bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Data from RNA Helicase DDX24 Stabilizes LAMB1 to Promote Hepatocellular Carcinoma Progression
Authors: Liu Tianze , Gan Hairun , He Simeng , Deng Jia , Hu Xinyan , Li Luting , Cai Li , He Jianzhong , Long Haoyu , Cai Jianxun , Li Hanjie , Zhang Qianqian , Wang Lijie , Chen Fangbin , Chen Yuming , Zhang Haopei , Li Jian , Yang Lukun , Liu Ye , Yang Jian-Hua , Kuang Dong-Ming , Pang Pengfei , He Huanhuan , Shan Hong
Published: March 2023

Supplementary Data from RNA Helicase DDX24 Stabilizes LAMB1 to Promote Hepatocellular Carcinoma Progression
Supplementary Data from IL6 and CCL18 Mediate Cross-talk between VHL-Deficient Kidney Cells and Macrophages during Development of Renal Cell Carcinoma
Authors: Nguyen Thi-Ngoc , Nguyen-Tran Hieu-Huy , Chen Chen-Yun , Hsu Tien
Published: March 2023

Supplementary Data from IL6 and CCL18 Mediate Cross-talk between VHL-Deficient Kidney Cells and Macrophages during Development of Renal Cell Carcinoma
Supplementary Data from Global DNA Methylation Analysis of Cancer-Associated Fibroblasts Reveals Extensive Epigenetic Rewiring Linked with RUNX1 Upregulation in Breast Cancer Stroma
Authors: Halperin Coral , Hey Joschka , Weichenhan Dieter , Stein Yaniv , Mayer Shimrit , Lutsik Pavlo , Plass Christoph , Scherz-Shouval Ruth
Published: March 2023

Supplementary Data from Global DNA Methylation Analysis of Cancer-Associated Fibroblasts Reveals Extensive Epigenetic Rewiring Linked with RUNX1 Upregulation in Breast Cancer Stroma
Supplementary Data from MET-Induced CD73 Restrains STING-Mediated Immunogenicity of EGFR-Mutant Lung Cancer
Authors: Yoshida Ryohei , Saigi Maria , Tani Tetsuo , Springer Benjamin F. , Shibata Hirofumi , Kitajima Shunsuke , Mahadevan Navin R. , Campisi Marco , Kim William , Kobayashi Yoshihisa , Thai Tran C. , Haratani Koji , Yamamoto Yurie , Sundararaman Shriram K. , Knelson Erik H. , Vajdi Amir , Canadas Israel , Uppaluri Ravindra , Paweletz Cloud P. , Miret Juan J. , Lizotte Patrick H. , Gokhale Prafulla C. , Jänne Pasi A. , Barbie David A.
Published: March 2023

Supplementary Data from MET-Induced CD73 Restrains STING-Mediated Immunogenicity of EGFR-Mutant Lung Cancer
Supplementary Table 3 from N-myc–Mediated Translation Control Is a Therapeutic Vulnerability in Medulloblastoma
Authors: Kuzuoglu-Ozturk Duygu , Aksoy Ozlem , Schmidt Christin , Lea Robin , Larson Jon D. , Phelps Ryan R.L. , Nasholm Nicole , Holt Megan , Contreras Adrian , Huang Miller , Wong-Michalak Shannon , Shao Hao , Wechsler-Reya Robert , Phillips Joanna J. , Gestwicki Jason E. , Ruggero Davide , Weiss William A.
Published: March 2023

Translation efficiency in Rapalink-1 and Rapamycin treated samples
Supplementary Dataset S7 from Loss of NF1 in Melanoma Confers Sensitivity to SYK Kinase Inhibition
Authors: Abecunas Cara , Whitehead Christopher E. , Ziemke Elizabeth K. , Baumann Douglas G. , Frankowski-McGregor Christy L. , Sebolt-Leopold Judith S. , Fallahi-Sichani Mohammad
Published: March 2023

Supplementary Dataset S7
Supplementary tables from ASPM Activates Hedgehog and Wnt Signaling to Promote Small Cell Lung Cancer Stemness and Progression
Authors: Cheng Li-Hsin , Hsu Chung-Chi , Tsai Hung-Wen , Liao Wen-Ying , Yang Pei-Ming , Liao Tai-Yan , Hsieh Hsiao-Yen , Chan Tze-Sian , Tsai Kelvin K.
Published: March 2023

This file contains Supplementary Tables 1-3
FigureS7 from Immunotherapeutic Targeting and PET Imaging of DLL3 in Small-Cell Neuroendocrine Prostate Cancer
Authors: Chou Jonathan , Egusa Emily A. , Wang Sinan , Badura Michelle L. , Lee Fei , Bidkar Anil P. , Zhu Jun , Shenoy Tanushree , Trepka Kai , Robinson Troy M. , Steri Veronica , Huang Jiaoti , Wang Yuzhuo , Small Eric J. , Chan Emily , Stohr Bradley A. , Ashworth Alan , Delafontaine Brant , Rottey Sylvie , Cooke Keegan S. , Hashemi Sadraei Nooshin , Yu Brian , Salvati Mark , Bailis Julie M. , Feng Felix Y. , Flavell Robert R. , Aggarwal Rahul
Published: March 2023

FigureS7
Table S1, S2, S3, S4, S5, S6 Supplementary Figure legends 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 Information
FigureS10 from Immunotherapeutic Targeting and PET Imaging of DLL3 in Small-Cell Neuroendocrine Prostate Cancer
Authors: Chou Jonathan , Egusa Emily A. , Wang Sinan , Badura Michelle L. , Lee Fei , Bidkar Anil P. , Zhu Jun , Shenoy Tanushree , Trepka Kai , Robinson Troy M. , Steri Veronica , Huang Jiaoti , Wang Yuzhuo , Small Eric J. , Chan Emily , Stohr Bradley A. , Ashworth Alan , Delafontaine Brant , Rottey Sylvie , Cooke Keegan S. , Hashemi Sadraei Nooshin , Yu Brian , Salvati Mark , Bailis Julie M. , Feng Felix Y. , Flavell Robert R. , Aggarwal Rahul
Published: March 2023

FigureS10
Figure S5 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 Figure5
Supplementary Data from Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma
Authors: Borgenvik Anna , Holmberg Karl O. , Bolin Sara , Zhao Miao , Savov Vasil , Rosén Gabriela , Hutter Sonja , Garancher Alexandra , Rahmanto Aldwin Suryo , Bergström Tobias , Olsen Thale Kristin , Mainwaring Oliver J. , Sattanino Damiana , Verbaan Annemieke D. , Rusert Jessica M. , Sundström Anders , Bravo Mar Ballester , Dang Yonglong , Wenz Amelie S. , Richardson Stacey , Fotaki Grammatiki , Hill Rebecca M. , Dubuc Adrian M. , Kalushkova Antonia , Remke Marc , Čančer Matko , Jernberg-Wiklund Helena , Giraud Géraldine , Chen Xingqi , Taylor Michael D. , Sangfelt Olle , Clifford Steven C. , Schüller Ulrich , Wechsler-Reya Robert J. , Weishaupt Holger , Swartling Fredrik J.
Published: March 2023

Supplementary figure 1
Supplementary Movie S4 from Plk1 Inhibitors and Abiraterone Synergistically Disrupt Mitosis and Kill Cancer Cells of Disparate Origin Independently of Androgen Receptor Signaling
Authors: Patterson Jesse C. , Varkaris Andreas , Croucher Peter J.P. , Ridinger Maya , Dalrymple Susan , Nouri Mannan , Xie Fang , Varmeh Shohreh , Jonas Oliver , Whitman Matthew A. , Chen Sen , Rashed Saleh , Makusha Lovemore , Luo Jun , Isaacs John T. , Erlander Mark G. , Einstein David J. , Balk Steven P. , Yaffe Michael B.
Published: March 2023

Identification of paired centromeres from sister chromatids
Supplementary Data 2 from KDM6A Loss Triggers an Epigenetic Switch That Disrupts Urothelial Differentiation and Drives Cell Proliferation in Bladder Cancer
Authors: Qiu Hong , Makarov Vladimir , Bolzenius Jennifer K. , Halstead Angela , Parker Yvonne , Wang Allen , Iyer Gopakumar V. , Wise Hannah , Kim Daniel , Thayaparan Varna , Lindner Daniel J. , Haber Georges-Pascal , Ting Angela H. , Ren Bing , Chan Timothy A. , Arora Vivek , Solit David B. , Lee Byron H.
Published: March 2023

ATF3 target genes downregulated in K2 that harbor FOXA1 peaks in RT4
Table S5 from The Oncogenic FOXL2 C134W Mutation Is a Key Driver of Granulosa Cell Tumors
Authors: Llano Elena , Todeschini Anne Laure , Felipe-Medina Natalia , Corte-Torres María D. , Condezo Yazmine B. , Sanchez-Martin Manuel , López-Tamargo Sara , Astudillo Aurora , Puente Xose S. , Pendas Alberto M. , Veitia Reiner A.
Published: March 2023

Table S5
Supplementary Data from Deregulation of SPOP in Cancer
Authors: Zhang Hui , Jin Xiaofeng , Huang Haojie
Published: March 2023

Supplementary Figures and Tables
Table S1 from Systematic Interrogation of Tumor Cell Resistance to Chimeric Antigen Receptor T-cell Therapy in Pancreatic Cancer
Authors: Hagel Kimberly R. , Arafeh Rand , Gang Sydney , Arnoff Taylor E. , Larson Rebecca C. , Doench John G. , Mathewson Nathan D. , Wucherpfennig Kai W. , Maus Marcela V. , Hahn William C.
Published: March 2023

genome-scale CRISPR-Cas9 screens
Figure S2 from YAP-Activated SATB2 Is a Coactivator of NRF2 That Amplifies Antioxidative Capacity and Promotes Tumor Progression in Renal Cell Carcinoma
Authors: Jin Juan , Chen Fen , He Wenfang , Zhao Li , Lin Bo , Zheng Danna , Chen Li , He Hongchao , He Qiang
Published: March 2023

Figure S2
Supplementary Table 2 from PARP Inhibition Induces Synthetic Lethality and Adaptive Immunity in LKB1-Mutant Lung Cancer
Authors: Long Li-Li , Ma Si-Cong , Guo Ze-Qin , Zhang Yan-Pei , Fan Zhenzhen , Liu Li-Juan , Liu Li , Han Duan-Duan , Leng Meng-Xin , Wang Jian , Guo Xue-Jun , Tan Jia-Le , Cai Xiao-Ting , Lin Yan , Pan Xinghua , Wu De-Hua , Bai Xue , Dong Zhong-Yi
Published: March 2023

LKB1-interacting proteins identified by LC-MS/MS analysis.
Supplementary Table 1 from Androgen Signaling Contributes to Sex Differences in Cancer by Inhibiting NF-κB Activation in T Cells and Suppressing Antitumor Immunity
Authors: Zhang Xiaomin , Cheng Limin , Gao Chengqi , Chen Jing , Liao Shuangye , Zheng Yongqiang , Xu Liping , He Jingjing , Wang Danyang , Fang Ziqian , Zhang Jianeng , Yan Min , Luan Yi , Chen Siyu , Chen Likun , Xia Xiaojun , Deng Chunhao , Chen Guokai , Li Wende , Liu Zexian , Zhou Penghui
Published: March 2023

Clinical characteristics for the NSCLC cohort analyzed the correlation between testosterone levels, prognosis and T cell infiltration
Supplementary Data from SMAD4 Loss Induces c-MYC–Mediated NLE1 Upregulation to Support Protein Biosynthesis, Colorectal Cancer Growth, and Metastasis
Authors: Loevenich Leon P. , Tschurtschenthaler Markus , Rokavec Matjaz , Silva Miguel G. , Jesinghaus Moritz , Kirchner Thomas , Klauschen Frederick , Saur Dieter , Neumann Jens , Hermeking Heiko , Jung Peter
Published: March 2023

Supplementary Materials
Oligonucleotides, qRT-PCR primer pairs, and Taqman probe assays used in this study.
Supplementary Fig-10 from The LncRNA LENOX Interacts with RAP2C to Regulate Metabolism and Promote Resistance to MAPK Inhibition in Melanoma
Authors: Gambi Giovanni , Mengus Gabrielle , Davidson Guillaume , Demesmaeker Ewout , Cuomo Alessandro , Bonaldi Tiziana , Katopodi Vicky , Malouf Gabriel G. , Leucci Eleonora , Davidson Irwin
Published: March 2023

MAPK inhibition increases LENOX expression downstream of TFAP2A.
Table ST1 from ROS Induction Targets Persister Cancer Cells with Low Metabolic Activity in NRAS-Mutated Melanoma
Authors: Eichhoff Ossia M. , Stoffel Corinne I. , Käsler Jan , Briker Luzia , Turko Patrick , Karsai Gergely , Zila Nina , Paulitschke Verena , Cheng Phil F. , Leitner Alexander , Bileck Andrea , Zamboni Nicola , Irmisch Anja , Balazs Zsolt , Tastanova Aizhan , Pascoal Susana , Johansen Pål , Wegmann Rebekka , Mena Julien , Othman Alaa , Viswanathan Vasanthi S. , Wenzina Judith , Aloia Andrea , Saltari Annalisa , Dzung Andreas , Krauthammer Michael , Schreiber Stuart L. , Hornemann Thorsten , Distel Martin , Snijder Berend , Dummer Reinhard , Levesque Mitchell P.
Published: March 2023

Table ST1: Summary of growth inhibitory IC50 values (including the corresponding 95% confident intervals (C.I.95%) conducted for neocuproine or MEKi (binimetinib) and primary human cell lines. The table includes the confirmed oncogenic mutation as well as the ratio of neocuproine normalized to the MEKi response.
Suppl.Figure S16 from ROS Induction Targets Persister Cancer Cells with Low Metabolic Activity in NRAS-Mutated Melanoma
Authors: Eichhoff Ossia M. , Stoffel Corinne I. , Käsler Jan , Briker Luzia , Turko Patrick , Karsai Gergely , Zila Nina , Paulitschke Verena , Cheng Phil F. , Leitner Alexander , Bileck Andrea , Zamboni Nicola , Irmisch Anja , Balazs Zsolt , Tastanova Aizhan , Pascoal Susana , Johansen Pål , Wegmann Rebekka , Mena Julien , Othman Alaa , Viswanathan Vasanthi S. , Wenzina Judith , Aloia Andrea , Saltari Annalisa , Dzung Andreas , Krauthammer Michael , Schreiber Stuart L. , Hornemann Thorsten , Distel Martin , Snijder Berend , Dummer Reinhard , Levesque Mitchell P.
Published: March 2023

S16: scRNA-sequencing analysis of xenograft tumors M130227
Suppl Figure S11 from ROS Induction Targets Persister Cancer Cells with Low Metabolic Activity in NRAS-Mutated Melanoma
Authors: Eichhoff Ossia M. , Stoffel Corinne I. , Käsler Jan , Briker Luzia , Turko Patrick , Karsai Gergely , Zila Nina , Paulitschke Verena , Cheng Phil F. , Leitner Alexander , Bileck Andrea , Zamboni Nicola , Irmisch Anja , Balazs Zsolt , Tastanova Aizhan , Pascoal Susana , Johansen Pål , Wegmann Rebekka , Mena Julien , Othman Alaa , Viswanathan Vasanthi S. , Wenzina Judith , Aloia Andrea , Saltari Annalisa , Dzung Andreas , Krauthammer Michael , Schreiber Stuart L. , Hornemann Thorsten , Distel Martin , Snijder Berend , Dummer Reinhard , Levesque Mitchell P.
Published: March 2023

S11: Immunohistological analysis of orthologic slice cultures.
Data from Control of Androgen Receptor Signaling in Prostate Cancer by the Cochaperone Small Glutamine–Rich Tetratricopeptide Repeat Containing Protein α
Authors: Buchanan Grant , Ricciardelli Carmela , Harris Jonathan M. , Prescott Jennifer , Yu Zoe Chiao-Li , Jia Li , Butler Lisa M. , Marshall Villis R. , Scher Howard I. , Gerald William L. , Coetzee Gerhard A. , Tilley Wayne D.
Published: March 2023

Abstract
Although the androgen receptor (AR) is accepted as the major determinant of prostate cancer cell survival throughout disease progression, it is currently unclear how the receptor sustains genomic signaling under conditions of systemic androgen ablation. Here, we show that the evolutionarily conserved Hsp70/Hsp90 cochaperone, small glutamine–rich tetratricopeptide repeat containing protein α (αSGT), interacts with the hinge region of the human AR in yeast and mammalian cells. Overexpression and RNA interference revealed that αSGT acts to (a) promote cytoplasmic compartmentalization of the AR, thereby silencing the receptors basal/ligand-independent transcriptional activity, (b) regulate the sensitivity of receptor signaling by androgens, and (c) limit the capacity of noncanonical ligands to induce AR agonist activity. Immunofluorescence, coactivator, and chromatin immunoprecipitation analyses strongly suggest that these effects of αSGT on AR function are mediated by interaction in the cytoplasm and are distinct from the receptors response to classic coregulators. Quantitative immunohistochemical analysis of αSGT and AR levels in a cohort of 32 primary and 64 metastatic human prostate cancers revealed dysregulation in the level of both proteins during disease progression. The significantly higher AR/αSGT ratio in metastatic samples is consistent with the sensitization of prostate tumor cells to androgen signaling with disease progression, particularly in a low-hormone environment. These findings implicate αSGT as a molecular rheostat of in vivo signaling competence by the AR, and provide new insight into the determinants of androgen sensitivity during prostate cancer progression. [Cancer Res 2007;67(20):10087–96]
Data from Suppression of Proximal T Cell Receptor Signaling and Lytic Function in CD8+ Tumor-Infiltrating T Cells
Authors: Monu Ngozi , Frey Alan B.
Published: March 2023

Abstract
CD8+ tumor-infiltrating lymphocytes (TIL) lack in vivo and in vitro lytic function due to a signaling deficit characterized by failure to flux calcium or activate tyrosine kinase activity upon contact with cognate tumor cells. Although CD3ζ is phosphorylated by conjugation in vitro with cognate tumor cells, showing that TIL are triggered, PLCγ-1, LAT, and ZAP70 are not activated and LFA-1 is not affinity-matured, and because p56lck is required for LFA-1 activation, this implies that the signaling blockade is very proximal. Here, we show that TIL signaling defects are transient, being reversed upon purification and brief culture in vitro, implying a fast-acting “switch”. Biochemical analysis of purified nonlytic TIL shows that contact with tumor cells causes transient activation of p56lck (∼10 s) which is rapidly inactivated. In contrast, tumor-induced activation of p56lck in lytic TIL is sustained coincident with downstream TCR signaling and lytic function. Shp-1 is robustly active in nonlytic TIL compared with lytic TIL, colocalizes with p56lck in nonlytic TIL, and inhibition of Shp-1 activity in lytic TIL in vitro blocks tumor-induced defective TIL cytolysis. Collectively, our data support the notion that contact of nonlytic TIL with tumor cells, and not with tumor-infiltrating myeloid-derived suppressor cells, causes activation of Shp-1 that rapidly dephosphorylates the p56lck activation motif (Y394), thus inhibiting effector phase functions. [Cancer Res 2007;67(23):11447–54]
Data from The Human let-7a-3 Locus Contains an Epigenetically Regulated MicroRNA Gene with Oncogenic Function
Authors: Brueckner Bodo , Stresemann Carlo , Kuner Ruprecht , Mund Cora , Musch Tanja , Meister Michael , Sültmann Holger , Lyko Frank
Published: March 2023

Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that repress their target mRNAs by complementary base pairing and induction of the RNA interference pathway. It has been shown that miRNA expression can be regulated by DNA methylation and it has been suggested that altered miRNA gene methylation might contribute to human tumorigenesis. In this study, we show that the human let-7a-3 gene on chromosome 22q13.31 is associated with a CpG island. Let-7a-3 belongs to the archetypal let-7 miRNA gene family and was found to be methylated by the DNA methyltransferases DNMT1 and DNMT3B. The gene was heavily methylated in normal human tissues but hypomethylated in some lung adenocarcinomas. Let-7a-3 hypomethylation facilitated epigenetic reactivation of the gene and elevated expression of let-7a-3 in a human lung cancer cell line resulted in enhanced tumor phenotypes and oncogenic changes in transcription profiles. Our results thus identify let-7a-3 as an epigenetically regulated miRNA gene with oncogenic function and suggest that aberrant miRNA gene methylation might contribute to the human cancer epigenome. [Cancer Res 2007;67(4):1419–23]
Data from Mechanism of All-Trans Retinoic Acid Effect on Tumor-Associated Myeloid-Derived Suppressor Cells
Authors: Nefedova Yulia , Fishman Mayer , Sherman Simon , Wang Xingyu , Beg Amer A. , Gabrilovich Dmitry I.
Published: March 2023

Abstract
Myeloid-derived suppressor cells (MDSC) play an important role in tumor escape by suppressing T-cell responses. MDSC represent a group of cells of myeloid lineage at different stages of differentiation. Increased arginase activity and production of reactive oxygen species (ROS) are among the main functional characteristics of these cells. Recent studies have shown that all-trans retinoic acid (ATRA) had a potent activity in eliminating MDSC in cancer patients and in tumor-bearing mice. ATRA differentiates these cells into mature myeloid cells. However, the mechanism of this effect is unclear. Here, we have shown that ATRA dramatically and specifically up-regulated gene expression and protein level of glutathione synthase (GSS) in MDSC. This resulted in accumulation of glutathione (GSH) in these cells, observed in both mice and cancer patients. Blockade of GSH synthesis cancelled the effect of ATRA on MDSC. Accumulation of GSH in these cells using N-acetyl-l-cysteine mimicked the effect of ATRA on MDSC differentiation. Analysis of potential mechanisms of ATRA effect on GSS revealed that ATRA regulates its expression not by directly binding to the promoter but primarily via activation of extracellular signal–regulated kinase 1/2. Thus, ATRA induced differentiation of MDSC primarily via neutralization of high ROS production in these cells. This novel mechanism involves specific up-regulation of GSS and accumulation of GSH and could be used in developing and monitoring therapeutic application of ATRA. [Cancer Res 2007;67(22):11021–8]
Data from Therapeutic Efficacy of ABT-737, a Selective Inhibitor of BCL-2, in Small Cell Lung Cancer
Authors: Hann Christine L. , Daniel Vincent C. , Sugar Elizabeth A. , Dobromilskaya Irina , Murphy Sara C. , Cope Leslie , Lin Xue , Hierman Jared S. , Wilburn Daniel L. , Watkins D. Neil , Rudin Charles M.
Published: March 2023

Abstract
Bcl-2 is a central regulator of cell survival that is overexpressed in the majority of small cell lung cancers (SCLC) and contributes to both malignant transformation and therapeutic resistance. We compared primary SCLC xenografts prepared from de novo human tumors with standard cell line–based xenografts in the evaluation of a novel and highly potent small molecule inhibitor of Bcl-2, ABT-737. ABT-737 induced dramatic regressions in tumors derived from some SCLC cell lines. In contrast, only one of three primary xenograft SCLC tumors showed significant growth inhibition with ABT-737. Explanations for this apparent dichotomy may include relatively low expression of Bcl-2 in the primary xenografts or inherent differences in the model systems. The addition of etoposide to ABT-737 in the primary xenografts resulted in significant decreases in tumor growth, underscoring the clinical potential of ABT-737 in combination therapy. To identify factors that may contribute to resistance to ABT-737 and related inhibitors, we isolated resistant derivatives of an initially sensitive cell line–based xenograft. Acquired resistance in this model was associated with decreases in the expression of the primary target Bcl-2, of proapoptotic partners of Bcl-2 (Bax and Bim), and of Bcl-2:Bim heterodimers. Expression profiling reveals 85 candidate genes demonstrating consistent changes in gene expression with acquired resistance. Taken together, these data have specific implications for the clinical development of Bcl-2 inhibitors for SCLC and broader implications for the testing of novel anticancer strategies in relevant preclinical models. [Cancer Res 2008;68(7):2321–8]
Data from Knock-in of Oncogenic Kras Does Not Transform Mouse Somatic Cells But Triggers a Transcriptional Response that Classifies Human Cancers
Authors: Arena Sabrina , Isella Claudio , Martini Miriam , de Marco Ario , Medico Enzo , Bardelli Alberto
Published: March 2023

Abstract
KRAS mutations are present at a high frequency in human cancers. The development of therapies targeting mutated KRAS requires cellular and animal preclinical models. We exploited adeno-associated virus–mediated homologous recombination to insert the Kras G12D allele in the genome of mouse somatic cells. Heterozygous mutant cells displayed a constitutively active Kras protein, marked morphologic changes, increased proliferation and motility but were not transformed. On the contrary, mouse cells in which we overexpressed the corresponding Kras cDNA were readily transformed. The levels of Kras activation in knock-in cells were comparable with those present in human cancer cells carrying the corresponding mutation. Kras-mutated cells were compared with their wild-type counterparts by gene expression profiling, leading to the definition of a “mutated Kras-KI signature” of 345 genes. This signature was capable of classifying mouse and human cancers according to their KRAS mutational status, with an accuracy similar to or better than published Ras signatures. The isogenic cells that we have developed recapitulate the oncogenic activation of KRAS occurring in cancer and represent new models for studying Kras-mediated transformation. Our results have implications for the identification of human tumors in which the oncogenic KRAS transcriptional response is activated and suggest new strategies to build mouse models of tumor progression. [Cancer Res 2007;67(18):8468–76]
Data from Cathepsin E Prevents Tumor Growth and Metastasis by Catalyzing the Proteolytic Release of Soluble TRAIL from Tumor Cell Surface
Authors: Kawakubo Tomoyo , Okamoto Kuniaki , Iwata Jun-ichi , Shin Masashi , Okamoto Yoshiko , Yasukochi Atsushi , Nakayama Keiichi I. , Kadowaki Tomoko , Tsukuba Takayuki , Yamamoto Kenji
Published: March 2023

Abstract
The aspartic proteinase cathepsin E is expressed predominantly in cells of the immune system and highly secreted by activated phagocytes, and deficiency of cathepsin E in mice results in a phenotype affecting immune responses. However, because physiologic substrates for cathepsin E have not yet been identified, the relevance of these observations to the physiologic functions of this protein remains speculative. Here, we show that cathepsin E specifically induces growth arrest and apoptosis in human prostate carcinoma tumor cell lines without affecting normal cells by catalyzing the proteolytic release of soluble tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) from the cell surface. The antitumor activity of cathepsin E was corroborated by in vivo studies with mice bearing human and mouse tumor transplants. Administration of purified cathepsin E into human tumor xenografts in nude mice dose-dependently induced apoptosis in the tumor cells to inhibit tumor growth. The growth, viability, and metastasis of mouse B16 melanoma cells were also more profound in cathepsin E–deficient mice compared with those in the syngeneic wild-type and transgenic mice overexpressing cathepsin E. Taken together, the number of apoptotic tumor cells, as well as tumor-infiltrating activated macrophages, was apparently reduced in cathepsin E–deficient mice compared with those in the other two groups, implying the positive correlation of endogenous cathepsin E levels with the extent of tumor suppression in vivo. These results thus indicate that cathepsin E plays a substantial role in host defense against tumor cells through TRAIL-dependent apoptosis and/or tumor-associated macrophage-mediated cytotoxicity. [Cancer Res 2007;67(22):10869–78]
Data from Targeting the Nuclear Factor-κB Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy
Authors: Sourbier Carole , Danilin Sabrina , Lindner Véronique , Steger Jacques , Rothhut Sylvie , Meyer Nicolas , Jacqmin Didier , Helwig Jean-Jacques , Lang Hervé , Massfelder Thierry
Published: March 2023

Abstract
Metastatic renal cell carcinoma (RCC) remains refractory to therapies. The nuclear factor-κB (NF-κB) transcription factor is involved in cell growth, cell motility, and vascularization. We evaluated whether targeting NF-κB could be of therapeutic and prognostic values in human RCC. The activation of the NF-κB pathway in human RCC cells and tumors was investigated by Western blot. In vitro, the effects of BAY 11-7085 and sulfasalazine, two NF-κB inhibitors, on tumor cell growth were investigated by cell counting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling, and fluorescence-activated cell sorting. Their specificity toward NF-κB was analyzed by Western blot, confocal microscopy, NF-κB small interfering RNA, and NF-κB transcription assay. In vivo, the effects of BAY 11-7085 on the growth of human RCC tumors were investigated in nude mice. A tissue microarray (TMA) containing 241 cases of human RCC with 12 to 22 years of clinical follow-up and corresponding normal tissues was built up to assess prognostic significance of activated NF-κB. NF-κB is constitutively activated in cultured cells expressing or not the von Hippel-Lindau (VHL) tumor suppressor gene as a consequence of Akt kinase activation and in tumors. In vitro and in vivo NF-κB inhibition blocked tumor cell growth by inducing cell apoptosis. On the TMA, NF-κB activation was correlated with tumor dimension but was not found to be an independent prognostic factor for patient survival. This report provides strong evidence that the mechanisms responsible for the intrinsic resistance of RCC cells to apoptosis converge on NF-κB independently of VHL expression and that targeting this pathway has great anticancer potential. [Cancer Res 2007;67(24):11668–76]
Data from Matrix Metalloproteinases-1 and -8 Improve the Distribution and Efficacy of an Oncolytic Virus
Authors: Mok Wilson , Boucher Yves , Jain Rakesh K.
Published: March 2023

Abstract
Oncolytic viral vectors show enormous potential for the treatment of many solid tumors. However, these vectors often suffer from insufficient delivery within tumors, which limits their efficacy in both preclinical and clinical settings. We have previously shown that tumor collagen can significantly hinder diffusion, and that its degradation can enhance the distribution and efficacy of an oncolytic herpes simplex virus (HSV) vector. Here, we identify two members of the matrix metalloproteinase (MMP) family of enzymes, MMP-1 and MMP-8, which can modulate the tumor matrix and enhance HSV delivery and efficacy. We show that overexpression of MMP-1 and MMP-8 in the human soft tissue sarcoma HSTS26T leads to a significant depletion of tumor-sulfated glycosaminoglycans. This increases the hydraulic conductivity of these tumors and enhances the flow of virus during injection. In control tumors, injected virus accumulates primarily in the periphery of the tumor. In contrast, we observed a more widespread distribution of virus around the injection site in MMP-1– and MMP-8–expressing tumors. Due to this enhanced vector delivery, MMP-expressing tumors respond significantly better to oncolytic HSV treatment than control tumors. Thus, these findings introduce a new approach to improve the delivery and efficacy of oncolytic viral vectors: modulation of tumor glycosaminoglycans to enhance convection. [Cancer Res 2007;67(22):10664–8]
Data from Cells Deficient in the FANC/BRCA Pathway Are Hypersensitive to Plasma Levels of Formaldehyde
Authors: Ridpath John R. , Nakamura Ayumi , Tano Keizo , Luke April M. , Sonoda Eiichiro , Arakawa Hiroshi , Buerstedde Jean-Marie , Gillespie David A.F. , Sale Julian E. , Yamazoe Mitsuyoshi , Bishop Douglas K. , Takata Minoru , Takeda Shunichi , Watanabe Masami , Swenberg James A. , Nakamura Jun
Published: March 2023

Abstract
Formaldehyde is an aliphatic monoaldehyde and is a highly reactive environmental human carcinogen. Whereas humans are continuously exposed to exogenous formaldehyde, this reactive aldehyde is a naturally occurring biological compound that is present in human plasma at concentrations ranging from 13 to 97 μmol/L. It has been well documented that DNA-protein crosslinks (DPC) likely play an important role with regard to the genotoxicity and carcinogenicity of formaldehyde. However, little is known about which DNA damage response pathways are essential for cells to counteract formaldehyde. In the present study, we first assessed the DNA damage response to plasma levels of formaldehyde using chicken DT40 cells with targeted mutations in various DNA repair genes. Here, we show that the hypersensitivity to formaldehyde is detected in DT40 mutants deficient in the BRCA/FANC pathway, homologous recombination, or translesion DNA synthesis. In addition, FANCD2-deficient DT40 cells are hypersensitive to acetaldehyde, but not to acrolein, crotonaldehyde, glyoxal, and methylglyoxal. Human cells deficient in FANCC and FANCG are also hypersensitive to plasma levels of formaldehyde. These results indicate that the BRCA/FANC pathway is essential to counteract DPCs caused by aliphatic monoaldehydes. Based on the results obtained in the present study, we are currently proposing that endogenous formaldehyde might have an effect on highly proliferating cells, such as bone marrow cells, as well as an etiology of cancer in Fanconi anemia patients. [Cancer Res 2007;67(23):11117–22]
Data from Histone Deacetylase Inhibitors Synergize p300 Autoacetylation that Regulates Its Transactivation Activity and Complex Formation
Authors: Stiehl Daniel P. , Fath Donna M. , Liang Dongming , Jiang Yubao , Sang Nianli
Published: March 2023

Abstract
p300/cyclic AMP–responsive element binding protein–binding protein (CBP) are general coactivators for multiple transcription factors involved in various cellular processes. Several highly conserved domains of p300/CBP serve as interacting sites for transcription factors and regulatory proteins. Particularly, the intrinsic histone acetyltransferase (HAT) activity and transactivation domains (TAD) play essential roles for their coactivating function. Autoacetylation of p300/CBP is commonly observed in cell-free HAT assays and has been implicated in the regulation of their HAT activity. Here, we show that six lysine-rich regions in several highly conserved functional domains of p300 are targeted by p300HAT for acetylation in cell-free systems. We show that p300 is susceptible to acetylation in cultured tumor cells and that its acetylation status is affected by histone deacetylase inhibitor trichostatin A. We further show that either treatment with deacetylase inhibitors or coexpression of Gal4-p300HAT, which alone has no transactivation activity, stimulates the activity of the COOH-terminal TAD of p300 (p300C-TAD). We have defined the minimal p300C-TAD and show that it is sufficient to respond to deacetylase inhibitors and is a substrate for p300HAT. Finally, we show that acetylated p300 possesses enhanced ability to interact with p53. Taken together, our data suggest that acetylation regulates p300C-TAD and that acetylation of p300/CBP may contribute to the dynamic regulation of their complex formation with various interacting partners. [Cancer Res 2007;67(5):2256–64]
Data from Heat Shock Protein B8, a Cyclin-Dependent Kinase–Independent Cyclin D1 Target Gene, Contributes to Its Effects on Radiation Sensitivity
Authors: Trent Sally , Yang Chuanwei , Li Cuiqi , Lynch Mary , Schmidt Emmett V.
Published: March 2023

Abstract
Overexpression of cyclin D1 is associated with many cancers, and its overexpression is especially associated with a poor prognosis in breast cancer. Paradoxically, cyclin D1 is known to enhance radiation sensitivity, a finding that has not yet been therapeutically exploited. Proposed cyclin D1 functions that could be involved in this effect include cyclin-dependent kinase (CDK)–dependent phosphorylation of retinoblastoma gene product (pRb), titration of p21/p27 complexes, and less well-characterized effects on gene expression. In this report, we sought to clarify the functions of cyclin D1 that might contribute to enhanced radiation sensitivity. Breast cancer cells stably overexpressing a cyclin D1 mutant (KE) that cannot interact with its CDK partners to phosphorylate pRb were as radiation sensitive as those expressing wild-type D1. Although cyclin D1 has been proposed to affect radiation sensitivity through interactions with p21, a cyclin D1 mutant defective for p21 interactions also increased radiation sensitivity. Cyclin D1 overexpression is generally confined to hormone receptor–positive breast cancers, wherein standard therapies include both radiation and hormonal therapies. Among several proposed CDK-independent cyclin D1 targets, we have identified heat shock protein B8 (HSPB8) as a target particularly associated with cyclin D1 and ER-positive tumors. We therefore evaluated its potential contribution to radiation sensitivity. Overexpression of HSPB8 markedly increased radiation sensitivity, and HSPB8 small interfering RNA blocked cyclin D1's enhancement of radiation sensitivity. Taken together, our results show that some of cyclin D1's effects on radiation sensitivity are CDK and p21 independent and identify HSPB8 as a candidate CDK-independent cyclin D1 target that can mediate its effects. [Cancer Res 2007;67(22):10774–81]
Data from Genetic Determinants of Mitochondrial Response to Arsenic in Yeast Saccharomyces cerevisiae
Authors: Vujcic Marija , Shroff Meghna , Singh Keshav K.
Published: March 2023

Abstract
We have used yeast Saccharomyces cerevisiae as a tool to identify the importance of mitochondrial processes involved in arsenic-induced carcinogenicity in humans. We screened 466 single-gene knockout strains of yeast S. cerevisiae known to be involved in biogenesis of mitochondria for sodium arsenite (AsIII) and sodium arsenate (AsV) sensitivity. We identified 72 arsenite-sensitive and 81 arsenate-sensitive mutants. We categorized the identified mutants based on the various mitochondrial processes, including nucleic acid metabolism, oxidative phosphorylation, protein synthesis, and vacuolar acidification. We have identified 65 human orthologues to proteins involved in arsenite sensitivity and 3 human orthologues to arsenite resistance. Furthermore, 23 human orthologues to arsenate sensitivity and 20 human orthologues to arsenate-resistant proteins, including MSH3, COX10, GCSH, PPOX, and MTHFD1, were also identified. Using PathwayAssist software, we did cellular network analysis between identified mitochondrial proteins. Three types of interactions, (a) protein-protein interactions, (b) common transcriptional regulators, and (c) common target genes, were identified. We found that RTG (retrograde) genes involved in mitochondria-to-nucleus signaling regulate both arsenite sensitivity and resistance. Furthermore, our study revealed that ABF1, a multifunctional transcriptional factor, regulates genes involved in both arsenite and arsenate sensitivity and resistance. However, REB1 and RAP1 transcriptional regulators were common to only arsenate- and arsenite-sensitive genes, respectively. These studies indicate that multiple pathways involved in mitochondrial biogenesis protect yeast S. cerevisiae from arsenic-induced toxicity. Together, our studies suggest that evolutionary conserved mitochondrial networks identified in yeast S. cerevisiae must play an important role in arsenic-induced carcinogenesis in humans. [Cancer Res 2007;67(20):9740–9]
Data from Telomerase-Specific T-Cell Immunity in Breast Cancer: Effect of Vaccination on Tumor Immunosurveillance
Authors: Domchek Susan M. , Recio Adri , Mick Rosemarie , Clark Carolyn E. , Carpenter Erica L. , Fox Kevin R. , DeMichele Angela , Schuchter Lynn M. , Leibowitz Michael S. , Wexler Michael H. , Vance Barbara A. , Beatty Gregory L. , Veloso Elizabeth , Feldman Michael D. , Vonderheide Robert H.
Published: March 2023

Abstract
The human telomerase reverse transcriptase (hTERT) is nearly universally overexpressed in human cancer, contributes critically to oncogenesis, and is recognized by cytotoxic T cells that lyse tumors. CD8+ T cells specific for hTERT naturally occur in certain populations of cancer patients in remission, but it remains poorly understood whether such T cells could contribute to tumor immunosurveillance. To address this issue, we induced hTERT-specific T cells in vivo via peptide vaccination in 19 patients with metastatic breast cancer who otherwise had no measurable T-cell responses to hTERT at baseline. Tumor-infiltrating lymphocytes (TIL) were evident after, but not before vaccination, with 4% to 13% of postvaccine CD8+ TIL specific for the immunizing hTERT peptide. Induction of TIL manifested clinically with tumor site pain and pruritus and pathologically with alterations in the tumor microenvironment, featuring histiocytic accumulation and widespread tumor necrosis. hTERT-specific CD8+ T cells were also evident after vaccination in the peripheral blood of patients and exhibited effector functions in vitro including proliferation, IFN-γ production, and tumor lysis. An exploratory landmark analysis revealed that median overall survival was significantly longer in those patients who achieved an immune response to hTERT peptide compared with patients who did not. Immune response to a control cytomegalovirus peptide in the vaccine did not correlate with survival. These results suggest that hTERT-specific T cells could contribute to the immunosurveillance of breast cancer and suggest novel opportunities for both therapeutic and prophylactic vaccine strategies for cancer. [Cancer Res 2007;67(21):1–9]
Data from MicroRNA-21 Knockdown Disrupts Glioma Growth In vivo and Displays Synergistic Cytotoxicity with Neural Precursor Cell–Delivered S-TRAIL in Human Gliomas
Authors: Corsten Maarten F. , Miranda Rafael , Kasmieh Randa , Krichevsky Anna M. , Weissleder Ralph , Shah Khalid
Published: March 2023

Abstract
Despite the development of new glioma therapies that allow for tumor-targeted in situ delivery of cytotoxic drugs, tumor resistance to apoptosis remains a key impediment to effective treatment. Mounting evidence indicates that microRNAs (miRNA) might play a fundamental role in tumorigenesis, controlling cell proliferation and apoptosis. In gliomas, microRNA-21 (miR-21) levels have been reported to be elevated and their knockdown is associated with increased apoptotic activity. We hypothesized that suppression of miR-21 might sensitize gliomas for cytotoxic tumor therapy. With the use of locked nucleic acid (LNA)-antimiR-21 oligonucleotides, bimodal imaging vectors, and neural precursor cells (NPC) expressing a secretable variant of the cytotoxic agent tumor necrosis factor–related apoptosis inducing ligand (S-TRAIL), we show that the combined suppression of miR-21 and NPC-S-TRAIL leads to a synergistic increase in caspase activity and significantly decreased cell viability in human glioma cells in vitro. This phenomenon persists in vivo, as we observed complete eradication of LNA-antimiR-21–treated gliomas subjected to the presence of NPC-S-TRAIL in the murine brain. Our results reveal the efficacy of miR-21 antagonism in murine glioma models and implicate miR-21 as a target for therapeutic intervention. Furthermore, our findings provide the basis for developing combination therapies using miRNA modulation and cytotoxic tumor therapies. [Cancer Res 2007;67(19):8994–9000]
Data from Vitamin E Analogues Inhibit Angiogenesis by Selective Induction of Apoptosis in Proliferating Endothelial Cells: The Role of Oxidative Stress
Authors: Dong Lan-Feng , Swettenham Emma , Eliasson Johanna , Wang Xiu-Fang , Gold Mikhal , Medunic Yasmine , Stantic Marina , Low Pauline , Prochazka Lubomir , Witting Paul K. , Turanek Jaroslav , Akporiaye Emmanuel T. , Ralph Stephen J. , Neuzil Jiri
Published: March 2023

Abstract
“Mitocans” from the vitamin E group of selective anticancer drugs, α-tocopheryl succinate (α-TOS) and its ether analogue α-TEA, triggered apoptosis in proliferating but not arrested endothelial cells. Angiogenic endothelial cells exposed to the vitamin E analogues, unlike their arrested counterparts, readily accumulated reactive oxygen species (ROS) by interfering with the mitochondrial redox chain and activating the intrinsic apoptotic pathway. The vitamin E analogues inhibited angiogenesis in vitro as assessed using the “wound-healing” and “tube-forming” models. Endothelial cells deficient in mitochondrial DNA (mtDNA) were resistant to the vitamin E analogues, both in ROS accumulation and apoptosis induction, maintaining their angiogenic potential. α-TOS inhibited angiogenesis in a mouse cancer model, as documented by ultrasound imaging. We conclude that vitamin E analogues selectively kill angiogenic endothelial cells, suppressing tumor growth, which has intriguing clinical implications. [Cancer Res 2007;67(24):11906–13]
Data from A Polycomb Repression Signature in Metastatic Prostate Cancer Predicts Cancer Outcome
Authors: Yu Jindan , Yu Jianjun , Rhodes Daniel R. , Tomlins Scott A. , Cao Xuhong , Chen Guoan , Mehra Rohit , Wang Xiaoju , Ghosh Debashis , Shah Rajal B. , Varambally Sooryanarayana , Pienta Kenneth J. , Chinnaiyan Arul M.
Published: March 2023

Abstract
The Polycomb Group (PcG) protein EZH2 is a critical component of a multiprotein complex that methylates Lys27 of histone 3 (H3K27), which consequently leads to the repression of target gene expression. We have previously reported that EZH2 is overexpressed in metastatic prostate cancer and is a marker of aggressive diseases in clinically localized solid tumors. However, the global set of genes directly regulated by PcG in tumors is largely unknown, and thus how PcG mediates tumor progression remains unclear. Herein we mapped genome-wide H3K27 methylation in aggressive, disseminated human prostate cancer tissues. Integrative analysis revealed that a significant subset of these genes are also targets of PcG in embryonic stem cells, and their repression in tumors is associated with poor prognosis. By stepwise cross-validation, we developed a “Polycomb repression signature” composed of 14 direct targets of PcG in metastatic tumors. Notably, solid tumor subtypes in which this gene signature is repressed show poor clinical outcome in multiple microarray data sets of tumors including breast and prostate cancer. Taken together, our results show a fingerprint of PcG-mediated transcriptional repression in metastatic prostate cancer that is reminiscent of stem cells and associated with cancer progression. Therefore, PcG proteins play a central role in the epigenetic silencing of target genes and functionally link stem cells, metastasis, and cancer survival. [Cancer Res 2007;67(22):10657–63]
Data from Targeting the BAF57 SWI/SNF Subunit in Prostate Cancer: A Novel Platform to Control Androgen Receptor Activity
Authors: Link Kevin A. , Balasubramaniam Sucharitha , Sharma Ankur , Comstock Clay E.S. , Godoy-Tundidor Sonia , Powers Nathan , Cao Khanh H. , Haelens Annemie , Claessens Frank , Revelo Monica P. , Knudsen Karen E.
Published: March 2023

Abstract
The androgen receptor (AR) is critical for disseminated prostate cancer proliferation and survival. AR activity is targeted either through prevention of ligand synthesis or through the use of antagonists that bind the COOH-terminal ligand-binding domain. Although initially effective, treatment fails due to restored AR activity in the presence of therapeutics. Thus, new means must be developed to target AR activity. The SWI/SNF chromatin remodeling complex is critical for AR transcriptional activity, and the BAF57 SWI/SNF subunit facilitates direct interaction with the receptor. Although selected SWI/SNF subunit expression is reduced in prostate cancer, we show that BAF57 is retained in human disease and is elevated in a subset of tumors. Functional analyses showed that BAF57 contributes uniquely to androgen-mediated stimulation of transcription without compromising the effectiveness of AR antagonists. Subsequent studies revealed that BAF57 is recruited to the AR DNA-binding domain/hinge region, which occurs concomitant with receptor activation. These data provided the basis for a novel inhibitor derived from BAF57 [BAF57 inhibitory peptide (BIPep)], which blocked AR residence on chromatin and resultant AR-dependent gene activation. Importantly, BIPep expression was sufficient to inhibit androgen-dependent prostate cancer cell proliferation in AR-positive cells. In summary, these data identify blockade of AR-BAF57 interaction as a novel means to target agonist-induced AR function in prostate cancer, and provide the first evidence that abrogation of SWI/SNF function can be developed as a point of therapeutic intervention in prostate cancer. [Cancer Res 2008;68(12):4551–8]