bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure S5 from STAT3/IRF1 Pathway Activation Sensitizes Cervical Cancer Cells to Chemotherapeutic Drugs
Authors: Walch-Rückheim Barbara , Pahne-Zeppenfeld Jennifer , Fischbach Jil , Wickenhauser Claudia , Horn Lars Christian , Tharun Lars , Büttner Reinhard , Mallmann Peter , Stern Peter , Kim Yoo-Jin , Bohle Rainer Maria , Rübe Christian , Ströder Russalina , Juhasz-Böss Ingolf , Solomayer Erich-Franz , Smola Sigrun
Published: April 2023

HeLa cells were co-transfected with 1.85 µg pEFBos-STAT3F or pEFBos control vector and 0.35 µg EGFP expression vector.
Supplementary Figure S6 from HBXIP and LSD1 Scaffolded by lncRNA Hotair Mediate Transcriptional Activation by c-Myc
Authors: Li Yinghui , Wang Zhen , Shi Hui , Li Hang , Li Leilei , Fang Runping , Cai Xiaoli , Liu Bowen , Zhang Xiaodong , Ye Lihong
Published: April 2023

The complex of c-Myc/HBXIP/Hotair/LSD1 contributes to the c-Myc-enhanced growth of breast cancer cell.
Supplementary Figure S4 from HBXIP and LSD1 Scaffolded by lncRNA Hotair Mediate Transcriptional Activation by c-Myc
Authors: Li Yinghui , Wang Zhen , Shi Hui , Li Hang , Li Leilei , Fang Runping , Cai Xiaoli , Liu Bowen , Zhang Xiaodong , Ye Lihong
Published: April 2023

The expression levels of LSD1 mRNA are positively associated with those of HBXIP and c-Myc mRNAs in breast cancer tissues.
Supplementary Figure S3 from HBXIP and LSD1 Scaffolded by lncRNA Hotair Mediate Transcriptional Activation by c-Myc
Authors: Li Yinghui , Wang Zhen , Shi Hui , Li Hang , Li Leilei , Fang Runping , Cai Xiaoli , Liu Bowen , Zhang Xiaodong , Ye Lihong
Published: April 2023

HBXIP is able to interact with c-Myc.
Supplementary Figure 2 from PTK6 Inhibition Suppresses Metastases of Triple-Negative Breast Cancer via SNAIL-Dependent E-Cadherin Regulation
Authors: Ito Koichi , Park Sun Hee , Nayak Anupma , Byerly Jessica H. , Irie Hanna Y.
Published: April 2023

Supplemental Fig. 2: PTK6 downregulation inhibits migration of TNBC cells independently of proliferation effects.
Supplementary Tables 1 through 4 from KLF4-Mediated Suppression of CD44 Signaling Negatively Impacts Pancreatic Cancer Stemness and Metastasis
Authors: Yan Yongmin , LI Zhiwei , Kong Xiangyu , Jia Zhiliang , Zuo Xiangsheng , Gagea Mihai , Huang Suyun , Wei Daoyan , Xie Keping
Published: April 2023

Supplementary Tables Table S1. CD44 expression and clinicopathologic characteristics; Table S2. KLF4 expression and clinicopathologic characteristics; Table S3. Specific primers for target and control genes; Table S4. Antibodies for target and control protein expression in Western blot analyses
Supplementary Figure 5 from RK-33 Radiosensitizes Prostate Cancer Cells by Blocking the RNA Helicase DDX3
Authors: Xie Min , Vesuna Farhad , Tantravedi Saritha , Bol Guus M. , Heerma van Voss Marise R. , Nugent Katriana , Malek Reem , Gabrielson Kathleen , van Diest Paul J. , Tran Phuoc T. , Raman Venu
Published: April 2023

Bar graph showing the percentage of positive cells stained for Ki67, cleaved Caspase 3 and gammaH2AX
Supplementary Figure 3 from RK-33 Radiosensitizes Prostate Cancer Cells by Blocking the RNA Helicase DDX3
Authors: Xie Min , Vesuna Farhad , Tantravedi Saritha , Bol Guus M. , Heerma van Voss Marise R. , Nugent Katriana , Malek Reem , Gabrielson Kathleen , van Diest Paul J. , Tran Phuoc T. , Raman Venu
Published: April 2023

Wound-healing or scratch assay of RK-33 on PC3
Supplementary Figure 2 from RK-33 Radiosensitizes Prostate Cancer Cells by Blocking the RNA Helicase DDX3
Authors: Xie Min , Vesuna Farhad , Tantravedi Saritha , Bol Guus M. , Heerma van Voss Marise R. , Nugent Katriana , Malek Reem , Gabrielson Kathleen , van Diest Paul J. , Tran Phuoc T. , Raman Venu
Published: April 2023

Wound-healing or scratch assay of RK-33 on DU145
Figure S1-S13 from Sialic Acid Blockade Suppresses Tumor Growth by Enhancing T-cell–Mediated Tumor Immunity
Authors: Büll Christian , Boltje Thomas J. , Balneger Natasja , Weischer Sarah M. , Wassink Melissa , van Gemst Jasper J. , Bloemendal Victor R. , Boon Louis , van der Vlag Johan , Heise Torben , den Brok Martijn H. , Adema Gosse J.
Published: April 2023

Fig. S1 Effect of intratumoral injections with 20 mg/kg S1 Ac53FaxNeu5Ac on B16-F10WT tumor growth. Fig. S2 Responsiveness of melanoma and neuroblastoma cells to Ac53FaxNeu5Ac. S2 Fig. S3 10 mg/kg Ac53FaxNeu5Ac injections are well tolerated. S3 Fig. S4 Immune cell infiltration of tumors injected S4 with Ac53FaxNeu5Ac. Fig. S5 Effect of intratumoral Ac53FaxNeu5Ac injections on S5 systemic sialylation. Fig. S6 Effect of intratumoral Ac53FaxNeu5Ac injections on tumor-infiltrating S6 immune cells and immune cell populations in (tumor-draining) lymph nodes and spleen. Fig. S7 Effect of intratumoral Ac53FaxNeu5Ac injections on S7 immune cell populations in (tumor-draining) lymph nodes and spleen. Fig. S8 Depletion of NK cells and CD8+ T cells prior to of B16-F10WT S8 tumor inoculation. Fig. S9 Combination of sialic acid blockade with clodronate liposomes S9 and anti-Gr-1 antibodies. Fig. S10 In vitro killing of Ac53FaxNeu5Ac-treated tumor cells and expression of S10 Siglecs on OT-I T cells Fig. S11 B16-F10OVA cell surface molecule expression and purification S11 and sialylation of OT-I CD8+ T cells. Fig. S12 Systemic effect of sialic acid blockade on CpG-induced S12 dendritic cell maturation. Fig. S13 Systemic effect of sialic acid blockade on CD8+ T cell numbers. S13
Supplementary Figures from miR-339 Promotes Development of Stem Cell Leukemia/Lymphoma Syndrome via Downregulation of the BCL2L11 and BAX Proapoptotic Genes
Authors: Hu Tianxiang , Chong Yating , Lu Sumin , Wang Rebecca , Qin Haiyan , Silva Jeane , Kitamura Eiko , Chang Chang-Sheng , Hawthorn LesleyAnn , Cowell John K.
Published: April 2023

Supplemental Figure 1 defining the immunophenotypes of SCLL cell lines used in this study. Supplemental figure 2 describes normalized miR339 and FGFR1 expression levels in normal B-cells and CLL compared with ALL. Supplemental figure 3 describes the target sites for miR339 in the BCL2L11 and BAX genes. Supplemental figure 4 shows luciferase reporter assays demonstrating the effectiveness of the miR sponges. Supplemental figure 5 shows flow cytometric analysis of apoptosis in cells treated with miR sponges. Supplemental figure 6 shows autopsy data and histopathology for mice transplanted with BBC2 cells overexpressing miR339.
Figure S5 from Evaluation of Explant Responses to STING Ligands: Personalized Immunosurgical Therapy for Head and Neck Squamous Cell Carcinoma
Authors: Baird Jason R. , Bell R. Bryan , Troesch Victoria , Friedman David , Bambina Shelly , Kramer Gwen , Blair Tiffany C. , Medler Terry , Wu Yaping , Sun Zhaoyu , de Gruijl Tanja D. , van de Ven Rieneke , Leidner Rom S. , Crittenden Marka R. , Gough Michael J.
Published: April 2023

Flow cytometry of cytokine producing cells
Movie S1 from Cancer Exacerbates Chemotherapy-Induced Sensory Neuropathy
Authors: Housley Stephen N. , Nardelli Paul , Carrasco Dario I. , Rotterman Travis M. , Pfahl Emily , Matyunina Lilya V. , McDonald John F. , Cope Timothy C.
Published: April 2023

Uneven ladder walking of an ApcWT+control rat.
Figure S18 from Cancer Exacerbates Chemotherapy-Induced Sensory Neuropathy
Authors: Housley Stephen N. , Nardelli Paul , Carrasco Dario I. , Rotterman Travis M. , Pfahl Emily , Matyunina Lilya V. , McDonald John F. , Cope Timothy C.
Published: April 2023

Neuronal signaling responses to slow and fast naturalistic stimulus in ApcWT+control and ApcPirc/++OX neurons.
Supplementary Data from Molecular Imaging of the Tumor Microenvironment Reveals the Relationship between Tumor Oxygenation, Glucose Uptake, and Glycolysis in Pancreatic Ductal Adenocarcinoma
Authors: Yamamoto Kazutoshi , Brender Jeffrey R. , Seki Tomohiro , Kishimoto Shun , Oshima Nobu , Choudhuri Rajani , Adler Stephen S. , Jagoda Elaine M. , Saito Keita , Devasahayam Nallathamby , Choyke Peter L. , Mitchell James B. , Krishna Murali C.
Published: April 2023

Complete and detailed descriptions of materials and methods are in the supplementary information, including animal studies, image registration, hyperpolarized 13C MRI, 18F-FDG PET, EPR imaging, Western blot, Immunohistochemistry, and statistical analysis. A supplementary Figure S contains H&E and CD31 staining of 100 μm thick slices from the center of the xenograft tumors to depict differences in vascularity are not the primer driver for the rim/interior difference in FDG uptake and O2 levels.
Figure S4 from HER2 CAR-T Cells Eradicate Uveal Melanoma and T-cell Therapy–Resistant Human Melanoma in IL2 Transgenic NOD/SCID IL2 Receptor Knockout Mice
Authors: Forsberg Elin M.V. , Lindberg Mattias F. , Jespersen Henrik , Alsén Samuel , Bagge Roger Olofsson , Donia Marco , Svane Inge Marie , Nilsson Ola , Ny Lars , Nilsson Lisa M. , Nilsson Jonas A.
Published: April 2023

Characterization of a novel uveal melanoma PDX models using clinical grade melanoma markers
Figure S7 from p38γ MAPK Is Essential for Aerobic Glycolysis and Pancreatic Tumorigenesis
Authors: Wang Fang , Qi Xiao-Mei , Wertz Ryan , Mortensen Matthew , Hagen Catherine , Evans John , Sheinin Yuri , James Michael , Liu Pengyuan , Tsai Susan , Thomas James , Mackinnon Alexander , Dwinell Michael , Myers Charles R. , Bartrons Bach Ramon , Fu Liwu , Chen Guan
Published: April 2023

Figure S7. PFD collaborates with PFK15 to inhibit glucose uptake, lactate secretion, and Pdac growth and upregulated p-PFKFB3 in Pdac specimens is positively correlated with overexpressed p38ÃƒÅ½Ã,Â³ and Glut2.
Supplementary Data from Metastatic Conditioning of Myeloid Cells at a Subcutaneous Synthetic Niche Reflects Disease Progression and Predicts Therapeutic Outcomes
Authors: Oakes Robert S. , Bushnell Grace G. , Orbach Sophia M. , Kandagatla Pridvi , Zhang Yining , Morris Aaron H. , Hall Matthew S. , LaFaire Petrina , Decker Joseph T. , Hartfield Rachel M. , Brooks Michael D. , Wicha Max S. , Jeruss Jacqueline S. , Shea Lonnie D.
Published: April 2023

Supplementary Materials and Methods, Figures, and Descriptions of Supplementary Data
Table S5 from A Circle RNA Regulatory Axis Promotes Lung Squamous Metastasis via CDR1-Mediated Regulation of Golgi Trafficking
Authors: Harrison Emily B. , Porrello Alessandro , Bowman Brittany M. , Belanger Adam R. , Yacovone Gabriella , Azam Salma H. , Windham Ian A. , Ghosh Subrata K. , Wang Menglin , Mckenzie Nicholas , Waugh Trent A. , Van Swearingen Amanda E.D. , Cohen Stephanie M. , Allen Devon G. , Goodwin Tyler J. , Mascenik Teresa , Bear James E. , Cohen Sarah , Randell Scott H. , Massion Pierre P. , Major Michael B. , Huang Leaf , Pecot Chad V.
Published: April 2023

Genes differentially expressed in LUSC TCGA in High CDR1-Low miR-671-5p tumors compared to Low CDR1-High miR-671 tumors.
Supplementary Figure S2 from Blocking Angiopoietin-2 Promotes Vascular Damage and Growth Inhibition in Mouse Tumors Treated with Small Doses of Radiation
Authors: Kallio Pauliina , Jokinen Elina , Högström Jenny , Das Suvendu , Heino Sarika , Lähde Marianne , Brodkin Jefim , Korhonen Emilia A. , Alitalo Kari
Published: April 2023

Supplementary Figure S2
Master Regulator Analysis from Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Authors: Voli Florida , Valli Emanuele , Lerra Luigi , Kimpton Kathleen , Saletta Federica , Giorgi Federico M. , Mercatelli Daniele , Rouaen Jourdin R.C. , Shen Sylvie , Murray Jayne E. , Ahmed-Cox Aria , Cirillo Giuseppe , Mayoh Chelsea , Beavis Paul A. , Haber Michelle , Trapani Joseph A. , Kavallaris Maria , Vittorio Orazio
Published: April 2023

Methods for Master Regulator Analysis
Supplementary Tables from FTO-Dependent N6-Methyladenosine Modifications Inhibit Ovarian Cancer Stem Cell Self-Renewal by Blocking cAMP Signaling
Authors: Huang Hao , Wang Yinu , Kandpal Manoj , Zhao Guangyuan , Cardenas Horacio , Ji Yanrong , Chaparala Anusha , Tanner Edward J. , Chen Jianjun , Davuluri Ramana V. , Matei Daniela
Published: April 2023

Supplemental tables include gene lists related to Figure 5, additional experimental data related to Figure S3I, and primers sequence. Table S1. Numbers of spheroids were counted for each cell dilution; Table S2. List of 20 genes that exhibit a significant change between control and FTO-overexpressing OVCAR5 cells in m6A peak levels, and abundance of the corresponding mRNA transcripta; Table S3. List of primers oligonucleotides; Table S4. Summary of the m6A-seq and RNA-seq; Table S5. List of top 50 hypo-methylation & down-regulated genes; Table S6: List of top 50 hypo-methylation &up-regulated genes.
Figure S3 from Intratumoral Copper Modulates PD-L1 Expression and Influences Tumor Immune Evasion
Authors: Voli Florida , Valli Emanuele , Lerra Luigi , Kimpton Kathleen , Saletta Federica , Giorgi Federico M. , Mercatelli Daniele , Rouaen Jourdin R.C. , Shen Sylvie , Murray Jayne E. , Ahmed-Cox Aria , Cirillo Giuseppe , Mayoh Chelsea , Beavis Paul A. , Haber Michelle , Trapani Joseph A. , Kavallaris Maria , Vittorio Orazio
Published: April 2023

Effect of copper levels on EGFR phosphorylation and PD-L1 protein stability
Supplementary Data from The Functional Landscape of Patient-Derived RNF43 Mutations Predicts Sensitivity to Wnt Inhibition
Authors: Yu Jia , Yusoff Permeen A. Mohamed , Woutersen Daniëlle T.J. , Goh Pamela , Harmston Nathan , Smits Ron , Epstein David M. , Virshup David M. , Madan Babita
Published: April 2023

Supplementary Methods, Figures and Tables.
Supplementary Table S2 from Slow-Cycling Cancer Stem Cells Regulate Progression and Chemoresistance in Colon Cancer
Authors: Shiokawa Daisuke , Sakai Hiroaki , Ohata Hirokazu , Miyazaki Toshiaki , Kanda Yusuke , Sekine Shigeki , Narushima Daichi , Hosokawa Masahito , Kato Mamoru , Suzuki Yutaka , Takeyama Haruko , Kambara Hideki , Nakagama Hitoshi , Okamoto Koji
Published: April 2023

Supplementary Table S2
Supplementary Table S1 from Slow-Cycling Cancer Stem Cells Regulate Progression and Chemoresistance in Colon Cancer
Authors: Shiokawa Daisuke , Sakai Hiroaki , Ohata Hirokazu , Miyazaki Toshiaki , Kanda Yusuke , Sekine Shigeki , Narushima Daichi , Hosokawa Masahito , Kato Mamoru , Suzuki Yutaka , Takeyama Haruko , Kambara Hideki , Nakagama Hitoshi , Okamoto Koji
Published: April 2023

Supplementary Table S1
Suppl Fig. 1 from Oligosaccharyltransferase Inhibition Overcomes Therapeutic Resistance to EGFR Tyrosine Kinase Inhibitors
Authors: Lopez Sambrooks Cecilia , Baro Marta , Quijano Amanda , Narayan Azeet , Cui Wei , Greninger Patricia , Egan Regina , Patel Abhijit , Benes Cyril H. , Saltzman W. Mark , Contessa Joseph N.
Published: April 2023

Apoptosis susceptibility of KRAS mutant A549 cell line following treatment with NGI-1, Erlotinib or both.
Supplementary Figures S1-S4 and Tables S1-S3 from A Rare Missense Variant in TCF7L2 Associates with Colorectal Cancer Risk by Interacting with a GWAS-Identified Regulatory Variant in the MYC Enhancer
Authors: Chang Jiang , Tian Jianbo , Yang Yang , Zhong Rong , Li Jiaoyuan , Zhai Kan , Ke Juntao , Lou Jiao , Chen Wei , Zhu Beibei , Shen Na , Zhang Yi , Gong Yajie , Zhu Ying , Zou Danyi , Peng Xiating , Huang Kun , Miao Xiaoping
Published: April 2023

It contains the PCA plots (Figure S1), QQ plot (Figure S2), regional plots (Figure S2) and luciferase reporter assay results for rs11169571 with hsa-mir-524-5p (Figure S4). It also contains the characteristic of study subjects (Table S1) and results of discovery (Table S3) and replication stages (Table S3).
Supplementary Table 3 from Cellular and Genetic Determinants of the Sensitivity of Cancer to α-Particle Irradiation
Authors: Yard Brian D. , Gopal Priyanka , Bannik Kristina , Siemeister Gerhard , Hagemann Urs B. , Abazeed Mohamed E.
Published: April 2023

SCNA and survival after irradiation.
Fig. S6 from Hes1 Is Essential in Proliferating Ductal Cell–Mediated Development of Intrahepatic Cholangiocarcinoma
Authors: Matsumori Tomoaki , Kodama Yuzo , Takai Atsushi , Shiokawa Masahiro , Nishikawa Yoshihiro , Matsumoto Tomonori , Takeda Haruhiko , Marui Saiko , Okada Hirokazu , Hirano Tomonori , Kuwada Takeshi , Sogabe Yuko , Kakiuchi Nobuyuki , Tomono Teruko , Mima Atsushi , Morita Toshihiro , Ueda Tatsuki , Tsuda Motoyuki , Yamauchi Yuki , Kuriyama Katsutoshi , Sakuma Yojiro , Ota Yuji , Maruno Takahisa , Uza Norimitsu , Marusawa Hiroyuki , Kageyama Ryoichiro , Chiba Tsutomu , Seno Hiroshi
Published: April 2023

PDC formation in Albcre; Hes1flox/flox and control mice with or without DDC diet.
Supplementary Materials and Methods from Predictive Signatures Inform the Effective Repurposing of Decitabine to Treat KRAS–Dependent Pancreatic Ductal Adenocarcinoma
Authors: Mottini Carla , Tomihara Hideo , Carrella Diego , Lamolinara Alessia , Iezzi Manuela , Huang Justin K. , Amoreo Carla A. , Buglioni Simonetta , Manni Isabella , Robinson Frederick S. , Minelli Rosalba , Kang Ya'an , Fleming Jason B. , Kim Michael P. , Bristow Christopher A. , Trisciuoglio Daniela , Iuliano Antonella , Del Bufalo Donatella , Di Bernardo Diego , Melisi Davide , Draetta Giulio F. , Ciliberto Gennaro , Carugo Alessandro , Cardone Luca
Published: April 2023

Supplementary Materials and Methods
Supplementary Movie 2 from The Amino-Terminal Oligomerization Domain of Angiopoietin-2 Affects Vascular Remodeling, Mammary Gland Tumor Growth, and Lung Metastasis in Mice
Authors: Kapiainen Emmi , Kihlström Minna K. , Pietilä Riikka , Kaakinen Mika , Ronkainen Veli-Pekka , Tu Hongmin , Heikkinen Anne , Devarajan Raman , Miinalainen Ilkka , Laitakari Anna , Ansarizadeh Mohammadhassan , Zhang Qin , Wei Gong-Hong , Ruddock Lloyd , Pihlajaniemi Taina , Elamaa Harri , Eklund Lauri
Published: April 2023

Visualization of basal cell surface of ANGPT2-GFP HUVECs during cell spreading.
Supplemental Figure 5 from Palmitoylated Proteins on AML-Derived Extracellular Vesicles Promote Myeloid-Derived Suppressor Cell Differentiation via TLR2/Akt/mTOR Signaling
Authors: Tohumeken Sehmus , Baur Rebecca , Böttcher Martin , Stoll Andrej , Loschinski Romy , Panagiotidis Konstantinos , Braun Martina , Saul Domenica , Völkl Simon , Baur Andreas S. , Bruns Heiko , Mackensen Andreas , Jitschin Regina , Mougiakakos Dimitrios
Published: April 2023

(A) Impact of anti-TLR4 antibodies on MDSC induction, (B) Impact of anti-TLR2 antibodies on pCREB activation, (C) Impact of PrK pre-treatment of AML-EV uptake, (D) Impact of chemotherapy on protein palmitoylation in AML-cells, and (E) Impact of 2-BP on EV release by AML-cells.
Supplementary Materials and Methods from Oncogenic BRAFV600E Governs Regulatory T-cell Recruitment during Melanoma Tumorigenesis
Authors: Shabaneh Tamer B. , Molodtsov Aleksey K. , Steinberg Shannon M. , Zhang Peisheng , Torres Gretel M. , Mohamed Gadisti A. , Boni Andrea , Curiel Tyler J. , Angeles Christina V. , Turk Mary Jo
Published: April 2023

Supplementary Materials and Methods
Figure S2 from Pharmacological Disruption of the Notch1 Transcriptional Complex Inhibits Tumor Growth by Selectively Targeting Cancer Stem Cells
Authors: Alvarez-Trotta Annamil , Guerrant William , Astudillo Luisana , Lahiry Mohini , Diluvio Giulia , Shersher Elena , Kaneku Hugo , Robbins David J. , Orton Darren , Capobianco Anthony J.
Published: April 2023

Off target effect evaluation of NADI-351
Figure S5 from Alterations in the Global Proteome and Phosphoproteome in Third Generation EGFR TKI Resistance Reveal Drug Targets to Circumvent Resistance
Authors: Zhang Xu , Maity Tapan K. , Ross Karen E. , Qi Yue , Cultraro Constance M. , Bahta Meriam , Pitts Stephanie , Keswani Meghana , Gao Shaojian , Nguyen Khoa Dang P. , Cowart Julie , Kirkali Fatos , Wu Cathy , Guha Udayan
Published: April 2023

Supplementary Fig.S5
Supplementary Table S1 from Genetic Risk for Overall Cancer and the Benefit of Adherence to a Healthy Lifestyle
Authors: Zhu Meng , Wang Tianpei , Huang Yanqian , Zhao Xiaoyu , Ding Yuqing , Zhu Mengyi , Ji Mengmeng , Wang Cheng , Dai Juncheng , Yin Rong , Xu Lin , Ma Hongxia , Wei Qingyi , Jin Guangfu , Hu Zhibin , Shen Hongbing
Published: April 2023

Single-nucleotide polymorphisms used to build the polygenic risk scores for each cancer.
Supplementary Figure from Immune Determinants of the Association between Tumor Mutational Burden and Immunotherapy Response across Cancer Types
Authors: Sinha Neelam , Sinha Sanju , Valero Cristina , Schäffer Alejandro A. , Aldape Kenneth , Litchfield Kevin , Chan Timothy A. , Morris Luc G.T. , Ruppin Eytan
Published: April 2023

Supplementary Figure from Immune Determinants of the Association between Tumor Mutational Burden and Immunotherapy Response across Cancer Types
Supplementary Figures from Neural Crest-Like Stem Cell Transcriptome Analysis Identifies LPAR1 in Melanoma Progression and Therapy Resistance
Authors: Liu Jianglan , Rebecca Vito W. , Kossenkov Andrew V. , Connelly Thomas , Liu Qin , Gutierrez Alexis , Xiao Min , Li Ling , Zhang Gao , Samarkina Anastasia , Zayasbazan Delaine , Zhang Jie , Cheng Chaoran , Wei Zhi , Alicea Gretchen M. , Fukunaga-Kalabis Mizuho , Krepler Clemens , Aza-Blanc Pedro , Yang Chih-Cheng , Delvadia Bela , Tong Cynthia , Huang Ye , Delvadia Maya , Morias Alice S. , Sproesser Katrin , Brafford Patricia , Wang Joshua X. , Beqiri Marilda , Somasundaram Rajasekharan , Vultur Adina , Hristova Denitsa M. , Wu Lawrence W. , Lu Yiling , Mills Gordon B. , Xu Wei , Karakousis Giorgos C. , Xu Xiaowei , Schuchter Lynn M. , Mitchell Tara C. , Amaravadi Ravi K. , Kwong Lawrence N. , Frederick Dennie T. , Boland Genevieve M. , Salvino Joseph M. , Speicher David W. , Flaherty Keith T. , Ronai Ze'ev A. , Herlyn Meenhard
Published: April 2023

Supplementary Figures
Data from Oxygen-Enhanced MRI Accurately Identifies, Quantifies, and Maps Tumor Hypoxia in Preclinical Cancer Models
Authors: O'Connor James P.B. , Boult Jessica K.R. , Jamin Yann , Babur Muhammad , Finegan Katherine G. , Williams Kaye J. , Little Ross A. , Jackson Alan , Parker Geoff J.M. , Reynolds Andrew R. , Waterton John C. , Robinson Simon P.
Published: April 2023

Abstract
There is a clinical need for noninvasive biomarkers of tumor hypoxia for prognostic and predictive studies, radiotherapy planning, and therapy monitoring. Oxygen-enhanced MRI (OE-MRI) is an emerging imaging technique for quantifying the spatial distribution and extent of tumor oxygen delivery in vivo. In OE-MRI, the longitudinal relaxation rate of protons (ΔR1) changes in proportion to the concentration of molecular oxygen dissolved in plasma or interstitial tissue fluid. Therefore, well-oxygenated tissues show positive ΔR1. We hypothesized that the fraction of tumor tissue refractory to oxygen challenge (lack of positive ΔR1, termed “Oxy-R fraction”) would be a robust biomarker of hypoxia in models with varying vascular and hypoxic features. Here, we demonstrate that OE-MRI signals are accurate, precise, and sensitive to changes in tumor pO2 in highly vascular 786-0 renal cancer xenografts. Furthermore, we show that Oxy-R fraction can quantify the hypoxic fraction in multiple models with differing hypoxic and vascular phenotypes, when used in combination with measurements of tumor perfusion. Finally, Oxy-R fraction can detect dynamic changes in hypoxia induced by the vasomodulator agent hydralazine. In contrast, more conventional biomarkers of hypoxia (derived from blood oxygenation-level dependent MRI and dynamic contrast–enhanced MRI) did not relate to tumor hypoxia consistently. Our results show that the Oxy-R fraction accurately quantifies tumor hypoxia noninvasively and is immediately translatable to the clinic. Cancer Res; 76(4); 787–95. ©2015 AACR.
Data from Inhibition of MUC1-C Suppresses MYC Expression and Attenuates Malignant Growth in KRAS Mutant Lung Adenocarcinomas
Authors: Bouillez Audrey , Rajabi Hasan , Pitroda Sean , Jin Caining , Alam Maroof , Kharbanda Akriti , Tagde Ashujit , Wong Kwok-Kin , Kufe Donald
Published: April 2023

Abstract
Dysregulation of MYC expression is a hallmark of cancer, but the development of agents that target MYC has remained challenging. The oncogenic MUC1-C transmembrane protein is, like MYC, aberrantly expressed in diverse human cancers. The present studies demonstrate that MUC1-C induces MYC expression in KRAS mutant non–small cell lung cancer (NSCLC) cells, an effect that can be suppressed by targeting MUC1-C via shRNA silencing, CRISPR editing, or pharmacologic inhibition with GO-203. MUC1-C activated the WNT/β-catenin (CTNNB1) pathway and promoted occupancy of MUC1-C/β-catenin/TCF4 complexes on the MYC promoter. MUC1-C also promoted the recruitment of the p300 histone acetylase (EP300) and, in turn, induced histone H3 acetylation and activation of MYC gene transcription. We also show that targeting MUC1-C decreased the expression of key MYC target genes essential for the growth and survival of NSCLC cells, such as TERT and CDK4. Based on these results, we found that the combination of GO-203 and the BET bromodomain inhibitor JQ1, which targets MYC transcription, synergistically suppressed MYC expression and cell survival in vitro as well as tumor xenograft growth. Furthermore, MUC1 expression significantly correlated with that of MYC and its target genes in human KRAS mutant NSCLC tumors. Taken together, these findings suggest a therapeutic approach for targeting MYC-dependent cancers and provide the framework for the ongoing clinical studies addressing the efficacy of MUC1-C inhibition in solid tumors. Cancer Res; 76(6); 1538–48. ©2016 AACR.
Data from Calcium-Sensing Receptor Promotes Breast Cancer by Stimulating Intracrine Actions of Parathyroid Hormone–Related Protein
Authors: Kim Wonnam , Takyar Farzin M. , Swan Karena , Jeong Jaekwang , VanHouten Joshua , Sullivan Catherine , Dann Pamela , Yu Herbert , Fiaschi-Taesch Nathalie , Chang Wenhan , Wysolmerski John
Published: April 2023

Abstract
Parathyroid hormone–related protein (PTHrP) contributes to the development and metastatic progression of breast cancer by promoting hypercalcemia, tumor growth, and osteolytic bone metastases, but it is not known how PTHrP is upregulated in breast tumors. Here we report a central role in this process for the calcium-sensing receptor, CaSR, which enables cellular responses to changes in extracellular calcium, through studies of CaSR–PTHrP interactions in the MMTV-PymT transgenic mouse model of breast cancer and in human breast cancer cells. CaSR activation stimulated PTHrP production by breast cancer cells in vitro and in vivo. Tissue-specific disruption of the casr gene in mammary epithelial cells in MMTV-PymT mice reduced tumor PTHrP expression and inhibited tumor cell proliferation and tumor outgrowth. CaSR signaling promoted the proliferation of human breast cancer cell lines and tumor cells cultured from MMTV-PyMT mice. Further, CaSR activation inhibited cell death triggered by high extracellular concentrations of calcium. The actions of the CaSR appeared to be mediated by nuclear actions of PTHrP that decreased p27kip1 levels and prevented nuclear accumulation of the proapoptotic factor apoptosis inducing factor. Taken together, our findings suggest that CaSR–PTHrP interactions might be a promising target for the development of therapeutic agents to limit tumor cell growth in bone metastases and in other microenvironments in which elevated calcium and/or PTHrP levels contribute to breast cancer progression. Cancer Res; 76(18); 5348–60. ©2016 AACR.
Data from Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy
Authors: Pilon-Thomas Shari , Kodumudi Krithika N. , El-Kenawi Asmaa E. , Russell Shonagh , Weber Amy M. , Luddy Kimberly , Damaghi Mehdi , Wojtkowiak Jonathan W. , Mulé James J. , Ibrahim-Hashim Arig , Gillies Robert J.
Published: April 2023

Abstract
Cancer immunotherapies, such as immune checkpoint blockade or adoptive T-cell transfer, can lead to durable responses in the clinic, but response rates remain low due to undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiveness of antitumor immunity. In this study, we directly investigated the effects of tumor acidity on the efficacy of immunotherapy. An acidic pH environment blocked T-cell activation and limited glycolysis in vitro. IFNγ release blocked by acidic pH did not occur at the level of steady-state mRNA, implying that the effect of acidity was posttranslational. Acidification did not affect cytoplasmic pH, suggesting that signals transduced by external acidity were likely mediated by specific acid-sensing receptors, four of which are expressed by T cells. Notably, neutralizing tumor acidity with bicarbonate monotherapy impaired the growth of some cancer types in mice where it was associated with increased T-cell infiltration. Furthermore, combining bicarbonate therapy with anti-CTLA-4, anti-PD1, or adoptive T-cell transfer improved antitumor responses in multiple models, including cures in some subjects. Overall, our findings show how raising intratumoral pH through oral buffers therapy can improve responses to immunotherapy, with the potential for immediate clinical translation. Cancer Res; 76(6); 1381–90. ©2015 AACR.
Data from YAP Mediates Tumorigenesis in Neurofibromatosis Type 2 by Promoting Cell Survival and Proliferation through a COX-2–EGFR Signaling Axis
Authors: Guerrant William , Kota Smitha , Troutman Scott , Mandati Vinay , Fallahi Mohammad , Stemmer-Rachamimov Anat , Kissil Joseph L.
Published: April 2023

Abstract
The Hippo–YAP pathway has emerged as a major driver of tumorigenesis in many human cancers. YAP is a transcriptional coactivator and while details of YAP regulation are quickly emerging, it remains unknown what downstream targets are critical for the oncogenic functions of YAP. To determine the mechanisms involved and to identify disease-relevant targets, we examined the role of YAP in neurofibromatosis type 2 (NF2) using cell and animal models. We found that YAP function is required for NF2-null Schwann cell survival, proliferation, and tumor growth in vivo. Moreover, YAP promotes transcription of several targets including PTGS2, which codes for COX-2, a key enzyme in prostaglandin biosynthesis, and AREG, which codes for the EGFR ligand, amphiregulin. Both AREG and prostaglandin E2 converge to activate signaling through EGFR. Importantly, treatment with the COX-2 inhibitor celecoxib significantly inhibited the growth of NF2-null Schwann cells and tumor growth in a mouse model of NF2. Cancer Res; 76(12); 3507–19. ©2016 AACR.
Data from miR-34a Silences c-SRC to Attenuate Tumor Growth in Triple-Negative Breast Cancer
Authors: Adams Brian D. , Wali Vikram B. , Cheng Christopher J. , Inukai Sachi , Booth Carmen J. , Agarwal Seema , Rimm David L. , Győrffy Balázs , Santarpia Libero , Pusztai Lajos , Saltzman W. Mark , Slack Frank J.
Published: April 2023

Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype with no clinically proven biologically targeted treatment options. The molecular heterogeneity of TNBC and lack of high frequency driver mutations other than TP53 have hindered the development of new and effective therapies that significantly improve patient outcomes. miRNAs, global regulators of survival and proliferation pathways important in tumor development and maintenance, are becoming promising therapeutic agents. We performed miRNA-profiling studies in different TNBC subtypes to identify miRNAs that significantly contribute to disease progression. We found that miR-34a was lost in TNBC, specifically within mesenchymal and mesenchymal stem cell–like subtypes, whereas expression of miR-34a targets was significantly enriched. Furthermore, restoration of miR-34a in cell lines representing these subtypes inhibited proliferation and invasion, activated senescence, and promoted sensitivity to dasatinib by targeting the proto-oncogene c-SRC. Notably, SRC depletion in TNBC cell lines phenocopied the effects of miR-34a reintroduction, whereas SRC overexpression rescued the antitumorigenic properties mediated by miR-34a. miR-34a levels also increased when cells were treated with c-SRC inhibitors, suggesting a negative feedback exists between miR-34a and c-SRC. Moreover, miR-34a administration significantly delayed tumor growth of subcutaneously and orthotopically implanted tumors in nude mice, and was accompanied by c-SRC downregulation. Finally, we found that miR-34a and SRC levels were inversely correlated in human tumor specimens. Together, our results demonstrate that miR-34a exerts potent antitumorigenic effects in vitro and in vivo and suggests that miR-34a replacement therapy, which is currently being tested in human clinical trials, represents a promising therapeutic strategy for TNBC. Cancer Res; 76(4); 927–39. ©2015 AACR.
Data from STAT3/IRF1 Pathway Activation Sensitizes Cervical Cancer Cells to Chemotherapeutic Drugs
Authors: Walch-Rückheim Barbara , Pahne-Zeppenfeld Jennifer , Fischbach Jil , Wickenhauser Claudia , Horn Lars Christian , Tharun Lars , Büttner Reinhard , Mallmann Peter , Stern Peter , Kim Yoo-Jin , Bohle Rainer Maria , Rübe Christian , Ströder Russalina , Juhasz-Böss Ingolf , Solomayer Erich-Franz , Smola Sigrun
Published: April 2023

Abstract
Neoadjuvant radio/chemotherapy regimens can markedly improve cervical cancer outcome in a subset of patients, while other patients show poor responses, but may encounter severe adverse effects. Thus, there is a strong need for predictive biomarkers to improve clinical management of cervical cancer patients. STAT3 is considered as a critical antiapoptotic factor in various malignancies. We therefore investigated STAT3 activation during cervical carcinogenesis and its impact on the response of cervical cancer cells to chemotherapeutic drugs. Tyr705-phosphorylated STAT3 increased from low-grade cervical intraepithelial neoplasia (CIN1) to precancerous CIN3 lesions. Notably, pTyr705-STAT3 activation significantly declined from CIN3 to invasive cancer, also when compared in the same clinical biopsy. pTyr705-STAT3 was also low or absent in cultured human cervical cancer cell lines, consistent with the in vivo expression data. Unexpectedly, IL6-type cytokine signaling inducing STAT3 activation rendered cervical cancer cells significantly more susceptible to chemotherapeutic drugs, that is, cisplatin or etoposide. This chemosensitization was STAT3-dependent and we identified IFN regulatory factor-1 (IRF1) as the STAT3-inducible mediator required for cell death enhancement. In line with these data, pTyr705-STAT3 significantly correlated with nuclear IRF1 expression in cervical cancer in vivo. Importantly, high IRF1 expression in pretreatment cervical cancer biopsy cells was associated with a significantly better response to neoadjuvant radio/chemotherapy of the patients. In summary, our study has identified a key role of the STAT3/IRF1 pathway for chemosensitization in cervical cancer. Our results suggest that pretherapeutic IRF1 expression should be evaluated as a novel predictive biomarker for neoadjuvant radio/chemotherapy responses. Cancer Res; 76(13); 3872–83. ©2016 AACR.
Data from The E3-ligase E6AP Represses Breast Cancer Metastasis via Regulation of ECT2-Rho Signaling
Authors: Mansour Mariam , Haupt Sue , Chan Ai-Leen , Godde Nathan , Rizzitelli Alexandra , Loi Sherene , Caramia Franco , Deb Siddhartha , Takano Elena A. , Bishton Mark , Johnstone Cameron , Monahan Brendon , Levav-Cohen Yarra , Jiang Yong-Hui , Yap Alpha S. , Fox Stephen , Bernard Ora , Anderson Robin , Haupt Ygal
Published: April 2023

Abstract
Metastatic disease is the major cause of breast cancer–related death and despite many advances, current therapies are rarely curative. Tumor cell migration and invasion require actin cytoskeletal reorganization to endow cells with capacity to disseminate and initiate the formation of secondary tumors. However, it is still unclear how these migratory cells colonize distant tissues to form macrometastases. The E6-associated protein, E6AP, acts both as an E3 ubiquitin-protein ligase and as a coactivator of steroid hormone receptors. We report that E6AP suppresses breast cancer invasiveness, colonization, and metastasis in mice, and in breast cancer patients, loss of E6AP associates with poor prognosis, particularly for basal breast cancer. E6AP regulates actin cytoskeletal remodeling via regulation of Rho GTPases, acting as a negative regulator of ECT2, a GEF required for activation of Rho GTPases. E6AP promotes ubiquitination and proteasomal degradation of ECT2 for which high expression predicts poor prognosis in breast cancer patients. We conclude that E6AP suppresses breast cancer metastasis by regulating actin cytoskeleton remodeling through the control of ECT2 and Rho GTPase activity. These findings establish E6AP as a novel suppressor of metastasis and provide a compelling rationale for inhibition of ECT2 as a therapeutic approach for patients with metastatic breast cancer. Cancer Res; 76(14); 4236–48. ©2016 AACR.
Data from Dietary Microbes Modulate Transgenerational Cancer Risk
Authors: Poutahidis Theofilos , Varian Bernard J. , Levkovich Tatiana , Lakritz Jessica R. , Mirabal Sheyla , Kwok Caitlin , Ibrahim Yassin M. , Kearney Sean M. , Chatzigiagkos Antonis , Alm Eric J. , Erdman Susan E.
Published: April 2023

Abstract
Environmental factors are suspected in the increase of obesity and cancer in industrialized countries but are poorly understood. Here, we used animal models to test how future generations may be affected by Westernized diets. We discover long-term consequences of grandmothers' in utero dietary exposures, leading to high rates of obesity and frequent cancers of lung and liver in two subsequent generations of mice. Transgenerational effects were transplantable using diet-associated bacteria communities alone. Consequently, feeding of beneficial microbes was sufficient to lower transgenerational risk for cancer and obesity regardless of diet history. Targeting microbes may be a highly effective population-based approach to lower risk for cancer. Cancer Res; 75(7); 1197–204. ©2015 AACR.
Data from Establishment and Characterization of an In Vitro Model of Ovarian Cancer Stem-like Cells with an Enhanced Proliferative Capacity
Authors: Ishiguro Tatsuya , Sato Ai , Ohata Hirokazu , Ikarashi Yoshinori , Takahashi Ryou-u , Ochiya Takahiro , Yoshida Masayuki , Tsuda Hitoshi , Onda Takashi , Kato Tomoyasu , Kasamatsu Takahiro , Enomoto Takayuki , Tanaka Kenichi , Nakagama Hitoshi , Okamoto Koji
Published: April 2023

Abstract
The establishment of cancer stem-like cell (CSC) culture systems may be instrumental in devising strategies to fight refractory cancers. Inhibition of the Rho kinase ROCK has been shown to favorably affect CSC spheroid cultures. In this study, we show how ROCK inhibition in human serous ovarian cancer (SOC) cells can help establish a CSC system, which illuminates cancer pathophysiology and its treatment in this setting. In the presence of a ROCK kinase inhibitor, spheroid cultures of SOC cells expressed characteristic CSC markers including ALDH1A1, CD133, and SOX2, along with differentiation and tumorigenic capabilities in mouse xenograft models of human SOC. High expression levels of ALDH, but not CD133, correlated with spheroid formation CSC marker expression and tumor forming capability. In clinical specimens of SOC, high levels of ALDH1A1 correlated with advanced stage and poor prognosis. Pharmacologic or genetic blockade of ALDH blocked cell proliferation and reduced expression of SOX2, the genetic ablation of which abolished spheroid formation, whereas SOX2 overexpression inhibited ALDH1A1 expression and blocked spheroid proliferation. Taken together, our findings illustrated a new method to culture human ovarian CSC, and they defined a reciprocal regulatory relationship between ALDH1A1 and SOX2, which impacts ovarian CSC proliferation and malignant progression. Cancer Res; 76(1); 150–60. ©2015 AACR.
Data from Radiation-Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation
Authors: Marmary Yitzhak , Adar Revital , Gaska Svetlana , Wygoda Annette , Maly Alexander , Cohen Jonathan , Eliashar Ron , Mizrachi Lina , Orfaig-Geva Carmit , Baum Bruce J. , Rose-John Stefan , Galun Eithan , Axelrod Jonathan H.
Published: April 2023

Abstract
Head and neck cancer patients treated by radiation commonly suffer from a devastating side effect known as dry-mouth syndrome, which results from the irreversible loss of salivary gland function via mechanisms that are not completely understood. In this study, we used a mouse model of radiation-induced salivary hypofunction to investigate the outcomes of DNA damage in the head and neck region. We demonstrate that the loss of salivary function was closely accompanied by cellular senescence, as evidenced by a persistent DNA damage response (γH2AX and 53BP1) and the expression of senescence-associated markers (SA-βgal, p19ARF, and DcR2) and secretory phenotype (SASP) factors (PAI-1 and IL6). Notably, profound apoptosis or necrosis was not observed in irradiated regions. Signs of cellular senescence were also apparent in irradiated salivary glands surgically resected from human patients who underwent radiotherapy. Importantly, using IL6 knockout mice, we found that sustained expression of IL6 in the salivary gland long after initiation of radiation-induced DNA damage was required for both senescence and hypofunction. Additionally, we demonstrate that IL6 pretreatment prevented both senescence and salivary gland hypofunction via a mechanism involving enhanced DNA damage repair. Collectively, these results indicate that cellular senescence is a fundamental mechanism driving radiation-induced damage in the salivary gland and suggest that IL6 pretreatment may represent a promising therapeutic strategy to preserve salivary gland function in head and neck cancer patients undergoing radiotherapy. Cancer Res; 76(5); 1170–80. ©2016 AACR.
Data from Abscopal Effects of Radiotherapy Are Enhanced by Combined Immunostimulatory mAbs and Are Dependent on CD8 T Cells and Crosspriming
Authors: Rodriguez-Ruiz María E. , Rodriguez Inmaculada , Garasa Saray , Barbes Benigno , Solorzano Jose Luis , Perez-Gracia Jose Luis , Labiano Sara , Sanmamed Miguel F. , Azpilikueta Arantza , Bolaños Elixabet , Sanchez-Paulete Alfonso R. , Aznar M. Angela , Rouzaut Ana , Schalper Kurt A. , Jure-Kunkel Maria , Melero Ignacio
Published: April 2023

Abstract
Preclinical and clinical evidence indicate that the proimmune effects of radiotherapy can be synergistically augmented with immunostimulatory mAbs to act both on irradiated tumor lesions and on distant, nonirradiated tumor sites. The combination of radiotherapy with immunostimulatory anti-PD1 and anti-CD137 mAbs was conducive to favorable effects on distant nonirradiated tumor lesions as observed in transplanted MC38 (colorectal cancer), B16OVA (melanoma), and 4T1 (breast cancer) models. The therapeutic activity was crucially performed by CD8 T cells, as found in selective depletion experiments. Moreover, the integrities of BATF-3–dependent dendritic cells specialized in crosspresentation/crosspriming of antigens to CD8+ T cells and of the type I IFN system were absolute requirements for the antitumor effects to occur. The irradiation regimen induced immune infiltrate changes in the irradiated and nonirradiated lesions featured by reductions in the total content of effector T cells, Tregs, and myeloid-derived suppressor cells, while effector T cells expressed more intracellular IFNγ in both the irradiated and contralateral tumors. Importantly, 48 hours after irradiation, CD8+ TILs showed brighter expression of CD137 and PD1, thereby displaying more target molecules for the corresponding mAbs. Likewise, PD1 and CD137 were induced on tumor-infiltrating lymphocytes from surgically excised human carcinomas that were irradiated ex vivo. These mechanisms involving crosspriming and CD8 T cells advocate clinical development of immunotherapy combinations with anti-PD1 plus anti-CD137 mAbs that can be synergistically accompanied by radiotherapy strategies, even if the disease is left outside the field of irradiation. Cancer Res; 76(20); 5994–6005. ©2016 AACR.
Data from Small RNAs Recruit Chromatin-Modifying Enzymes MMSET and Tip60 to Reconfigure Damaged DNA upon Double-Strand Break and Facilitate Repair
Authors: Wang Qinhong , Goldstein Michael
Published: April 2023

Abstract
Recent reports have demonstrated that DNA double-strand break (DSB)–induced small RNAs (diRNA) play an important role in the DNA damage response (DDR). However, the molecular mechanism by which diRNAs regulate the DDR remains unclear. Here, we report that Dicer- and Drosha-dependent diRNAs function as guiding molecules to promote the recruitment of the methyltransferase MMSET (WHSC1) and the acetyltransferase Tip60 (KAT5) to the DSB, where local levels of histone H4 di- and tri-methylation at lysine 20 (H4K20me2, 3) and H4 acetylation at lysine 16 (H4K16Ac) were enhanced. These histone modification events resulted in an open, flexible chromatin configuration, as indicated by the increased release of histones γH2AX, H2AX, and H3 from damaged chromatin. Furthermore, we found that diRNA-associated AGO2 interacted with MMSET and Tip60 and that the diRNA binding and catalytic activities of AGO2 were dispensable for the interaction but required for the recruitment of MMSET and Tip60 to DSBs. Consequently, diRNA-mediated chromatin remodeling promoted DSB repair by enhancing the recruitment of Rad51 and BRCA1 to the DSB site. Taken together, our findings reveal an unexpected direct role for diRNAs in regulating chromatin remodeling to facilitate DSB repair, revealing a new layer of DDR regulation involving specialized RNA molecules. Cancer Res; 76(7); 1904–15. ©2016 AACR.
Data from Drosophila Brat and Human Ortholog TRIM3 Maintain Stem Cell Equilibrium and Suppress Brain Tumorigenesis by Attenuating Notch Nuclear Transport
Authors: Mukherjee Subhas , Tucker-Burden Carol , Zhang Changming , Moberg Kenneth , Read Renee , Hadjipanayis Costas , Brat Daniel J.
Published: April 2023

Abstract
Cancer stem cells exert enormous influence on neoplastic behavior, in part by governing asymmetric cell division and the balance between self-renewal and multipotent differentiation. Growth is favored by deregulated stem cell division, which enhances the self-renewing population and diminishes the differentiation program. Mutation of a single gene in Drosophila, Brain Tumor (Brat), leads to disrupted asymmetric cell division resulting in dramatic neoplastic proliferation of neuroblasts and massive larval brain overgrowth. To uncover the mechanisms relevant to deregulated cell division in human glioma stem cells, we first developed a novel adult Drosophila brain tumor model using brat-RNAi driven by the neuroblast-specific promoter inscuteable. Suppressing Brat in this population led to the accumulation of actively proliferating neuroblasts and a lethal brain tumor phenotype. brat-RNAi caused upregulation of Notch signaling, a node critical for self-renewal, by increasing protein expression and enhancing nuclear transport of Notch intracellular domain (NICD). In human glioblastoma, we demonstrated that the human ortholog of Drosophila Brat, tripartite motif-containing protein 3 (TRIM3), similarly suppressed NOTCH1 signaling and markedly attenuated the stem cell component. We also found that TRIM3 suppressed nuclear transport of active NOTCH1 (NICD) in glioblastoma and demonstrated that these effects are mediated by direct binding of TRIM3 to the Importin complex. Together, our results support a novel role for Brat/TRIM3 in maintaining stem cell equilibrium and suppressing tumor growth by regulating NICD nuclear transport. Cancer Res; 76(8); 2443–52. ©2016 AACR.