bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure S2 from Leptin Signaling Mediates Obesity-Associated CSC Enrichment and EMT in Preclinical TNBC Models
Authors: Bowers Laura W. , Rossi Emily L. , McDonell Shannon B. , Doerstling Steven S. , Khatib Subreen A. , Lineberger Claire G. , Albright Jody E. , Tang Xiaohu , deGraffenried Linda A. , Hursting Stephen D.
Published: April 2023

Body weight of C57BL/6 mice that supplied sera for in vitro experiments.
Supplementary Figure 6 from EMT-Derived Alterations in Glutamine Metabolism Sensitize Mesenchymal Breast Cells to mTOR Inhibition
Authors: Karvelsson Sigurdur Trausti , Sigurdsson Arnar , Seip Kotryna , Grinde Maria Tunset , Wang Qiong , Johannsson Freyr , Mælandsmo Gunhild Mari , Moestue Siver Andreas , Rolfsson Ottar , Halldorsson Skarphedinn
Published: April 2023

IDH2 knockdown effects on D492 and D492M. A) Real-Time PCR from D492, D492M and their IDH2 -silenced cell lines showing the gene expression levels of IDH2 and IDH1. B) Effect of IDH2 silencing on the reductive contribution of glutamate and 1,2-13C-glucose to palmitate in D492 and D492M. C) Proliferation of D492 and D492M WT and IDH2-knockdown cell lines (mean + sem, n=8). D) Effect of IDH2 silencing on the NADPH/NADP+ ratio in D492 and D492M. E) Effect of IDH2 silencing on the contribution of 1-13C-glutamine to proline. F) Effect of IDH2 silencing on the contribution of 1-13C-glutamine to oxidized glutathione (GSSG). Student's two-tailed t-test (with Benjamini-Hochberg adjustment for multiple comparisons) was used to estimate significance of results.
Supplementary Materials from EWS-FLI1 and Menin Converge to Regulate ATF4 Activity in Ewing Sarcoma
Authors: Jiménez Jennifer A. , Apfelbaum April A. , Hawkins Allegra G. , Svoboda Laurie K. , Kumar Abhijay , Ruiz Ramon Ocadiz , Garcia Alessandra X. , Haarer Elena , Nwosu Zeribe C. , Bradin Joshua , Purohit Trupta , Chen Dong , Cierpicki Tomasz , Grembecka Jolanta , Lyssiotis Costas A. , Lawlor Elizabeth R.
Published: April 2023

shRNA sequences, plasmid information, western blot antibodies
Supplementary Figure S1 from A Novel Therapeutic Strategy Targeting the Mesenchymal Phenotype of Malignant Pleural Mesothelioma by Suppressing LSD1
Authors: Wirawan Aditya , Tajima Ken , Takahashi Fumiyuki , Mitsuishi Yoichiro , Winardi Wira , Hidayat Moulid , Hayakawa Daisuke , Matsumoto Naohisa , Izumi Kenta , Asao Tetsuhiko , Ko Ryo , Shimada Naoko , Takamochi Kazuya , Suzuki Kenji , Abe Masaaki , Hino Okio , Sekido Yoshitaka , Takahashi Kazuhisa
Published: April 2023

Supplementary Figure S1 shows that TGFβ1 treatment in MPM cells.
Figure S5 from Adaptor Protein ShcD/SHC4 Interacts with Tie2 Receptor to Synergistically Promote Glioma Cell Invasion
Authors: Tilak Manali , Alural Begüm , Wismer Sarah E. , Brasher Megan I. , New Laura A. , Sheridan Steven D. , Perlis Roy H. , Coppolino Marc G. , Lalonde Jasmin , Jones Nina
Published: April 2023

U87-derived spheroids expressing ShcD and/or Tie2 show similar 2D migration but differ in 3D invasion into organoids.
Supplementary Table 1 from Destrin Contributes to Lung Adenocarcinoma Progression by Activating Wnt/β-Catenin Signaling Pathway
Authors: Zhang Hui-Juan , Chang Wen-Jing , Jia Cai-Yun , Qiao Ling , Zhou Jing , Chen Qing , Zheng Xiao-Wei , Zhang Jian-Hua , Li Hong-Chao , Yang Zheng-Yan , Liu Zhong-Hua , Liu Guang-Chao , Ji Shao-Ping , Lu Feng
Published: April 2023

Supplementary Table 1. The differentially expressed proteins of normal and early - stage lung cancer tissues identified by LC-MS/MS analysis (N: normal; T: tumor).
Supplementary Figures 1-4,Table S1 from Paracrine Placental Growth Factor Signaling in Response to Ionizing Radiation Is p53-Dependent and Contributes to Radioresistance
Authors: Kazimova Tamara , Tschanz Fabienne , Sharma Ashish , Telarovic Irma , Wachtel Marco , Pedot Gloria , Schäfer Beat , Pruschy Martin
Published: April 2023

Supplementary Data supporting results of main manuscript; with other cell lines; with control experiments; includes data table Figure S1. PlGF secretion is increased in multiple cell lines after irradiation. Figure S2. PlGF mRNA expression is increased in response to IR. Figure S3. P53 is a major regulator of PlGF in response to IR. Figure S4. Generation of PlGF knockout cell lines using CRISPR/Cas9 system. Table S1. Correlation of genetic background to tumor cell lines to early PlGF expression in response to IR.
FigureS4 from Adipokine Apelin/APJ Pathway Promotes Peritoneal Dissemination of Ovarian Cancer Cells by Regulating Lipid Metabolism
Authors: Dogra Samrita , Neelakantan Deepika , Patel Maulin M. , Griesel Beth , Olson Ann , Woo Sukyung
Published: April 2023

SSO inhibits lipid droplet accumulation
Supplementary Figure S6 from Platinum-Induced Ubiquitination of Phosphorylated H2AX by RING1A Is Mediated by Replication Protein A in Ovarian Cancer
Authors: Sriramkumar Shruthi , Matthews Timothy D. , Ghobashi Ahmed H. , Miller Samuel A. , VanderVere-Carozza Pamela S. , Pawelczak Katherine S. , Nephew Kenneth P. , Turchi John J. , O'Hagan Heather M.
Published: April 2023

RING1A knockdown reduces phosphorylation of pS345 Chk1 and repair of cisplatin DNA damage
Supplementary Data Figure S1-2 Tables S1-5 from Crenolanib Regulates ERK and AKT/mTOR Signaling Pathways in RAS/BRAF-Mutated Colorectal Cancer Cells and Organoids
Authors: Fujino Shiki , Miyoshi Norikatsu , Ito Aya , Yasui Masayoshi , Ohue Masayuki , Ogino Takayuki , Takahashi Hidekazu , Uemura Mamoru , Matsuda Chu , Mizushima Tsunekazu , Doki Yuichiro , Eguchi Hidetoshi
Published: April 2023

Fig. S1. mRNA expressions and mutations of crenolanib targeting tyrosine kinase receptors in various cancers. Fig. S2. Cells expressing EGFP under Oct3/4 promoter Table S1. The culture medium used for starvation and experiments for colorectal cancer cell line Table S2. Modified stem cell culture medium Table S3. The culture medium used for starvation and experiments for patients derived organoid Table S4. Primer sequences and universal probe libraries Table S5. Primary antibodies used in western blotting analysis
Supplementary Fig. S6 from AXL Inhibition Induces DNA Damage and Replication Stress in Non–Small Cell Lung Cancer Cells and Promotes Sensitivity to ATR Inhibitors
Authors: Ramkumar Kavya , Stewart C. Allison , Cargill Kasey R. , Della Corte Carminia M. , Wang Qi , Shen Li , Diao Lixia , Cardnell Robert J. , Peng David H. , Rodriguez B. Leticia , Fan You-Hong , Heymach John V. , Wang Jing , Gay Carl M. , Gibbons Don L. , Byers Lauren A.
Published: April 2023

Supplementary Fig. S6: BGB324/VX-970 treatment induces widespread γH2Ax foci formation.
Supplementary Figure from A Recurrent ADPRHL1 Germline Mutation Activates PARP1 and Confers Prostate Cancer Risk in African American Families
Authors: Zhang Guanyi , Wang Zemin , Bavarva Jasmin , Kuhns Katherine J. , Guo Jianhui , Ledet Elisa M. , Qian Chiping , Lin Yuan , Fang Zhide , Zabaleta Jovanny , Valle Luis Del , Hu Jennifer J. , Mandal Diptasri , Liu Wanguo
Published: April 2023

Supplementary Figure from A Recurrent ADPRHL1 Germline Mutation Activates PARP1 and Confers Prostate Cancer Risk in African American Families
Supplementary Data from Modeling Androgen Deprivation Therapy–Induced Prostate Cancer Dormancy and Its Clinical Implications
Authors: Dong Xin , Xue Hui , Mo Fan , Lin Yen-yi , Lin Dong , Wong Nelson K.Y. , Sun Yingqiang , Wilkinson Scott , Ku Anson T. , Hao Jun , Ci Xinpei , Wu Rebecca , Haegert Anne , Silver Rebecca , Taplin Mary-Ellen , Balk Steven P. , Alumkal Joshi J. , Sowalsky Adam G. , Gleave Martin , Collins Colin , Wang Yuzhuo
Published: April 2023

Supplementary Data from Modeling Androgen Deprivation Therapy–Induced Prostate Cancer Dormancy and Its Clinical Implications
Supplementary Data from Pan-Cancer Analysis Reveals Recurrent BCAR4 Gene Fusions across Solid Tumors
Authors: Nickless Andrew , Zhang Jin , Othoum Ghofran , Webster Jace , Inkman Matthew J. , Coonrod Emily , Fontes Sherron , Rozycki Emily B. , Maher Christopher A. , White Nicole M.
Published: April 2023

Supplementary Data from Pan-Cancer Analysis Reveals Recurrent BCAR4 Gene Fusions across Solid Tumors
Supplementary Methods, Supplementary Figures 1-3, Supplementary Tables 1-9 from DOT1 L Regulates Ovarian Cancer Stem Cells by Activating β-catenin Signaling
Authors: Zhang Yaqi , Wang Yinu , Valdivia Andres , Huang Hao , Matei Daniela
Published: April 2023

S1. DOT1L is important for stemness in OC cells.
S2. Inhibition of DOT1L activity reduces ALDH+ ovarian CSCs.
S3. Inhibition of DOT1L activity inhibits Wnt pathway.
Table S1. Cell culture conditions
Table S2. Antibodies
Table S3. shRNA sequences
Table S4. qRT-PCR Primers
Table S5. ChIP-PCR Primers
Table S6. Effects of DOT1L knockdown on tumor initiation capacity
Table S7. Estimated 1/stem cell frequency in shCtrl and shDOT1L
OVCAR5 cells in serial dilution assay experiment.
Table S8. Top 35 downregulated genes from the RNA-sequencing analysis of OVCAR5 cells transduced with shRNA targeting DOT1L versus control shRNA.
Table S9. Top 35 upregulated genes from the RNA-sequencing analysis of OVCAR5 cells transduced with shRNA targeting DOT1L versus control shRNA.
Supplementary Figure from Tumor Microenvironment Acidity Triggers Lipid Accumulation in Liver Cancer via SCD1 Activation
Authors: Ding Ming , Zhang Shuwei , Guo Yajuan , Yao Jingjing , Shen Qinghong , Huang Min , Chen Wenbo , Yu Shaofang , Zheng Yaqiu , Lin Yuefang , Yan Wenxin , Liu Zhongqiu , Su Tao , Lu Linlin
Published: April 2023

Supplementary Figure from Tumor Microenvironment Acidity Triggers Lipid Accumulation in Liver Cancer via SCD1 Activation
Supplementary Figure 5 from XIAP and PHB1 Regulate Anoikis through Competitive Binding to TRAF6
Authors: Yang Bo , Lou Chao , Chen Shengkai , Zhang Zhiyuan , Xu Qin
Published: April 2023

S5. Quantitative analysis of protein expression.
Supplementary Table S1 from Sox2 Is an Oncogenic Driver of Small-Cell Lung Cancer and Promotes the Classic Neuroendocrine Subtype
Authors: Voigt Ellen , Wallenburg Madeline , Wollenzien Hannah , Thompson Ethan , Kumar Kirtana , Feiner Joshua , McNally Moira , Friesen Hunter , Mukherjee Malini , Afeworki Yohannes , Kareta Michael S.
Published: April 2023

Description of mice used in this study
Supplementary Figure 4 from XIAP and PHB1 Regulate Anoikis through Competitive Binding to TRAF6
Authors: Yang Bo , Lou Chao , Chen Shengkai , Zhang Zhiyuan , Xu Qin
Published: April 2023

S4. XIAP did not cause K63 ubiquitination of TRAF6. The time course of TRAF6 expression level and the corresponding degree of K63 ubiquitination in suspended HN4 cells.
Supplementary Figure S9 from Sox2 Is an Oncogenic Driver of Small-Cell Lung Cancer and Promotes the Classic Neuroendocrine Subtype
Authors: Voigt Ellen , Wallenburg Madeline , Wollenzien Hannah , Thompson Ethan , Kumar Kirtana , Feiner Joshua , McNally Moira , Friesen Hunter , Mukherjee Malini , Afeworki Yohannes , Kareta Michael S.
Published: April 2023

High magnification of tumors stained for ASCL1, NEUROD1, and MYC in relation to Figure 5E
Supplementary Figure 3 from XIAP and PHB1 Regulate Anoikis through Competitive Binding to TRAF6
Authors: Yang Bo , Lou Chao , Chen Shengkai , Zhang Zhiyuan , Xu Qin
Published: April 2023

S3. Quantitative analysis of protein expression.
Supplementary Figure S7 from Sox2 Is an Oncogenic Driver of Small-Cell Lung Cancer and Promotes the Classic Neuroendocrine Subtype
Authors: Voigt Ellen , Wallenburg Madeline , Wollenzien Hannah , Thompson Ethan , Kumar Kirtana , Feiner Joshua , McNally Moira , Friesen Hunter , Mukherjee Malini , Afeworki Yohannes , Kareta Michael S.
Published: April 2023

Subtype validation of cell lines
Supplementary Table 2 from GATM-Mediated Creatine Biosynthesis Enables Maintenance of FLT3-ITD–Mutant Acute Myeloid Leukemia
Authors: Zhang Yuan , Newsom Kimberly J. , Zhang Mei , Kelley Jeffry S. , Starostik Petr
Published: April 2023

The overlapped DEGs in MOLM14 cells and MV4-11 cells after FLT3-ITD inhibition
Supplementary Figure from Intronic Cis-Element DR8 in hTERT Is Bound by Splicing Factor SF3B4 and Regulates hTERT Splicing in Non–Small Cell Lung Cancer
Authors: Slusher Aaron L. , Kim Jeongjin J. , Ribick Mark , Pollens-Voigt Jesse , Bankhead Armand , Palmbos Phillip L. , Ludlow Andrew T.
Published: April 2023

Supplementary Figure from Intronic Cis-Element DR8 in hTERT Is Bound by Splicing Factor SF3B4 and Regulates hTERT Splicing in Non–Small Cell Lung Cancer
Supplementary Figure from Plasticity within Aldehyde Dehydrogenase–Positive Cells Determines Prostate Cancer Radiosensitivity
Authors: Schwarz Franziska M. , Schniewind Iñaki , Besso Maria J. , Lange Steffen , Linge Annett , Patil Shivaprasad G. , Löck Steffen , Klusa Daria , Dietrich Antje , Voss-Böhme Anja , Nowrouzi Ali , Krause Mechthild , Dubrovska Anna , Kurth Ina , Peitzsch Claudia
Published: April 2023

Supplementary Figure from Plasticity within Aldehyde Dehydrogenase–Positive Cells Determines Prostate Cancer Radiosensitivity
Supplementary Tables 1 - 5. Supplementary Figures 1 - 3 from COMMD3-Mediated Endosomal Trafficking of HER2 Inhibits the Progression of Ovarian Carcinoma
Authors: Wang Shiqing , Liu Yuxin , Li Siyu , Chen Yanan , Liu Yanhua , Yan Jie , Wu Jiayi , Li Jia , Wang Longlong , Xiang Rong , Shi Yi , Qin Xuan , Yang Shuang
Published: April 2023

Table S1. Differential receptor proteins detected by mass spectrometry
Table S2. Antibodies used in this study
Table S3. RT-qPCR primers
Table S4. shRNA
Table S5. The top 20 candidate genes screened by MAGeCK analysis algorithm
Figure S1. The construction of stable cell lines
Figure S2. The cell cycle in SK-OV-3 cells
Figure S3. COMMD3 inhibits OC cell proliferation and metastasis migration in vitro in a HER2-dependent manner
Data from Suppression of Ser/Thr Phosphatase 4 (PP4C/PPP4C) Mimics a Novel Post-Mitotic Action of Fostriecin, Producing Mitotic Slippage Followed by Tetraploid Cell Death
Authors: Theobald Benjamin , Bonness Kathy , Musiyenko Alla , Andrews Joel F. , Urban Gudrun , Huang Xizhong , Dean Nicholas M. , Honkanen Richard E.
Published: April 2023

Abstract
Fostriecin is a natural product purified from Sterptomyces extracts with antitumor activity sufficient to warrant human clinical trials. Unfortunately, difficulties associated with supply and stable drug formulation stalled further development. At a molecular level, fostriecin is known to act as a catalytic inhibitor of four PPP-family phosphatases, and reports describing the design of molecules in this class suggest derivatives targeting enzymes within the fostriecin-sensitive subfamily can be successful. However, it is not clear if the tumor-selective cytotoxicity of fostriecin results from the inhibition of a specific phosphatase, multiple phosphatases, or a limited subset of fostriecin sensitive phosphatases. How the inhibition of sensitive phosphatases contributes to tumor-selective cytotoxicity is also not clear. Here, high-content time-lapse imaging of live cells revealed novel insight into the cellular actions of fostriecin, showing that fostriecin-induced apoptosis is not simply induced following a sustained mitotic arrest. Rather, apoptosis occurred in an apparent second interphase produced when tetraploid cells undergo mitotic slippage. Comparison of the actions of fostriecin and antisense-oligonucleotides specifically targeting human fostriecin-sensitive phosphatases revealed that the suppression PP4C alone is sufficient to mimic many actions of fostriecin. Importantly, targeted suppression of PP4C induced apoptosis, with death occurring in tetraploid cells following mitotic slippage. This effect was not observed following the suppression of PP1C, PP2AC, or PP5C. These data clarify PP4C as a fostriecin-sensitive phosphatase and demonstrate that the suppression of PP4C triggers mitotic slippage/apoptosis.

Implications: Future development of fostriecin class inhibitors should consider PP4C as a potentially important target. Mol Cancer Res; 11(8); 845–55. ©2013 AACR.
Data from Epigenetic Control of NF-κB-Dependent FAS Gene Transcription during Progression of Myelodysplastic Syndromes
Authors: Ettou Sandrine , Humbrecht Catherine , Benet Blandine , Billot Katy , d'Allard Diane , Mariot Virginie , Goodhardt Michele , Kosmider Olivier , Mayeux Patrick , Solary Eric , Fontenay Michaela
Published: April 2023

Abstract
The death domain containing TNF receptor 6 (CD95/Fas) is a direct target for the NF-κB transcription factor and is repressed in solid tumors such as colon carcinomas. Previously, we reported that the Fas death receptor, while overexpressed in low-risk myelodysplastic syndromes (MDS), becomes undetectable on CD34+ progenitors when the disease progresses to secondary acute myeloid leukemia (AML). This study determined the interplay between NF-κB and Fas during MDS progression. We first observed that Fas was induced by TNF-α in the HL60 cell line. In these cells, p65 (RELA) was associated with the FAS promoter, and inhibition of the NF-κB pathway by an IKKα inhibitor (BAY11-7082) or lentiviral expression of a nondegradable mutant of IκBα (IκSR) blocked Fas expression. In contrast, TNF-α failed to induce Fas expression in the colon carcinoma cell line SW480, due to hypermethylation of the FAS promoter. Azacitidine rescued p65 binding on FAS promoter in vitro, and subsequently Fas expression in SW480 cells. Furthermore, inhibition of the NF-κB pathway decreased the expression of Fas in MDS CD45loCD34+ bone marrow cells. However, despite the nuclear expression of p65, Fas was often low on CD45loCD34+ AML cells. TNF-α failed to stimulate its expression, while azacitidine efficiently rescued p65 binding and Fas reexpression. Overall, these data suggest that DNA methylation at NF-κB sites is responsible for FAS gene silencing. Mol Cancer Res; 11(7); 724–35. ©2013 AACR.
Data from Procollagen Lysyl Hydroxylase 2 Is Essential for Hypoxia-Induced Breast Cancer Metastasis
Authors: Gilkes Daniele M. , Bajpai Saumendra , Wong Carmen C. , Chaturvedi Pallavi , Hubbi Maimon E. , Wirtz Denis , Semenza Gregg L.
Published: April 2023

Abstract
Metastasis is the leading cause of death among patients who have breast cancer. Understanding the role of the extracellular matrix (ECM) in the metastatic process may lead to the development of improved therapies to treat patients with cancer. Intratumoral hypoxia, found in the majority of breast cancers, is associated with an increased risk of metastasis and mortality. We found that in hypoxic breast cancer cells, hypoxia-inducible factor 1 (HIF-1) activates transcription of the PLOD1 and PLOD2 genes encoding procollagen lysyl hydroxylases that are required for the biogenesis of collagen, which is a major constituent of the ECM. High PLOD2 expression in breast cancer biopsies is associated with increased risk of mortality. We show that PLOD2 is critical for fibrillar collagen formation by breast cancer cells, increases tumor stiffness, and is required for metastasis to lymph nodes and lungs. Mol Cancer Res; 11(5); 456–66. ©2013 AACR.
Data from Towards Sustained Silencing of HER2/neu in Cancer By Epigenetic Editing
Authors: Falahi Fahimeh , Huisman Christian , Kazemier Hinke G. , van der Vlies Pieter , Kok Klaas , Hospers Geke A.P. , Rots Marianne G.
Published: April 2023

Abstract
The human epidermal growth factor receptor-2 (HER2/neu/ERBB2) is overexpressed in several cancer types. Although therapies targeting the HER2/neu protein result in inhibition of cell proliferation, the anticancer effect might be further optimized by limiting HER2/neu expression at the DNA level. Towards this aim, epigenetic editing was performed to suppress HER2/neu expression by inducing epigenetic silencing marks on the HER2/neu promoter.HER2/neu expression and HER2/neu promoter epigenetic modification status were determined in a panel of ovarian and breast cancer cell lines. HER2/neu-overexpressing cancer cells were transduced to express a zinc finger protein (ZFP), targeting the HER2/neugene, fused to histone methyltransferases (G9a, SUV39-H1)/super KRAB domain (SKD). Epigenetic assessment of the HER2/neu promoter showed that HER2/neu-ZFP fused to G9a efficiently induced the intended silencing histone methylation mark (H3K9me2). Importantly, H3K9me2 induction was associated with a dramatic downregulation of HER2/neu expression in HER2/neu- overexpressing cells. Downregulation by SKD, traditionally considered transient in nature, was associated with removal of the histone acetylation mark (H3ac). The downregulation of HER2/neu by induced H3K9 methylation and/or reduced H3 acetylation was sufficient to effectively inhibit cellular metabolic activity and clonogenicity. Furthermore, genome-wide analysis indicated preferential binding of the ZFP to its target sequence. These results not only show that H3K9 methylation can be induced but also that this epigenetic mark was instructive in promoting downregulation of HER2/neu expression.

Implications: Epigenetic editing provides a novel (synergistic) approach to modulate expression of oncogenes. Mol Cancer Res; 11(9); 1029–39. ©2013 AACR.
Data from Deubiquitinase OTUD6B Isoforms Are Important Regulators of Growth and Proliferation
Authors: Sobol Anna , Askonas Caroline , Alani Sara , Weber Megan J. , Ananthanarayanan Vijayalakshmi , Osipo Clodia , Bocchetta Maurizio
Published: April 2023

Abstract
Deubiquitinases (DUB) are increasingly linked to the regulation of fundamental processes in normal and cancer cells, including DNA replication and repair, programmed cell death, and oncogenes and tumor suppressor signaling. Here, evidence is presented that the deubiquitinase OTUD6B regulates protein synthesis in non–small cell lung cancer (NSCLC) cells, operating downstream from mTORC1. OTUD6B associates with the protein synthesis initiation complex and modifies components of the 48S preinitiation complex. The two main OTUD6B splicing isoforms seem to regulate protein synthesis in opposing fashions: the long OTUD6B-1 isoform is inhibitory, while the short OTUD6B-2 isoform stimulates protein synthesis. These properties affect NSCLC cell proliferation, because OTUD6B-1 represses DNA synthesis while OTUD6B-2 promotes it. Mutational analysis and downstream mediators suggest that the two OTUD6B isoforms modify different cellular targets. OTUD6B-2 influences the expression of cyclin D1 by promoting its translation while regulating (directly or indirectly) c-Myc protein stability. This phenomenon appears to have clinical relevance as NSCLC cells and human tumor specimens have a reduced OTUD6B-1/OTUD6B-2 mRNA ratio compared with normal samples. The global OTUD6B expression level does not change significantly between nonneoplastic and malignant tissues, suggesting that modifications of splicing factors during the process of transformation are responsible for this isoform switch.

Implications: Because protein synthesis inhibition is a viable treatment strategy for NSCLC, these data indicate that OTUD6B isoform 2, being specifically linked to NSCLC growth, represents an attractive, novel therapeutic target and potential biomarker for early diagnosis of malignant NSCLC. Mol Cancer Res; 15(2); 117–27. ©2016 AACR.
Data from Novel Regulation of Integrin Trafficking by Rab11-FIP5 in Aggressive Prostate Cancer
Authors: Das Lipsa , Gard Jaime M.C. , Prekeris Rytis , Nagle Raymond B. , Morrissey Colm , Knudsen Beatrice S. , Miranti Cindy K. , Cress Anne E.
Published: April 2023

Abstract
The laminin-binding integrins, α3β1 and α6β1, are needed for tumor metastasis and their surface expression is regulated by endocytic recycling. β1 integrins share the Rab11 recycling machinery, but the trafficking of α3β1 and α6β1 are distinct by an unknown mechanism. Using a mouse PDX tumor model containing human metastatic prostate cancer, Rab11 family interacting protein 5 (Rab11-FIP5) was identified as a lead candidate for α6β1 trafficking. Rab11-FIP5 and its membrane-binding domain were required for α6β1 recycling, without affecting the other laminin-binding integrin (i.e., α3β1) or unrelated membrane receptors like CD44, transferrin receptor, or E-cadherin. Depletion of Rab11-FIP5 resulted in the intracellular accumulation of α6β1 in the Rab11 recycling compartment, loss of cell migration on laminin, and an unexpected loss of α6β1 recycling in cell–cell locations. Taken together, these data demonstrate that α6β1 is distinct from α3β1 via Rab11-FIP5 recycling and recycles in an unexpected cell–cell location.

Implications: Rab11-FIP5–dependent α6β1 integrin recycling may be selectively targeted to limit migration of prostate cancer cells into laminin-rich tissues. Mol Cancer Res; 16(8); 1319–31. ©2018 AACR.
Data from Molecular Signature and Mechanisms of Hepatitis D Virus–Associated Hepatocellular Carcinoma
Authors: Diaz Giacomo , Engle Ronald E. , Tice Ashley , Melis Marta , Montenegro Stephanie , Rodriguez-Canales Jaime , Hanson Jeffrey , Emmert-Buck Michael R. , Bock Kevin W. , Moore Ian N. , Zamboni Fausto , Govindarajan Sugantha , Kleiner David E. , Farci Patrizia
Published: April 2023

Abstract
There is limited data on the molecular mechanisms whereby hepatitis D virus (HDV) promotes liver cancer. Therefore, serum and liver specimens obtained at the time of liver transplantation from well-characterized patients with HDV-HCC (n = 5) and with non-HCC HDV cirrhosis (n = 7) were studied using an integrated genomic approach. Transcriptomic profiling was performed using laser capture–microdissected (LCM) malignant and nonmalignant hepatocytes, tumorous and nontumorous liver tissue from patients with HDV-HCC, and liver tissue from patients with non-HCC HDV cirrhosis. HDV-HCC was also compared with hepatitis B virus (HBV) HBV-HCC alone, and hepatitis C virus (HCV) HCV-HCC. HDV malignant hepatocytes were characterized by an enrichment of upregulated transcripts associated with pathways involved in cell-cycle/DNA replication, damage, and repair (Sonic Hedgehog, GADD45, DNA-damage-induced 14-3-3σ, cyclins and cell-cycle regulation, cell cycle: G2–M DNA-damage checkpoint regulation, and hereditary breast cancer). Moreover, a large network of genes identified functionally relate to DNA repair, cell cycle, mitotic apparatus, and cell division, including 4 cancer testis antigen genes, attesting to the critical role of genetic instability in this tumor. Besides being overexpressed, these genes were also strongly coregulated. Gene coregulation was high not only when compared with nonmalignant hepatocytes, but also to malignant hepatocytes from HBV-HCC alone or HCV-HCC. Activation and coregulation of genes critically associated with DNA replication, damage, and repair point to genetic instability as an important mechanism of HDV hepatocarcinogenesis. This specific HDV-HCC trait emerged also from the comparison of the molecular pathways identified for each hepatitis virus–associated HCC. Despite the dependence of HDV on HBV, these findings suggest that HDV and HBV promote carcinogenesis by distinct molecular mechanisms.

Implications: This study identifies a molecular signature of HDV-associated hepatocellular carcinoma and suggests the potential for new biomarkers for early diagnostics. Mol Cancer Res; 16(9); 1406–19. ©2018 AACR.
Data from CREBBP/EP300 Bromodomain Inhibition Affects the Proliferation of AR-Positive Breast Cancer Cell Lines
Authors: Garcia-Carpizo Veronica , Ruiz-Llorente Sergio , Sarmentero Jacinto , González-Corpas Ana , Barrero Maria J.
Published: April 2023

Abstract
Inhibitors that prevent the binding of bromodomains to acetylated histones hold therapeutic potential. However, the effects of targeting most of the 60 different bromodomains found in the human proteome remain unexplored. Here, we investigate the molecular mechanisms responsible for the antiproliferative properties of CREBBP/EP300 bromodomain inhibition in ER-negative breast cancer cell lines. We show using genetic and chemical approaches that CREBBP/EP300 bromodomains are critical to support the proliferation of the triple-negative breast cancer cell line MDA-MB-453. Analysis of the transcriptional pathways affected by CREBBP/EP300 bromodomain inhibitors reveals that the expression of genes associated with super-enhancers is downregulated, which in turn are occupied by very high levels of androgen receptor (AR) in MDA-MB-453 cells. Treatment of MDA-MB-453 with CREBBP/EP300 bromodomain inhibitors downregulates the expression of an AR-dependent signature distinctive of breast cancer tumors that express AR and causes a decrease in H3K27ac levels at AR-binding sites. In accordance, in prostate cancer cell lines that express AR CREBBP/EP300 bromodomain inhibitors downregulate the expression of genes bound by AR and associated with super-enhancers. In summary, we report that triple-negative breast cancer cell lines that express AR are particularly sensitive to CREBBP/EP300 bromodomain inhibitors and consequently these inhibitors hold potential to treat this type of cancer.
Implications:
AR-dependent cancer cell lines are sensitive to CREBBP/EP300 bromodomain inhibitors
Data from UNC-45A Is a Novel Microtubule-Associated Protein and Regulator of Paclitaxel Sensitivity in Ovarian Cancer Cells
Authors: Mooneyham Ashley , Iizuka Yoshie , Yang Qing , Coombes Courtney , McClellan Mark , Shridhar Vijayalakshmi , Emmings Edith , Shetty Mihir , Chen Liqiang , Ai Teng , Meints Joyce , Lee Michael K. , Gardner Melissa , Bazzaro Martina
Published: April 2023

Abstract
UNC-45A, a highly conserved member of the UCS (UNC45A/CRO1/SHE4P) protein family of cochaperones, plays an important role in regulating cytoskeletal-associated functions in invertebrates and mammalian cells, including cytokinesis, exocytosis, cell motility, and neuronal development. Here, for the first time, UNC-45A is demonstrated to function as a mitotic spindle-associated protein that destabilizes microtubules (MT) activity. Using in vitro biophysical reconstitution and total internal reflection fluorescence microscopy analysis, we reveal that UNC-45A directly binds to taxol-stabilized MTs in the absence of any additional cellular cofactors or other MT-associated proteins and acts as an ATP-independent MT destabilizer. In cells, UNC-45A binds to and destabilizes mitotic spindles, and its depletion causes severe defects in chromosome congression and segregation. UNC-45A is overexpressed in human clinical specimens from chemoresistant ovarian cancer and that UNC-45A–overexpressing cells resist chromosome missegregation and aneuploidy when treated with clinically relevant concentrations of paclitaxel. Lastly, UNC-45A depletion exacerbates paclitaxel-mediated stabilizing effects on mitotic spindles and restores sensitivity to paclitaxel.
Implications:
These findings reveal novel and significant roles for UNC-45A in regulation of cytoskeletal dynamics, broadening our understanding of the basic mechanisms regulating MT stability and human cancer susceptibility to paclitaxel, one of the most widely used chemotherapy agents for the treatment of human cancers.
Data from The Activation of MEK/ERK Signaling Pathway by Bone Morphogenetic Protein 4 to Increase Hepatocellular Carcinoma Cell Proliferation and Migration
Authors: Chiu Chiang-Yen , Kuo Kung-Kai , Kuo Tzu-Lei , Lee King-The , Cheng Kuang-Hung
Published: April 2023

Abstract
Hepatocellular carcinoma (HCC) is one of the most common visceral malignancies worldwide, with a very high incidence and poor prognosis. Bone morphogenesis protein 4 (BMP4), which belongs to the TGF-β superfamily of proteins, is a multifunctional cytokine, which exerts its biologic effects through SMAD- and non-SMAD-dependent pathways, and is also known to be involved in human carcinogenesis. However, the effects of the BMP4 signaling in liver carcinogenesis are not yet clearly defined. Here, we first show that BMP4 and its receptor, BMPR1A, are overexpressed in a majority of primary HCCs and that it promotes the growth and migration of HCC cell lines in vitro. We also establish that BMP4 can induce HCC cyclin-dependent kinase (CDK)1 and cyclin B1 upregulation to accelerate cell-cycle progression. Our study indicates that the induction of HCC cell proliferation is independent of the SMAD signaling pathway, as Smad4 knockdown of HCC cell lines still leads to the upregulation of CDK1 and cyclin B1 expression after BMP4 treatment. Using mitogen-activated protein/extracellular signal-regulated kinase (MEK) selective inhibitors, the induction of CDK1, cyclin B1 mRNA and protein were shown to be dependent on the activation of MEK/extracellular signal-regulated kinase (ERK) signaling. In vivo xenograft studies confirmed that the BMPR1A-knockdown cells were significantly less tumorigenic than the control groups. Our findings show that the upregulation of BMP4 and BMPR1A in HCC promotes the proliferation and metastasis of HCC cells and that CDK1 and cyclin B1 are important SMAD-independent molecular targets in BMP4 signaling pathways, during the HCC tumorigenesis. It is proposed that BMP4 signaling pathways may have potential as new therapeutic targets in HCC treatment. Mol Cancer Res; 10(3); 415–27. ©2012 AACR.
Data from Induction of Antiproliferative Connective Tissue Growth Factor Expression in Wilms' Tumor Cells by Sphingosine-1-Phosphate Receptor 2
Authors: Li Mei-Hong , Sanchez Teresa , Pappalardo Anna , Lynch Kevin R. , Hla Timothy , Ferrer Fernando
Published: April 2023

Abstract
Connective tissue growth factor (CTGF), a member of the CCN family of secreted matricellular proteins, regulates fibrosis, angiogenesis, cell proliferation, apoptosis, tumor growth, and metastasis. However, the role of CTGF and its regulation mechanism in Wilms' tumor remains largely unknown. We found that the bioactive lipid sphingosine-1-phosphate (S1P) induced CTGF expression in a concentration- and time-dependent manner in a Wilms' tumor cell line (WiT49), whereas FTY720-phosphate, an S1P analogue that binds all S1P receptors except S1P2, did not. Further, the specific S1P2 antagonist JTE-013 completely inhibited S1P-induced CTGF expression, whereas the S1P1 antagonist VPC44116 did not, indicating that this effect was mediated by S1P2. This was confirmed by adenoviral transduction of S1P2 in WiT49 cells, which showed that overexpression of S1P2 increased the expression of CTGF. Induction of CTGF by S1P was sensitive to ROCK inhibitor Y-27632 and c-Jun NH2-terminal kinase inhibitor SP600125, suggesting the requirement of RhoA/ROCK and c-Jun NH2-terminal kinase pathways for S1P-induced CTGF expression. Interestingly, the expression levels of CTGF were decreased in 8 of 10 Wilms' tumor tissues compared with matched normal tissues by quantitative real-time PCR and Western blot analysis. In vitro, human recombinant CTGF significantly inhibited the proliferation of WiT49 cells. In addition, overexpression of CTGF resulted in significant inhibition of WiT49 cell growth. Taken together, these data suggest that CTGF protein induced by S1P2 might act as a growth inhibitor in Wilms' tumor. (Mol Cancer Res 2008;6(10):1649–56)
Data from Cancer-Associated Fibroblasts Induce Matrix Metalloproteinase–Mediated Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma Cells
Authors: Johansson Ann-Charlotte , Ansell Anna , Jerhammar Fredrik , Lindh Maja Bradic , Grénman Reidar , Munck-Wikland Eva , Östman Arne , Roberg Karin
Published: April 2023

Abstract
A growing body of evidence suggests that components of the tumor microenvironment, including cancer-associated fibroblasts (CAF), may modulate the treatment sensitivity of tumor cells. Here, we investigated the possible influence of CAFs on the sensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines to cetuximab, an antagonistic epidermal growth factor receptor (EGFR) antibody. Cetuximab treatment caused a reduction in the proliferation rate of HNSCC cell lines, whereas the growth of HNSCC-derived CAF cultures was unaffected. When tumor cells were cocultured with CAFs in a transwell system, the cetuximab-induced growth inhibition was reduced, and a complete protection from growth inhibition was observed in one of the tumor cell lines investigated. Media that had been conditioned by CAFs offered protection from cetuximab treatment in a concentration-dependent manner, suggesting that the resistance to treatment was mediated by CAF-derived soluble factors. The coculture of HNSCC cell lines with CAFs resulted in an elevated expression of matrix metalloproteinase-1 (MMP-1) in both the tumor cells and CAFs. Moreover, the CAF-induced resistance was partly abolished by the presence of an MMP inhibitor. However, CAFs treated with siRNA targeting MMP-1 still protected tumor cells from cetuximab treatment, suggesting that several MMPs may cooperate to facilitate resistance or that the protective effect is mediated by another member of the MMP family. These results identify a novel CAF-dependent modulation of cetuximab sensitivity and suggest that inhibiting MMPs may improve the effects of EGFR-targeted therapy. Mol Cancer Res; 10(9); 1158–68. ©2012 AACR.
Data from Radium-223–Induced Bystander Effects Cause DNA Damage and Apoptosis in Disseminated Tumor Cells in Bone Marrow
Authors: Canter Brian S. , Leung Calvin N. , Fritton J. Christopher , Bäck Tom , Rajon Didier , Azzam Edouard I. , Howell Roger W.
Published: April 2023

Abstract
Radiation-induced bystander effects have been implicated in contributing to the growth delay of disseminated tumor cells (DTC) caused by 223RaCl2, an alpha particle–emitting radiopharmaceutical. To understand how 223RaCl2 affects the growth, we have quantified biological changes caused by direct effects of radiation and bystander effects caused by the emitted radiations on DTC and osteocytes. Characterizing these effects contribute to understanding the efficacy of alpha particle–emitting radiopharmaceuticals and guide expansion of their use clinically. MDA-MB-231 or MCF-7 human breast cancer cells were inoculated intratibially into nude mice that were previously injected intravenously with 50 or 600 kBq/kg 223RaCl2. At 1-day and 3-days postinoculation, tibiae were harvested and examined for DNA damage (γ-H2AX foci) and apoptosis in osteocytes and cancer cells located within and beyond the range (70 μm) of alpha particles emitted from the bone surface. Irradiated and bystander MDA-MB-231 and MCF-7 cells harbored DNA damage. Bystander MDA-MB-231 cells expressed DNA damage at both treatment levels while bystander MCF-7 cells required the higher administered activity. Osteocytes also had DNA damage regardless of inoculated cancer cell line. The extent of DNA damage was quantified by increases in low (1–2 foci), medium (3–5 foci), and high (5+ foci) damage. MDA-MB-231 but not MCF-7 bystander cells showed increases in apoptosis in 223RaCl2-treated animals, as did irradiated osteocytes. In summary, radiation-induced bystander effects contribute to DTC cytotoxicity caused by 223RaCl2.
Implications:
This observation supports clinical investigation of the efficacy of 223RaCl2 to prevent breast cancer DTC from progressing to oligometastases.
Data from Combined Targeting of PARG and Wee1 Causes Decreased Cell Survival and DNA Damage in an S-Phase–Dependent Manner
Authors: Agostini Lebaron C. , Jain Aditi , Shupp Alison , Nevler Avinoam , McCarthy Grace , Bussard Karen M. , Yeo Charles J. , Brody Jonathan R.
Published: April 2023

Abstract
The DNA damage response (DDR) pathway sets the stage for tumorigenesis and provides both an opportunity for drug efficacy and resistance. Therapeutic approaches to target the DDR pathway include aiming to increase the efficacy of cytotoxic chemotherapies and synergistic drug strategies to enhance DNA damage, and hence cell death. Here, we report the first preclinical evaluation of a novel synergistic approach by using both genetic and small-molecule inhibition methods of silencing the DDR-related protein, poly (ADP-ribose) glycohydrolase (PARG), and the checkpoint kinase inhibitor, Wee1, in pancreatic ductal adenocarcinoma (PDAC) and colorectal carcinoma cells in vitro and in vivo. Mechanistically, we demonstrate that coinhibition of PARG and Wee1 synergistically decreased cell survival and increased DNA damage in an S-phase–dependent manner.
Implications:
In preclinical models, we demonstrate the efficacy and mechanism of action of targeting both PARG and Wee1 in PDAC and colorectal carcinoma cells.
Visual Overview:
http://mcr.aacrjournals.org/content/molcanres/19/2/207/F1.large.jpg.
Data from HER2 Isoforms Uniquely Program Intratumor Heterogeneity and Predetermine Breast Cancer Trajectories During the Occult Tumorigenic Phase
Authors: Ginzel Joshua D. , Acharya Chaitanya R. , Lubkov Veronica , Mori Hidetoshi , Boone Peter G. , Rochelle Lauren K. , Roberts Wendy L. , Everitt Jeffrey I. , Hartman Zachary C. , Crosby Erika J. , Barak Lawrence S. , Caron Marc G. , Chen Jane Q. , Hubbard Neil E. , Cardiff Robert D. , Borowsky Alexander D. , Lyerly H. Kim , Snyder Joshua C.
Published: April 2023

Abstract
HER2-positive breast cancers are among the most heterogeneous breast cancer subtypes. The early amplification of HER2 and its known oncogenic isoforms provide a plausible mechanism in which distinct programs of tumor heterogeneity could be traced to the initial oncogenic event. Here a Cancer rainbow mouse simultaneously expressing fluorescently barcoded wildtype (WTHER2), exon-16 null (d16HER2), and N-terminally truncated (p95HER2) HER2 isoforms is used to trace tumorigenesis from initiation to invasion. Tumorigenesis was visualized using whole-gland fluorescent lineage tracing and single-cell molecular pathology. We demonstrate that within weeks of expression, morphologic aberrations were already present and unique to each HER2 isoform. Although WTHER2 cells were abundant throughout the mammary ducts, detectable lesions were exceptionally rare. In contrast, d16HER2 and p95HER2 induced rapid tumor development. d16HER2 incited homogenous and proliferative luminal-like lesions which infrequently progressed to invasive phenotypes whereas p95HER2 lesions were heterogenous and invasive at the smallest detectable stage. Distinct cancer trajectories were observed for d16HER2 and p95HER2 tumors as evidenced by oncogene-dependent changes in epithelial specification and the tumor microenvironment. These data provide direct experimental evidence that intratumor heterogeneity programs begin very early and well in advance of screen or clinically detectable breast cancer.
Implications:
Although all HER2 breast cancers are treated equally, we show a mechanism by which clinically undetected HER2 isoforms program heterogenous cancer phenotypes through biased epithelial specification and adaptations within the tumor microenvironment.
Data from Silencing of SmgGDS, a Novel mTORC1 Inducer That Binds to RHEBs, Inhibits Malignant Mesothelioma Cell Proliferation
Authors: Sato Tatsuhiro , Mukai Satomi , Ikeda Haruna , Mishiro-Sato Emi , Akao Ken , Kobayashi Toshiyuki , Hino Okio , Shimono Wataru , Shibagaki Yoshio , Hattori Seisuke , Sekido Yoshitaka
Published: April 2023

Abstract
Malignant mesothelioma (MM) is an aggressive tumor that typically develops after a long latency following asbestos exposure. Although mechanistic target of rapamycin complex 1 (mTORC1) activation enhances MM cell growth, the mTORC1 inhibitor everolimus has shown limited efficacy in clinical trials of MM patients. We explored the mechanism underlying mTORC1 activation in MM cells and its effects on cell proliferation and progression. Analysis of the expression profiles of 87 MMs from The Cancer Genome Atlas revealed that 40 samples (46%) displayed altered expression of RPTOR (mTORC1 component) and genes immediately upstream that activate mTORC1. Among them, we focused on RHEB and RHEBL1, which encode direct activators of mTORC1. Exogenous RHEBL1 expression enhanced MM cell growth, indicating that RHEB–mTORC1 signaling acts as a pro-oncogenic cascade. We investigated molecules that directly activate RHEBs, identifying SmgGDS as a novel RHEB-binding protein. SmgGDS knockdown reduced mTORC1 activation and inhibited the proliferation of MM cells with mTORC1 activation. Interestingly, SmgGDS displayed high binding affinity with inactive GDP-bound RHEBL1, and its knockdown reduced cytosolic RHEBL1 without affecting its activation. These findings suggest that SmgGDS retains GDP-bound RHEBs in the cytosol, whereas GTP-bound RHEBs are localized on intracellular membranes to promote mTORC1 activation. We revealed a novel role for SmgGDS in the RHEB–mTORC1 pathway and its potential as a therapeutic target in MM with aberrant mTORC1 activation.
Implications:
Our data showing that SmgGDS regulates RHEB localization to activate mTORC1 indicate that SmgGDS can be used as a new therapeutic target for MM exhibiting mTORC1 activation.
Data from Adipokine Apelin/APJ Pathway Promotes Peritoneal Dissemination of Ovarian Cancer Cells by Regulating Lipid Metabolism
Authors: Dogra Samrita , Neelakantan Deepika , Patel Maulin M. , Griesel Beth , Olson Ann , Woo Sukyung
Published: April 2023

Abstract
Adipose tissue, which can provide adipokines and nutrients to tumors, plays a key role in promoting ovarian cancer metastatic lesions in peritoneal cavity. The adipokine apelin promotes ovarian cancer metastasis and progression through its receptor APJ, which regulates cell proliferation, energy metabolism, and angiogenesis. The objective of this study was to investigate the functional role and mechanisms of the apelin-APJ pathway in ovarian cancer metastasis, especially in context of tumor cell–adipocyte interactions. When co-cultured in the conditioned media (AdipoCM) derived from 3T3-L1 adipocytes, which express and secrete high apelin, human ovarian cancer cells with high APJ expression showed significant increases in migration and invasion in vitro. We also found that cells expressing high levels of APJ had increased cell adhesion to omentum ex vivo, and preferentially “home-in” on the omentum in vivo. These apelin-induced pro-metastatic effects were reversed by APJ antagonist F13A in a dose-dependent manner. Apelin-APJ activation increased lipid droplet accumulation in ovarian cancer cells, which was further intensified in the presence of AdipoCM and reversed by F13A or APJ knockdown. Mechanistically, this increased lipid uptake was mediated by CD36 upregulation via APJ-STAT3 activation, and the lipids were utilized in promoting fatty acid oxidation via activation of AMPK-CPT1a axis. Together, our studies demonstrate that adipocyte-derived apelin activates APJ-expressing tumor cells in a paracrine manner, promoting lipid uptake and utilization and providing energy for ovarian cancer cell survival at the metastatic sites. Hence, the apelin-APJ pathway presents a novel therapeutic target to curb ovarian cancer metastasis.
Implications:
Targeting the APJ pathway in high-grade serous ovarian carcinoma is a novel strategy to inhibit peritoneal metastasis.