini Claudio , Veronese Nicola , Dowiak Cameron , Ng Tammy , Trujillo Maria A. , Huang Bo , Pflüger Michael J. , Macgregor-Das Anne M. , Lionheart Gemma , Jones Danielle , Fujikura Kohei , Nguyen-Ngoc Kim-Vy , Neumann Neil M. , Groot Vincent P. , Hasanain Alina , van Oosten A. Floortje , Fischer Sandra E. , Gallinger Steven , Singhi Aatur D. , Zureikat Amer H. , Brand Randall E. , Gaida Matthias M. , Heinrich Stefan , Burkhart Richard A. , He Jin , Wolfgang Christopher L. , Goggins Michael G. , Thompson Elizabeth D. , Roberts Nicholas J. , Ewald Andrew J. , Wood Laura D.
Published: March 2023

Supplementary Video 6. Time-lapse analysis of SMAD4-mutant PDAC organoids: Dox+TGFβ-.
Table S1 from SIRT1-Mediated Expression of CD24 and Epigenetic Suppression of Novel Tumor Suppressor miR-1185-1 Increases Colorectal Cancer Stemness
Authors: Wang Teh-Wei , Chern Edward , Hsu Chao-Wei , Tseng Kuo-Chang , Chao Hsiao-Mei
Published: March 2023

Primers and antibodies list
Supplementary Table 2 from P2X7 Receptor Activity Limits Accumulation of T Cells within Tumors
Authors: Romagnani Andrea , Rottoli Elsa , Mazza Emilia Maria Cristina , Rezzonico-Jost Tanja , De Ponte Conti Benedetta , Proietti Michele , Perotti Michela , Civanelli Elisa , Perruzza Lisa , Catapano Alberico L. , Baragetti Andrea , Tenedini Elena , Tagliafico Enrico , Falzoni Simonetta , Di Virgilio Francesco , Norata Giuseppe Danilo , Bicciato Silvio , Grassi Fabio
Published: March 2023

Supplementary Table 2
Figures S1-S6 from Brain Tumor Stem Cell Dependence on Glutaminase Reveals a Metabolic Vulnerability through the Amino Acid Deprivation Response Pathway
Authors: Restall Ian J. , Cseh Orsolya , Richards Laura M. , Pugh Trevor J. , Luchman H. Artee , Weiss Samuel
Published: March 2023

Supplementary Figures S1-S6 with Legends
Figure S4 from Modeling Acquired Resistance to the Second-Generation Androgen Receptor Antagonist Enzalutamide in the TRAMP Model of Prostate Cancer
Authors: Cerasuolo Marianna , Maccarinelli Federica , Coltrini Daniela , Mahmoud Ali Mokhtar , Marolda Viviana , Ghedini Gaia Cristina , Rezzola Sara , Giacomini Arianna , Triggiani Luca , Kostrzewa Magdalena , Verde Roberta , Paris Debora , Melck Dominique , Presta Marco , Ligresti Alessia , Ronca Roberto
Published: March 2023

Simulation and treatment of TRAMP mice treated with enzalutamide, cabazitaxel and the combination
Figure S3 from Modeling Acquired Resistance to the Second-Generation Androgen Receptor Antagonist Enzalutamide in the TRAMP Model of Prostate Cancer
Authors: Cerasuolo Marianna , Maccarinelli Federica , Coltrini Daniela , Mahmoud Ali Mokhtar , Marolda Viviana , Ghedini Gaia Cristina , Rezzola Sara , Giacomini Arianna , Triggiani Luca , Kostrzewa Magdalena , Verde Roberta , Paris Debora , Melck Dominique , Presta Marco , Ligresti Alessia , Ronca Roberto
Published: March 2023

Time courses of pH and oxygen in presence of enzalutamide continuous treatment
Supplementary Table S1 from Bidirectional Regulation between NDRG1 and GSK3β Controls Tumor Growth and Is Targeted by Differentiation Inducing Factor-1 in Glioblastoma
Authors: Ito Hiroshi , Watari Kosuke , Shibata Tomohiro , Miyamoto Tomofumi , Murakami Yuichi , Nakahara Yukiko , Izumi Hiroto , Wakimoto Hiroaki , Kuwano Michihiko , Abe Tatsuya , Ono Mayumi
Published: March 2023

ST1:Clinical characteristics of 28 patients with GBM, from whom tumor samples are analyzed.
Supplementary Figure 2 from Fibroblasts from Distinct Pancreatic Pathologies Exhibit Disease-Specific Properties
Authors: Barrera Lawrence N. , Evans Anthony , Lane Brian , Brumskill Sarah , Oldfield Frances E. , Campbell Fiona , Andrews Timothy , Lu Zipeng , Perez-Mancera Pedro A. , Liloglou Triantafillos , Ashworth Milton , Jalali Mehdi , Dawson Rebecca , Nunes Quentin , Phillips Phoebe A. , Timms John F. , Halloran Christopher , Greenhalf William , Neoptolemos John P. , Costello Eithne
Published: March 2023

Differentially expressed transcripts (mRNA and microRNA) between disease-associated fibroblasts and normal activated (NA) or normal fibroblasts (NF).
Supplementary Data from Targeting the Metabolic Response to Statin-Mediated Oxidative Stress Produces a Synergistic Antitumor Response
Authors: McGregor Grace H. , Campbell Andrew D. , Fey Sigrid K. , Tumanov Sergey , Sumpton David , Blanco Giovanny Rodriguez , Mackay Gillian , Nixon Colin , Vazquez Alexei , Sansom Owen J. , Kamphorst Jurre J.
Published: March 2023

Figure S1 shows the effect of statins on cholesterol and coenzyme Q levels and synthesis. Figure S2 shows statins reduce oxidative phosphorylation and hence increase glucose uptake and lactate secretion. Figure S3 shows the metabolic rewiring that occurs as a consequence of statin-mediated ROS production. Figure S4 shows simvastatin treatment in vivo does not alter cholesterol or dolichol synthesis or systemic coenzyme Q synthesis. Figure S5 shows simvastatin and AZD6244 are synergistic.
Supplementary Data Text from Lymphoma Angiogenesis Is Orchestrated by Noncanonical Signaling Pathways
Authors: Gloger Marleen , Menzel Lutz , Grau Michael , Vion Anne-Clemence , Anagnostopoulos Ioannis , Zapukhlyak Myroslav , Gerlach Kerstin , Kammertöns Thomas , Hehlgans Thomas , Zschummel Maria , Lenz Georg , Gerhardt Holger , Höpken Uta E. , Rehm Armin
Published: March 2023

Supplementary Material+Methods, Legends, References
Supplementary Data Table S1 from Lymphoma Angiogenesis Is Orchestrated by Noncanonical Signaling Pathways
Authors: Gloger Marleen , Menzel Lutz , Grau Michael , Vion Anne-Clemence , Anagnostopoulos Ioannis , Zapukhlyak Myroslav , Gerlach Kerstin , Kammertöns Thomas , Hehlgans Thomas , Zschummel Maria , Lenz Georg , Gerhardt Holger , Höpken Uta E. , Rehm Armin
Published: March 2023

Top GO and GSEA pathways
miRNA array from A Sox2:miR-486-5p Axis Regulates Survival of GBM Cells by Inhibiting Tumor Suppressor Networks
Authors: Lopez-Bertoni Hernando , Kotchetkov Ivan S. , Mihelson Nicole , Lal Bachchu , Rui Yuan , Ames Heather , Lugo-Fagundo Maria , Guerrero-Cazares Hugo , Quiñones-Hinojosa Alfredo , Green Jordan J. , Laterra John
Published: March 2023

File containing full results from the miRNA array used in this study.
Table S2 from Rare BRIP1 Missense Alleles Confer Risk for Ovarian and Breast Cancer
Authors: Moyer Cassandra L. , Ivanovich Jennifer , Gillespie Jessica L. , Doberstein Rachel , Radke Marc R. , Richardson Marcy E. , Kaufmann Scott H. , Swisher Elizabeth M. , Goodfellow Paul J.
Published: March 2023

ClinVar variant interpretations from May 2019 for variants identified in discovery cohorts
Table S2 from Aquaporin-7 Regulates the Response to Cellular Stress in Breast Cancer
Authors: Dai Chen , Charlestin Verodia , Wang Man , Walker Zachary T. , Miranda-Vergara Maria Cristina , Facchine Beth A. , Wu Junmin , Kaliney William J. , Dovichi Norman J. , Li Jun , Littlepage Laurie E.
Published: March 2023

Prognostic values of metabolite and gene hubs on patient survival.
Table S2 from Subcellular Distribution of p53 by the p53-Responsive lncRNA NBAT1 Determines Chemotherapeutic Response in Neuroblastoma
Authors: Mitra Sanhita , Muralidharan Somsundar Veppil , Di Marco Mirco , Juvvuna Prasanna Kumar , Kosalai Subazini Thankaswamy , Reischl Silke , Jachimowicz Daniel , Subhash Santhilal , Raimondi Ivan , Kurian Leo , Huarte Maite , Kogner Per , Fischer Matthias , Johnsen John Inge , Mondal Tanmoy , Kanduri Chandrasekhar
Published: March 2023

Differentially expressed genes in SH-SY5Y neuroblastoma cells after treatment with nutlin-3a, as detected by RNA-seq.
Supplemental Movie 1 from YAP Enhances Tumor Cell Dissemination by Promoting Intravascular Motility and Reentry into Systemic Circulation
Authors: Benjamin David C. , Kang Joon Ho , Hamza Bashar , King Emily M. , Lamar John M. , Manalis Scott R. , Hynes Richard O.
Published: March 2023

Movie showing blood flow through the Duct of Cuvier of a 2-day-old zebrafish embryo.
Supplementary Table S3 from Integrated Genomic Characterization of the Human Immunome in Cancer
Authors: Li Yongsheng , Burgman Brandon , McGrail Daniel J. , Sun Ming , Qi Dan , Shukla Sachet A. , Wu Erxi , Capasso Anna , Lin Shiaw-Yih , Wu Catherine J. , Eckhardt S. Gail , Mills Gordon B. , Li Bo , Sahni Nidhi , Yi S. Stephen
Published: March 2023

Table S3. Critical regions of immunological genes that are associated with immune response in cancer.
Figure S6 from Tumor Cell–Derived IL1β Promotes Desmoplasia and Immune Suppression in Pancreatic Cancer
Authors: Das Shipra , Shapiro Beny , Vucic Emily A. , Vogt Sandra , Bar-Sagi Dafna
Published: March 2023

TLR4 signaling induces IL-1b expression in tumor cells in response to the pancreatic microbiome.
Supplementary Materials and Methods from Oncogenic BRAFV600E Governs Regulatory T-cell Recruitment during Melanoma Tumorigenesis
Authors: Shabaneh Tamer B. , Molodtsov Aleksey K. , Steinberg Shannon M. , Zhang Peisheng , Torres Gretel M. , Mohamed Gadisti A. , Boni Andrea , Curiel Tyler J. , Angeles Christina V. , Turk Mary Jo
Published: March 2023

Supplementary Materials and Methods
Figure S6 from Oncogenic BRAFV600E Governs Regulatory T-cell Recruitment during Melanoma Tumorigenesis
Authors: Shabaneh Tamer B. , Molodtsov Aleksey K. , Steinberg Shannon M. , Zhang Peisheng , Torres Gretel M. , Mohamed Gadisti A. , Boni Andrea , Curiel Tyler J. , Angeles Christina V. , Turk Mary Jo
Published: March 2023

Histologic and molecular analysis of nevus-induced skin
Supplementary method from Psychiatric Disorders Are Associated with Increased Risk of Sepsis Following a Cancer Diagnosis
Authors: Liu Qianwei , Song Huan , Andersson Therese M.-L. , Magnusson Patrik K.E. , Zhu Jianwei , Smedby Karin E. , Fang Fang
Published: March 2023

Supplementary method describes details of statistical models, including effect of covariates and degrees of freedom.
Supplementary Tables S1-S2 from Psychiatric Disorders Are Associated with Increased Risk of Sepsis Following a Cancer Diagnosis
Authors: Liu Qianwei , Song Huan , Andersson Therese M.-L. , Magnusson Patrik K.E. , Zhu Jianwei , Smedby Karin E. , Fang Fang
Published: March 2023

Table S1: ICD-10 codes for cancer. Table S2: ICD-10 codes for sepsis and infection.
Supplementary Figures S1-S2 from Psychiatric Disorders Are Associated with Increased Risk of Sepsis Following a Cancer Diagnosis
Authors: Liu Qianwei , Song Huan , Andersson Therese M.-L. , Magnusson Patrik K.E. , Zhu Jianwei , Smedby Karin E. , Fang Fang
Published: March 2023

Figure S1. Flow chart. Figure S2 Hazard ratios and 95% confidence intervals of sepsis among cancer patients with psychiatric disorders (defined through clinical diagnosis of psychiatric disorder more than one year before cancer diagnosis) compared to cancer patients without psychiatric disorders, a cohort study in Sweden, 2006-2014.
Figure S2 from Oncogenic BRAFV600E Governs Regulatory T-cell Recruitment during Melanoma Tumorigenesis
Authors: Shabaneh Tamer B. , Molodtsov Aleksey K. , Steinberg Shannon M. , Zhang Peisheng , Torres Gretel M. , Mohamed Gadisti A. , Boni Andrea , Curiel Tyler J. , Angeles Christina V. , Turk Mary Jo
Published: March 2023

Tumor Ag-specific Tregs expand in draining lymph nodes
Supplementary Legends from Loss of ARID1A Promotes Epithelial–Mesenchymal Transition and Sensitizes Pancreatic Tumors to Proteotoxic Stress
Authors: Tomihara Hideo , Carbone Federica , Perelli Luigi , Huang Justin K. , Soeung Melinda , Rose Johnathon L. , Robinson Frederick S. , Lissanu Deribe Yonathan , Feng Ningping , Takeda Mitsunobu , Inoue Akira , Poggetto Edoardo Del , Deem Angela K. , Maitra Anirban , Msaouel Pavlos , Tannir Nizar M. , Draetta Giulio F. , Viale Andrea , Heffernan Timothy P. , Bristow Christopher A. , Carugo Alessandro , Genovese Giannicola
Published: March 2023

Legends of Supplementary Figures and Tables
Supplementary Figure 3 from Loss of ARID1A Promotes Epithelial–Mesenchymal Transition and Sensitizes Pancreatic Tumors to Proteotoxic Stress
Authors: Tomihara Hideo , Carbone Federica , Perelli Luigi , Huang Justin K. , Soeung Melinda , Rose Johnathon L. , Robinson Frederick S. , Lissanu Deribe Yonathan , Feng Ningping , Takeda Mitsunobu , Inoue Akira , Poggetto Edoardo Del , Deem Angela K. , Maitra Anirban , Msaouel Pavlos , Tannir Nizar M. , Draetta Giulio F. , Viale Andrea , Heffernan Timothy P. , Bristow Christopher A. , Carugo Alessandro , Genovese Giannicola
Published: March 2023

Supplementary Figure 3. NVP-AUY922 toxicity in vivo and effect of gemcitabine treatment in ARID1A knock-out PDAC models in vitro and in vivo.
Supplementary Figure 1 from Loss of ARID1A Promotes Epithelial–Mesenchymal Transition and Sensitizes Pancreatic Tumors to Proteotoxic Stress
Authors: Tomihara Hideo , Carbone Federica , Perelli Luigi , Huang Justin K. , Soeung Melinda , Rose Johnathon L. , Robinson Frederick S. , Lissanu Deribe Yonathan , Feng Ningping , Takeda Mitsunobu , Inoue Akira , Poggetto Edoardo Del , Deem Angela K. , Maitra Anirban , Msaouel Pavlos , Tannir Nizar M. , Draetta Giulio F. , Viale Andrea , Heffernan Timothy P. , Bristow Christopher A. , Carugo Alessandro , Genovese Giannicola
Published: March 2023

Supplementary Figure 1. Characterization of 23 PDAC cell lines.
Supplementary Figure Legend from Endothelin-1–Mediated Drug Resistance in EGFR-Mutant Non-Small Cell Lung Carcinoma
Authors: Pulido Inés , Ollosi Stephen , Aparisi Salvador , Becker Jeffrey H. , Aliena-Valero Alicia , Benet Marta , Rodríguez María L. , López Adrián , Tamayo-Torres Eva , Chuliá-Peris Lourdes , García-Cañaveras Juan Carlos , Soucheray Margaret , Dalheim Annika V. , Salom Juan B. , Qiu Wei , Kaja Simon , Fernández-Coronado Javier Alcácer , Alandes Sandra , Alcácer Javier , Al-Shahrour Fátima , Borgia Jeffrey A. , Juan Oscar , Nishimura Michael I. , Lahoz Agustín , Carretero Julián , Shimamura Takeshi
Published: March 2023

Supplementary Figure Legend
Supplementary Table S3 from FGFR3 Destabilizes PD-L1 via NEDD4 to Control T-cell–Mediated Bladder Cancer Immune Surveillance
Authors: Jing Weiqiang , Wang Ganyu , Cui Zhiwei , Xiong Gaozhong , Jiang Xin , Li Yue , Li Wushan , Han Bo , Chen Shouzhen , Shi Benkang
Published: March 2023

Supplementary Table S3
Figure S4 from Stromal Reprogramming through Dual PDGFRα/β Blockade Boosts the Efficacy of Anti–PD-1 Immunotherapy in Fibrotic Tumors
Authors: Akiyama Takahiko , Yasuda Tadahito , Uchihara Tomoyuki , Yasuda-Yoshihara Noriko , Tan Benjy J.Y. , Yonemura Atsuko , Semba Takashi , Yamasaki Juntaro , Komohara Yoshihiro , Ohnishi Koji , Wei Feng , Fu Lingfeng , Zhang Jun , Kitamura Fumimasa , Yamashita Kohei , Eto Kojiro , Iwagami Shiro , Tsukamoto Hirotake , Umemoto Terumasa , Masuda Mari , Nagano Osamu , Satou Yorifumi , Saya Hideyuki , Tan Patrick , Baba Hideo , Ishimoto Takatsugu
Published: March 2023

Supplementary Figure4
Data from Six1 Overexpression in Mammary Cells Induces Genomic Instability and Is Sufficient for Malignant Transformation
Authors: Coletta Ricardo D. , Christensen Kimberly L. , Micalizzi Douglas S. , Jedlicka Paul , Varella-Garcia Marileila , Ford Heide L.
Published: March 2023

Abstract
Homeoproteins are transcription factors that act as master regulators of development and are frequently dysregulated in cancers. During embryogenesis, the Six1 homeoprotein is essential for the expansion of precursor cell populations that give rise to muscle and kidney, among other organs. Six1 overexpression is observed in numerous cancers, resulting in increased proliferation, survival, and metastasis. Here, we investigate whether Six1 can play a causal role in mammary tumor initiation. We show that Six1 overexpression in MCF12A mammary epithelial cells promotes multiple properties associated with malignant transformation, including increased proliferation, genomic instability, and anchorage-independent growth. We further show that this transformation is dependent on up-regulation of its transcriptional target, cyclin A1, which is normally expressed in the embryonic mammary gland but dramatically reduced in the adult gland. Six1-transformed MCF12A cells are tumorigenic in nude mice, forming aggressive tumors that are locally invasive and exhibit peritumoral lymphovascular invasion. In human breast carcinomas, expression of Six1 and cyclin A1 mRNA correlate strongly with each other (P < 0.0001), and expression of Six1 and cyclin A1 each correlate with Ki67, a marker of proliferation (P < 0.0001 and P = 0.014, respectively). Together, our data indicate that Six1 overexpression is sufficient for malignant transformation of immortalized, nontumorigenic mammary epithelial cells, and suggest that the mechanism of this transformation involves inappropriate reexpression of cyclin A1 in the adult mammary gland. [Cancer Res 2008;68(7):2204–13]
Data from Cyclin-Dependent Kinase 2/Cyclin E Complex Is Involved in p120 Catenin (p120ctn)–Dependent Cell Growth Control: A New Role for p120ctn in Cancer
Authors: Chartier Nicolas T. , Oddou Christiane I. , Lainé Michèle G. , Ducarouge Benjamin , Marie Christiane A. , Block Marc R. , Jacquier-Sarlin Muriel R.
Published: March 2023

Abstract
Depending on its cellular localization, p120 catenin (p120ctn) can participate in various processes, such as cadherin-dependent cell-cell adhesion, actin cytoskeleton remodeling, and intracellular trafficking. Recent studies also indicate that p120ctn could regulate cell proliferation and contact inhibition. This report describes a new function of p120ctn in the regulation of cell cycle progression. Overexpression of the p120ctn isoform 3A in human colon adenocarcinoma cells (HT-29) results in cytoplasmic accumulation of the protein, as observed in many tumors. This cytoplasmic increase is correlated with a reduction in proliferation and inhibition of DNA synthesis. Under these conditions, experiments on synchronized cells revealed a prolonged S phase associated with cyclin E stabilization. Both confocal microscopy and biochemical analysis showed that cyclin E and cyclin-dependent kinase 2 colocalized with p120ctn in centrosomes during mitosis. These proteins are associated in a functional complex evidenced by coimmunoprecipitation experiments and the emergence of Thr199-phosphorylated nucleophosmin/B23. Such post-translational modification of this centrosomal target has been shown to trigger the initiation of centrosome duplication. Therefore, p120ctn-mediated accumulation of cyclin E in centrosomes may participate in abnormal amplification of centrosomes and the inhibition of DNA replication, thus leading to aberrant mitosis and polyploidy. Because these modifications are often observed in cancer, p120ctn may represent a new therapeutic target for future therapy. [Cancer Res 2007;67(20):9781–90]
Data from Silibinin Sensitizes Human Glioma Cells to TRAIL-Mediated Apoptosis via DR5 Up-regulation and Down-regulation of c-FLIP and Survivin
Authors: Son Yong-gyu , Kim Eun Hee , Kim Jin Yeop , Kim Seung U. , Kwon Taeg Kyu , Yoon A-Rum , Yun Chae-Ok , Choi Kyeong Sook
Published: March 2023

Abstract
Silibinin, a flavonoid isolated from Silybum marianum, has been reported to have cancer chemopreventive and therapeutic effects. Here, we show that treatment with subtoxic doses of silibinin in combination with tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) induces rapid apoptosis in TRAIL-resistant glioma cells, but not in human astrocytes, suggesting that this combined treatment may offer an attractive strategy for safely treating gliomas. Although the proteolytic processing of procaspase-3 by TRAIL was partially blocked in glioma cells, cotreatment with silibinin efficiently recovered TRAIL-induced caspase activation in these cells. Silibinin treatment up-regulated DR5, a death receptor of TRAIL, in a transcription factor CHOP-dependent manner. Furthermore, treatment with silibinin down-regulated the protein levels of the antiapoptotic proteins FLIPL, FLIPS, and survivin through proteasome-mediated degradation. Taken together, our results show that the activity of silibinin to modulate multiple components in the death receptor–mediated apoptotic pathway is responsible for its ability to recover TRAIL sensitivity in TRAIL-resistant glioma cells. [Cancer Res 2007;67(17):8274–84]
Data from Centrosomal PKCβII and Pericentrin Are Critical for Human Prostate Cancer Growth and Angiogenesis
Authors: Kim Jeewon , Choi Yoon-La , Vallentin Alice , Hunrichs Ben S. , Hellerstein Marc K. , Peehl Donna M. , Mochly-Rosen Daria
Published: March 2023

Abstract
Angiogenesis is critical in the progression of prostate cancer. However, the interplay between the proliferation kinetics of tumor endothelial cells (angiogenesis) and tumor cells has not been investigated. Also, protein kinase C (PKC) regulates various aspects of tumor cell growth, but its role in prostate cancer has not been investigated in detail. Here, we found that the proliferation rates of endothelial and tumor cells oscillate asynchronously during the growth of human prostate cancer xenografts. Furthermore, our analyses suggest that PKCβII was activated during increased angiogenesis and that PKCβII plays a key role in the proliferation of endothelial cells and tumor cells in human prostate cancer; treatment with a PKCβII-selective inhibitor, βIIV5-3, reduced angiogenesis and tumor cell proliferation. We also find a unique effect of PKCβII inhibition on normalizing pericentrin (a protein regulating cytokinesis), especially in endothelial cells as well as in tumor cells. PKCβII inhibition reduced the level and mislocalization of pericentrin and normalized microtubule organization in the tumor endothelial cells. Although pericentrin has been known to be up-regulated in epithelial cells of prostate cancers, its level in tumor endothelium has not been studied in detail. We found that pericentrin is up-regulated in human tumor endothelium compared with endothelium adjacent to normal glands in tissues from prostate cancer patients. Our results suggest that a PKCβII inhibitor such as βIIV5-3 may be used to reduce prostate cancer growth by targeting both angiogenesis and tumor cell growth. [Cancer Res 2008;68(16):6831–9]
Data from Functional and Clinical Evidence for NDRG2 as a Candidate Suppressor of Liver Cancer Metastasis
Authors: Lee Dong Chul , Kang Yun Kyung , Kim Woo Ho , Jang Ye Jin , Kim Dong Joon , Park In Young , Sohn Bo Hwa , Sohn Hyun Ahm , Lee Hee Gu , Lim Jong Seok , Kim Jae Wha , Song Eun Young , Kim Dong Min , Lee Mi-Ni , Oh Goo Taeg , Kim Soo Jung , Park Kyung Chan , Yoo Hyang Sook , Choi Jong Young , Yeom Young Il
Published: March 2023

Abstract
We searched for potential suppressors of tumor metastasis by identifying the genes that are frequently down-regulated in hepatocellular carcinomas (HCC) while being negatively correlated with clinical parameters relevant to tumor metastasis, and we report here on the identification of N-myc downstream regulated gene 2 (NDRG2) as a promising candidate. NDRG2 expression was significantly reduced in HCC compared with nontumor or normal liver tissues [87.5% (35 of 40) and 62% (62 of 100) at RNA and protein levels, respectively]. Reduction of NDRG2 expression was intimately associated with promoter hypermethylation because its promoter region was found to carry extensively methylated CpG sites in HCC cell lines and primary tumors. Immunohistochemical analysis of NDRG2 protein in 100 HCC patient tissues indicated that NDRG2 expression loss is significantly correlated with aggressive tumor behaviors such as late tumor-node-metastasis (TNM) stage (P = 0.012), differentiation grade (P = 0.024), portal vein thrombi (P = 0.011), infiltrative growth pattern (P = 0.015), nodal/distant metastasis (P = 0.027), and recurrent tumor (P = 0.021), as well as shorter patient survival rates. Ectopically expressed NDRG2 suppressed invasion and migration of a highly invasive cell line, SK-Hep-1, and experimental tumor metastasis in vivo, whereas small interfering RNA–mediated knockdown resulted in increased invasion and migration of a weakly invasive cell line, PLC/PRF/5. In addition, NDRG2 could antagonize transforming growth factor β1–mediated tumor cell invasion by specifically down-regulating the expression of matrix metalloproteinase 2 and laminin 332 pathway components, with concomitant suppression of Rho GTPase activity. These results suggest that NDRG2 can inhibit extracellular matrix–based, Rho-driven tumor cell invasion and migration and thereby play important roles in suppressing tumor metastasis in HCC. [Cancer Res 2008;68(11):4210–20]
Data from Triggering Senescence Programs Suppresses Chk1 Kinase and Sensitizes Cells To Genotoxic Stresses
Authors: Gabai Vladimir L. , O'Callaghan-Sunol Cornelia , Meng Le , Sherman Michael Y. , Yaglom Julia
Published: March 2023

Abstract
Depletion of the major heat shock protein Hsp72 leads to activation of the senescence program in a variety of tumor cell lines via both p53-dependent and p53-independent pathways. Here, we found that the Hsp72-depleted cells show defect in phosphorylation and activation of the protein kinase Chk1 by genotoxic stresses, such as UVC irradiation or camptothecin. Under these conditions, phosphorylation of Rad17 was also suppressed, whereas phosphorylation of p53 at Ser15 was not affected, indicating a specific defect in phosphorylation of a subset of the ATR kinase substrates. Similarly, suppression of Chk1 activation was seen when senescence signaling was triggered by direct stimulation of p53, depletion of Cdc2, or overexpression of the cell cycle inhibitors p21 or p16. Thus, defect in Chk1 activation was not a consequence of the chaperone imbalance, but rather a downstream effect of activation of the senescence signaling. Inhibition of Chk1 was associated with inefficient inter-S phase checkpoint, as Hsp72 depleted cells failed to halt cell cycle progression upon UVC irradiation. Accordingly, sensitivity of cells to genotoxic stimuli after Hsp72 depletion was significantly enhanced. Thus, activation of the senescence signaling causes a defect in the DNA damage response manifested in increased sensitivity to genotoxic stresses. [Cancer Res 2008;68(6):1834–42]
Data from A Bicistronic CYCLIN D1-TROP2 mRNA Chimera Demonstrates a Novel Oncogenic Mechanism in Human Cancer
Authors: Guerra Emanuela , Trerotola Marco , Dell' Arciprete Roberta , Bonasera Veronica , Palombo Barbara , El-Sewedy Tarek , Ciccimarra Tommaso , Crescenzi Carlo , Lorenzini Franco , Rossi Cosmo , Vacca Giovanna , Lattanzio Rossano , Piantelli Mauro , Alberti Saverio
Published: March 2023

Abstract
A chimeric CYCLIN D1-TROP2 mRNA was isolated from human ovarian and mammary cancer cells. The CYCLIN D1-TROP2 mRNA was shown to be a potent oncogene as it transforms naïve, primary cells in vitro and induces aggressive tumor growth in vivo in cooperation with activated RAS. Silencing of the chimeric mRNA inhibits the growth of breast cancer cells. The CYCLIN D1-TROP2 mRNA was expressed by a large fraction of the human gastrointestinal, ovarian, and endometrial tumors analyzed. It is most frequently detected in intestinal cell aneuploid cancers and it is coexpressed with activated RAS oncogenes, consistent with a cooperative transforming activity in human cancers. The chimeric mRNA is a bicistronic transcript of post transcriptional origin that independently translates the Cyclin D1 and Trop-2 proteins. This is a novel mechanism of CYCLIN D1 activation that achieves the truncation of the CYCLIN D1 mRNA in the absence of chromosomal rearrangements. This leads to a higher CYCLIN D1 mRNA stability, with inappropriate expression during the cell cycle. The stabilized CYCLIN D1 mRNA cooperates with TROP2 in stimulating the growth of the expressing cells. These findings show a novel epigenetic, oncogenic mechanism, which seems to be widespread in human cancers. [Cancer Res 2008;68(19):8113–21]
Data from BIBF 1120: Triple Angiokinase Inhibitor with Sustained Receptor Blockade and Good Antitumor Efficacy
Authors: Hilberg Frank , Roth Gerald J. , Krssak Martin , Kautschitsch Susanna , Sommergruber Wolfgang , Tontsch-Grunt Ulrike , Garin-Chesa Pilar , Bader Gerd , Zoephel Andreas , Quant Jens , Heckel Armin , Rettig Wolfgang J.
Published: March 2023

Abstract
Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a novel treatment modality in oncology. Preclinical findings suggest that long-term clinical outcomes may improve with blockade of additional proangiogenic receptor tyrosine kinases: platelet-derived growth factor receptors (PDGFR) and fibroblast growth factor receptors (FGFR). BIBF 1120 is an indolinone derivative potently blocking VEGF receptor (VEGFR), PDGFR and FGFR kinase activity in enzymatic assays (IC50, 20–100 nmol/L). BIBF 1120 inhibits mitogen-activated protein kinase and Akt signaling pathways in three cell types contributing to angiogenesis, endothelial cells, pericytes, and smooth muscle cells, resulting in inhibition of cell proliferation (EC50, 10–80 nmol/L) and apoptosis. In all tumor models tested thus far, including human tumor xenografts growing in nude mice and a syngeneic rat tumor model, BIBF 1120 is highly active at well-tolerated doses (25–100 mg/kg daily p.o.), as measured by magnetic resonance imaging of tumor perfusion after 3 days, reducing vessel density and vessel integrity after 5 days, and inducing profound growth inhibition. A distinct pharmacodynamic feature of BIBF 1120 in cell culture is sustained pathway inhibition (up to 32 hours after 1-hour treatment), suggesting slow receptor off-kinetics. Although BIBF 1120 is rapidly metabolized in vivo by methylester cleavage, resulting in a short mean residence time, once daily oral dosing is fully efficacious in xenograft models. These distinctive pharmacokinetic and pharmacodynamic properties may help explain clinical observations with BIBF 1120, currently entering phase III clinical development. [Cancer Res 2008;68(12):4774–82]
Data from CD8+ T-Cell Responses against Hemoglobin-β Prevent Solid Tumor Growth
Authors: Komita Hideo , Zhao Xi , Taylor Jennifer L. , Sparvero Louis J. , Amoscato Andrew A. , Alber Sean , Watkins Simon C. , Pardee Angela D. , Wesa Amy K. , Storkus Walter J.
Published: March 2023

Abstract
Bone marrow–derived dendritic cells engineered using recombinant adenovirus to secrete high levels of IL-12p70 dramatically inhibited the growth of established CMS4 sarcomas in BALB/c mice after intratumoral administration. An analysis of splenic CD8+ T cells in regressor mice revealed a strong, complex reactivity pattern against high-performance liquid chromatography (HPLC)–resolved peptides isolated by acid elution from single-cell suspensions of surgically resected CMS4 lesions. Mass spectrometry analyses defined two major overlapping peptide species that derive from the murine hemoglobin-β (HBB) protein within the most stimulatory HPLC fractions. Although cultured CMS4 tumor cells failed to express HBB mRNA based on reverse transcription-PCR analyses, prophylactic vaccination of BALB/c mice with vaccines containing HBB peptides promoted specific CD8+ T-cell responses that protected mice against a subsequent challenge with CMS4 or unrelated syngeneic (HBBneg) tumors of divergent histology (sarcoma, carcinomas of the breast or colon). In situ imaging suggested that vaccines limit or destabilize tumor-associated vascular structures, potentially by promoting immunity against HBB+ vascular pericytes. Importantly, there were no untoward effects of vaccination with the HBB peptide on peripheral RBC numbers, RBC hemoglobin content, or vascular structures in the brain or eye. [Cancer Res 2008;68(19):8076–84]
Data from Hypoxia-Inducible Factor-1α Obstructs a Wnt Signaling Pathway by Inhibiting the hARD1-Mediated Activation of β-Catenin
Authors: Lim Ji-Hong , Chun Yang-Sook , Park Jong-Wan
Published: March 2023

Abstract
Although a splice variant of mouse mARD1s was found to acetylate and destabilize hypoxia-inducible factor-1α (HIF-1α), human hARD1 has no such activities. Nonetheless, hARD1 has been reported to bind directly with HIF-1α. Here, we addressed the functional significance of the hARD1–HIF-1α interaction. Because hARD1 acetylates and activates β-catenin, we examined whether HIF-1α regulates the hARD1-mediated activation of Wnt signaling. It was found that HIF-1α binds hARD1 through the oxygen-dependent degradation domain and, in so doing, dissociates hARD1 from β-catenin, which prevents β-catenin acetylation. In LiCl-stimulated HEK293 or cancer cell lines with active Wnt signaling, β-catenin acetylation and activity were suppressed in hypoxia, and these suppressions were mediated by HIF-1α. Moreover, HIF-1α disruption of hARD1/β-catenin repressed TCF4 activity, resulting in c-Myc suppression and p21cip1 induction. In addition, we confirmed that the HIF-1α NH2 terminal inactivates TCF4 by directly binding β-catenin. In conclusion, HIF-1α was found to inactivate the Wnt signaling by binding to hARD1 or β-catenin, which may contribute to the hypoxia-induced growth arrest of tumor cells. [Cancer Res 2008;68(13):5177–84]
Data from Tissue Inhibitor of Metalloproteinase-3 via Oncolytic Herpesvirus Inhibits Tumor Growth and Vascular Progenitors
Authors: Mahller Yonatan Y. , Vaikunth Sachin S. , Ripberger Maria C. , Baird William H. , Saeki Yoshinaga , Cancelas Jose A. , Crombleholme Timothy M. , Cripe Timothy P.
Published: March 2023

Abstract
Malignant solid tumors remain a significant clinical challenge, necessitating innovative therapeutic approaches. Oncolytic viral therapy is a nonmutagenic, biological anticancer therapeutic shown to be effective against human cancer in early studies. Because matrix metalloproteinases (MMP) play important roles in the pathogenesis and progression of cancer, we sought to determine if “arming” an oncolytic herpes simplex virus (oHSV) with an MMP-antagonizing transgene would increase virus-mediated antitumor efficacy. We generated oHSVs that express human tissue inhibitor of metalloproteinases 3 (TIMP3) or firefly luciferase and designated them rQT3 and rQLuc, respectively. We evaluated the antitumor efficacy of these viruses against neuroblastoma and malignant peripheral nerve sheath tumor (MPNST) xenografts. Relative to rQLuc, rQT3-infected primary human MPNST and neuroblastoma cells exhibited equivalent virus replication but increased cytotoxicity and reduced MMP activity. In vivo, rQT3-treated tumors showed delayed tumor growth, increased peak levels of infectious virus, immature collagen extracellular matrix, and reduced tumor vascular density. Remarkably, rQT3 treatment reduced circulating endothelial progenitors, suggesting virus-mediated antivasculogenesis. We conclude that rQT3 enhanced antitumor efficacy through multiple mechanisms, including direct cytotoxicity, elevated virus titer, and reduced tumor neovascularization. These findings support the further development of combined TIMP-3 and oncolytic virotherapy for cancer. [Cancer Res 2008;68(4):1170–9]
Data from Dual-Specificity Phosphatase 1 Ubiquitination in Extracellular Signal-Regulated Kinase–Mediated Control of Growth in Human Hepatocellular Carcinoma
Authors: Calvisi Diego F. , Pinna Federico , Meloni Floriana , Ladu Sara , Pellegrino Rossella , Sini Marcella , Daino Lucia , Simile Maria M. , De Miglio Maria R. , Virdis Patrizia , Frau Maddalena , Tomasi Maria L. , Seddaiu Maria A. , Muroni Maria R. , Feo Francesco , Pascale Rosa M.
Published: March 2023

Abstract
Sustained activation of extracellular signal-regulated kinase (ERK) has been detected previously in numerous tumors in the absence of RAS-activating mutations. However, the molecular mechanisms responsible for ERK-unrestrained activity independent of RAS mutations remain unknown. Here, we evaluated the effects of the functional interactions of ERK proteins with dual-specificity phosphatase 1 (DUSP1), a specific inhibitor of ERK, and S-phase kinase-associated protein 2 (SKP2)/CDC28 protein kinase 1b (CKS1) ubiquitin ligase complex in human hepatocellular carcinoma (HCC). Levels of DUSP1, as assessed by real-time reverse transcription–PCR and Western blot analysis, were significantly higher in tumors with better prognosis (as defined by the length of patients' survival) when compared with both normal and nontumorous surrounding livers, whereas DUSP1 protein expression sharply declined in all HCC with poorer prognosis. In the latter HCC subtype, DUSP1 inactivation was due to either ERK/SKP2/CKS1-dependent ubiquitination or promoter hypermethylation associated with loss of heterozygosity at the DUSP1 locus. Noticeably, expression levels of DUSP1 inversely correlated with those of activated ERK, as well as with proliferation index and microvessel density, and directly with apoptosis and survival rate. Subsequent functional studies revealed that DUSP1 reactivation led to suppression of ERK, CKS1, and SKP2 activity, inhibition of proliferation and induction of apoptosis in human hepatoma cell lines. Taken together, the present data indicate that ERK achieves unrestrained activity during HCC progression by triggering ubiquitin-mediated proteolysis of its specific inhibitor DUSP1. Thus, DUSP1 may represent a valuable prognostic marker and ERK, CKS1, or SKP2 potential therapeutic targets for human HCC. [Cancer Res 2008;68(11):4192–200]
Data from Coordinated Epidermal Growth Factor Receptor Pathway Gene Overexpression Predicts Epidermal Growth Factor Receptor Inhibitor Sensitivity in Pancreatic Cancer
Authors: Jimeno Antonio , Tan Aik Choon , Coffa Jordy , Rajeshkumar N.V. , Kulesza Peter , Rubio-Viqueira Belen , Wheelhouse Jenna , Diosdado Begoña , Messersmith Wells A. , Iacobuzio-Donahue Christine , Maitra Anirban , Varella-Garcia Marileila , Hirsch Fred R. , Meijer Gerrit A. , Hidalgo Manuel
Published: March 2023

Abstract
The epidermal growth factor receptor (EGFR) inhibitor erlotinib is approved for treatment of pancreatic cancer but the overall activity is minimal, and known predictive factors for EGFR inhibitor efficacy are infrequent in this disease. We tested the hypothesis that global activation of the EGFR pathway is predictive of EGFR inhibitor efficacy. Pancreatic cancer tumors directly xenografted at surgery were treated with the EGFR inhibitors erlotinib and cetuximab and analyzed for biological features. Two of 10 tumors were sensitive, and by global gene expression profiling with gene set enrichment analysis, the EGFR pathway was highly expressed in sensitive compared with resistant tumors. The core gene components driving EGFR pathway overexpression were pathway ligands and positive effectors. In a prospective validation, the EGFR pathway-based signature correctly predicted anti-EGFR treatment response in eight additional tumors and was not predictive of response to gemcitabine and CI1040 (a MEK inhibitor). Analysis of EGFR, KRAS, and PIK3CA mutations and gene amplification by fluorescence in situ hybridization and multiplex ligation-dependent probe amplification showed that none of these genetic abnormalities were neither predictive nor responsible for the EGFR pathway activation. Coordinated overexpression of the EGFR pathway predicts susceptibility to EGFR inhibitors in pancreatic cancer. These results suggest a phenomenon of pathway addiction and support the value of unbiased system biology approaches in drug development. [Cancer Res 2008;68(8):2841–9]