bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from PDLIM2 Is a Marker of Adhesion and β-Catenin Activity in Triple-Negative Breast Cancer
Authors: Cox Orla T. , Edmunds Shelley J. , Simon-Keller Katja , Li Bo , Moran Bruce , Buckley Niamh E. , Bustamante-Garrido Milan , Healy Nollaig , O'Flanagan Ciara H. , Gallagher William M. , Kennedy Richard D. , Bernards René , Caldas Carlos , Chin Suet-Feung , Marx Alexander , O'Connor Rosemary
Published: March 2024

Abstract
The PDLIM2 protein regulates stability of transcription factors including NF-κB and STATs in epithelial and hemopoietic cells. PDLIM2 is strongly expressed in certain cancer cell lines that exhibit an epithelial-to-mesenchymal phenotype, and its suppression is sufficient to reverse this phenotype. PDLIM2 supports the epithelial polarity of nontransformed breast cells, suggesting distinct roles in tumor suppression and oncogenesis. To better understand its overall function, we investigated PDLIM2 expression and activity in breast cancer. PDLIM2 protein was present in 60% of tumors diagnosed as triple-negative breast cancer (TNBC), and only 20% of other breast cancer subtypes. High PDLIM2 expression in TNBC was positively correlated with adhesion signaling and β-catenin activity. Interestingly, PDLIM2 was restricted to the cytoplasm/membrane of TNBC cells and excluded from the nucleus. In breast cell lines, PDLIM2 retention in the cytoplasm was controlled by cell adhesion, and translocation to the nucleus was stimulated by insulin-like growth factor-1 or TGFβ. Cytoplasmic PDLIM2 was associated with active β-catenin and ectopic expression of PDLIM2 was sufficient to increase β-catenin levels and its transcriptional activity in reporter assays. Suppression of PDLIM2 inhibited tumor growth in vivo, whereas overexpression of PDLIM2 disrupted growth in 3D cultures. These results suggest that PDLIM2 may serve as a predictive biomarker for a large subset of TNBC whose phenotype depends on adhesion-regulated β-catenin activity and which may be amenable to therapies that target these pathways.
Significance:
This study shows that PDLIM2 expression defines a subset of triple-negative breast cancer that may benefit from targeting the β-catenin and adhesion signaling pathways.
Data from DNA Polymerase Eta Prevents Tumor Cell-Cycle Arrest and Cell Death during Recovery from Replication Stress
Authors: Barnes Ryan P. , Tsao Wei-Chung , Moldovan George-Lucian , Eckert Kristin A.
Published: March 2024

Abstract
Neoplastic transformation and genome instability are enhanced by replication stress, conditions that slow or stall DNA replication forks. Consequently, cancer cells require multiple enzymes and checkpoint signaling pathways to mitigate replication stress for their viability and proliferation. Targeting proteins that enhance cancer cell survival during replication stress is a recent approach in clinical strategies, especially when targets produce synthetic lethality. DNA polymerase eta (Pol η) has many key functions in genome stability, particularly for translesion synthesis. Here we demonstrate that endogenous Pol η displays significant protein induction and forms intense foci throughout the nucleus in response to replication stress induced by drugs that do not directly form DNA adducts. During replication stress, Pol η-deficient cells displayed hyperactivation of the ATR replication checkpoint and arrested late in the cell cycle. During recovery from replication stress, Pol η-deficient cells continue to display aberrant phenotypes, including delayed cell-cycle progression, apoptosis, and cell survival. Depletion or inhibition of ATR was synthetically lethal with Pol η deficiency, particularly when tumor cells were treated with replication stress-inducing drugs. Together our data expand knowledge of the cellular environments that increase endogenous Pol η expression beyond DNA damaging agents and demonstrate that Pol η regulation is central to the replication stress response. Because Pol η is aberrantly expressed in several tumor types, our results are critical for developing more effective chemotherapy approaches and identify coinhibition of Pol η and ATR as a potential therapeutic strategy.
Significance:
This study demonstrates that replication stress upregulates Pol η (POLH) in tumor cells and reveals a role for Pol η in tumor cell recovery following replication stress.
Data from Specific Targeting of MTAP-Deleted Tumors with a Combination of 2′-Fluoroadenine and 5′-Methylthioadenosine
Authors: Tang Baiqing , Lee Hyung-Ok , An Serim S. , Cai Kathy Q. , Kruger Warren D.
Published: March 2024

Abstract
Homozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene is a frequent event in a wide variety of human cancers and is a possible molecular target for therapy. One potential therapeutic strategy to target MTAP-deleted tumors involves combining toxic purine analogues such as 6′-thioguanine (6TG) or 2′-fluoroadenine (2FA) with the MTAP substrate 5′-deoxy-5′-methylthioadenosine (MTA). The rationale is that excess MTA will protect normal MTAP+ cells from purine analogue toxicity because MTAP catalyzes the conversion of MTA to adenine, which then inhibits the conversion of purine base analogues into nucleotides. However, in MTAP− tumor cells, no protection takes place because adenine is not formed. Here, we examine the effects of 6TG and 2FA in combination with MTA in vitro and in vivo. In vitro, MTA protected against both 6TG and 2FA toxicity in an MTAP-dependent manner, shifting the IC50 concentration by one to three orders of magnitude. However, in mice, MTA protected against toxicity from 2FA but failed to protect against 6TG. Addition of 100 mg/kg MTA to 20 mg/kg 2FA entirely reversed the toxicity of 2FA in a variety of tissues and the treatment was well tolerated by mice. The 2FA+MTA combination inhibited tumor growth of four different MTAP− human tumor cell lines in mouse xenograft models. Our results suggest that 2FA+MTA may be a promising combination for treating MTAP-deleted tumors.

Significance: Loss of MTAP occurs in about 15% of all human cancers; the MTAP protection strategy presented in this study could be very effective in treating these cancers. Cancer Res; 78(15); 4386–95. ©2018 AACR.
Data from TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells
Authors: Li Taiwen , Fan Jingyu , Wang Binbin , Traugh Nicole , Chen Qianming , Liu Jun S. , Li Bo , Liu X. Shirley
Published: March 2024

Abstract
Recent clinical successes of cancer immunotherapy necessitate the investigation of the interaction between malignant cells and the host immune system. However, elucidation of complex tumor–immune interactions presents major computational and experimental challenges. Here, we present Tumor Immune Estimation Resource (TIMER; cistrome.shinyapps.io/timer) to comprehensively investigate molecular characterization of tumor–immune interactions. Levels of six tumor-infiltrating immune subsets are precalculated for 10,897 tumors from 32 cancer types. TIMER provides 6 major analytic modules that allow users to interactively explore the associations between immune infiltrates and a wide spectrum of factors, including gene expression, clinical outcomes, somatic mutations, and somatic copy number alterations. TIMER provides a user-friendly web interface for dynamic analysis and visualization of these associations, which will be of broad utilities to cancer researchers. Cancer Res; 77(21); e108–10. ©2017 AACR.
Data from Tenascin-C and Integrin α9 Mediate Interactions of Prostate Cancer with the Bone Microenvironment
Authors: San Martin Rebeca , Pathak Ravi , Jain Antrix , Jung Sung Yun , Hilsenbeck Susan G. , Piña-Barba María C. , Sikora Andrew G. , Pienta Kenneth J. , Rowley David R.
Published: March 2024

Abstract
Deposition of the extracellular matrix protein tenascin-C is part of the reactive stroma response, which has a critical role in prostate cancer progression. Here, we report that tenascin C is expressed in the bone endosteum and is associated with formation of prostate bone metastases. Metastatic cells cultured on osteo-mimetic surfaces coated with tenascin C exhibited enhanced adhesion and colony formation as mediated by integrin α9β1. In addition, metastatic cells preferentially migrated and colonized tenascin-C–coated trabecular bone xenografts in a novel system that employed chorioallantoic membranes of fertilized chicken eggs as host. Overall, our studies deepen knowledge about reactive stroma responses in the bone endosteum that accompany prostate cancer metastasis to trabecular bone, with potential implications to therapeutically target this process in patients. Cancer Res; 77(21); 5977–88. ©2017 AACR.
Data from TIP: A Web Server for Resolving Tumor Immunophenotype Profiling
Authors: Xu Liwen , Deng Chunyu , Pang Bo , Zhang Xinxin , Liu Wei , Liao Gaoming , Yuan Huating , Cheng Peng , Li Feng , Long Zhilin , Yan Min , Zhao Tingting , Xiao Yun , Li Xia
Published: March 2024

Abstract
Systematically tracking the tumor immunophenotype is required to understand the mechanisms of cancer immunity and improve clinical benefit of cancer immunotherapy. However, progress in current research is hindered by the lack of comprehensive immune activity resources and easy-to-use tools for biologists, clinicians, and researchers to conveniently evaluate immune activity during the “cancer-immunity cycle.” We developed a user-friendly one-stop shop web tool called TIP to comprehensively resolve tumor immunophenotype. TIP has the capability to rapidly analyze and intuitively visualize the activity of anticancer immunity and the extent of tumor-infiltrating immune cells across the seven-step cancer-immunity cycle. Also, we precalculated the pan-cancer immunophenotype for 11,373 samples from 33 The Cancer Genome Atlas human cancers that allow users to obtain and compare immunophenotype of pan-cancer samples. We expect TIP to be useful in a large number of emerging cancer immunity studies and development of effective immunotherapy biomarkers. TIP is freely available for use at http://biocc.hrbmu.edu.cn/TIP/.
Significance:
TIP is a one-stop shop platform that can help biologists, clinicians, and researchers conveniently evaluate anticancer immune activity with their own gene expression data.

See related commentary by Hirano, p. 6536
Data from Chemotherapy-Induced Macrophage Infiltration into Tumors Enhances Nanographene-Based Photodynamic Therapy
Authors: Zhao Yang , Zhang Chenran , Gao Liquan , Yu Xinhe , Lai Jianhao , Lu Dehua , Bao Rui , Wang Yanpu , Jia Bing , Wang Fan , Liu Zhaofei
Published: March 2024

Abstract
Increased recruitment of tumor-associated macrophages (TAM) to tumors following chemotherapy promotes tumor resistance and recurrence and correlates with poor prognosis. TAM depletion suppresses tumor growth, but is not highly effective due to the effects of tumorigenic mediators from other stromal sources. Here, we report that adoptive macrophage transfer led to a dramatically enhanced photodynamic therapy (PDT) effect of 2-(1-hexyloxyethyl)-2-devinyl pyropheophor-bide-alpha (HPPH)-coated polyethylene glycosylated nanographene oxide [GO(HPPH)-PEG] by increasing its tumor accumulation. Moreover, tumor treatment with commonly used chemotherapeutic drugs induced an increase in macrophage infiltration into tumors, which also enhanced tumor uptake and the PDT effects of GO(HPPH)-PEG, resulting in tumor eradication. Macrophage recruitment to tumors after chemotherapy was visualized noninvasively by near-infrared fluorescence and single-photon emission CT imaging using F4/80-specific imaging probes. Our results demonstrate that chemotherapy combined with GO(HPPH)-PEG PDT is a promising strategy for the treatment of tumors, especially those resistant to chemotherapy. Furthermore, TAM-targeted molecular imaging could potentially be used to predict the efficacy of combination therapy and select patients who would most benefit from this treatment approach. Cancer Res; 77(21); 6021–32. ©2017 AACR.
Data from Lactic Acid Accumulation in the Tumor Microenvironment Suppresses 18F-FDG Uptake
Authors: Türkcan Silvan , Kiru Louise , Naczynski Dominik J. , Sasportas Laura S. , Pratx Guillem
Published: March 2024

Abstract
The process by which tumor cells take up 2-[18F]fluoro-2-deoxy-D-glucose (FDG) is heterogeneous and influenced by a multitude of factors. In mouse tumor grafts, the core of the tumor often presents lower FDG uptake than the periphery. Whether this pattern is caused by the intrinsic avidity of individual cells for FDG, the density of viable cells in the tumor, or the perfusion of the radiotracer remains unknown. In this study, we used radioluminescence microscopy to measure FDG uptake in single cells isolated from the core and periphery of the tumor and found that differences in FDG uptake persist on the level of single cells. Single cells from the core of 4T1 and MDA-MB-231 tumors grafts took up 26% to 84% less FDG than those from the periphery. These differences were observed in mice with large tumors (>8 mm diameter) but not in those with smaller tumors. To explain the origin of these differences, we examined the influence of three microenvironmental factors on FDG uptake. Hypoxia was ruled out as a possible explanation because its presence in the core would increase and not decrease FDG uptake. Higher cell proliferation in the periphery was consistent with higher FDG uptake, but there was no evidence of a causal relationship. Finally, lactate was higher in the core of the tumor, and it suppressed FDG uptake in a dose-dependent fashion. We therefore conclude that lactic acidosis—the combination of lactate ion buildup and acidic pH—can increase the heterogeneity of FDG uptake in MDA-MB-231 and 4T1 tumor grafts.
Significance:
Analysis of single cells from heterogeneous tumors reveals the role played by the tumor microenvironment, lactic acidosis in particular, on the uptake by tumor cells of 18F-FDG, a PET imaging agent.
Data from Caveolae-Mediated Endocytosis Is Critical for Albumin Cellular Uptake and Response to Albumin-Bound Chemotherapy
Authors: Chatterjee Moumita , Ben-Josef Edgar , Robb Ryan , Vedaie Marall , Seum Star , Thirumoorthy Krishnan , Palanichamy Kamalakannan , Harbrecht Matthew , Chakravarti Arnab , Williams Terence M.
Published: March 2024

Abstract
Nab-paclitaxel, a nanoparticle conjugate of paclitaxel to human albumin, exhibits efficacy in pancreatic cancer, non–small cell lung cancer and breast cancer. However, there is a lack of predictive biomarkers to identify patients who might benefit most from its administration. This study addresses this gap in knowledge by identifying that caveolin-1 (Cav-1) is a candidate mechanism-based biomarker. Caveolae are small membrane invaginations important for transendothelial albumin uptake. Cav-1, the principal structural component of caveolae, is overexpressed in the cancers noted above that respond to nab-paclitaxel. Thus, we hypothesized that Cav-1 may be critical for albumin uptake in tumors and perhaps determine their response to this drug. Cav-1 protein levels correlated positively with nab-paclitaxel sensitivity. RNAi-mediated attenuation of Cav-1 expression reduced uptake of albumin and nab-paclitaxel in cancer cells and rendered them resistant to nab-paclitaxel–induced apoptosis. Conversely, Cav-1 overexpression enhanced sensitivity to nab-paclitaxel. Selection for cellular resistance to nab-paclitaxel in cell culture correlated with a loss of Cav-1 expression. In mouse xenograft models, cancer cells, where Cav-1 was attenuated, exhibited resistance to the antitumor effects of nab-paclitaxel therapy. Overall, our findings suggest Cav-1 as a predictive biomarker for the response to nab-paclitaxel and other albumin-based cancer therapeutic drugs. Cancer Res; 77(21); 5925–37. ©2017 AACR.
Data from Tethering IL2 to Its Receptor IL2Rβ Enhances Antitumor Activity and Expansion of Natural Killer NK92 Cells
Authors: Jounaidi Youssef , Cotten Joseph F. , Miller Keith W. , Forman Stuart A.
Published: March 2024

Abstract
IL2 is an immunostimulatory cytokine for key immune cells including T cells and natural killer (NK) cells. Systemic IL2 supplementation could enhance NK-mediated immunity in a variety of diseases ranging from neoplasms to viral infection. However, its systemic use is restricted by its serious side effects and limited efficacy due to activation of T regulatory cells (Tregs). IL2 signaling is mediated through interactions with a multi-subunit receptor complex containing IL2Rα, IL2Rβ, and IL2Rγ. Adult natural killer (NK) cells express only IL2Rβ and IL2Rγ subunits and are therefore relatively insensitive to IL2. To overcome these limitations, we created a novel chimeric IL2-IL2Rβ fusion protein of IL2 and its receptor IL2Rβ joined via a peptide linker (CIRB). NK92 cells expressing CIRB (NK92CIRB) were highly activated and expanded indefinitely without exogenous IL2. When compared with an IL2-secreting NK92 cell line, NK92CIRB were more activated, cytotoxic, and resistant to growth inhibition. Direct contact with cancer cells enhanced the cytotoxic character of NK92CIRB cells, which displayed superior in vivo antitumor effects in mice. Overall, our results showed how tethering IL2 to its receptor IL2Rβ eliminates the need for IL2Rα and IL2Rβ, offering a new tool to selectively activate and empower immune therapy. Cancer Res; 77(21); 5938–51. ©2017 AACR.
Data from Retinoic Acid–Related Orphan Receptor C Regulates Proliferation, Glycolysis, and Chemoresistance via the PD-L1/ITGB6/STAT3 Signaling Axis in Bladder Cancer
Authors: Cao Dalong , Qi Zihao , Pang Yangyang , Li Haoran , Xie Huyang , Wu Junlong , Huang Yongqiang , Zhu Yao , Shen Yijun , Zhu Yiping , Dai Bo , Hu Xin , Ye Dingwei , Wang Ziliang
Published: March 2024

Abstract
Retinoic acid–related orphan receptor C (RORC) is a member of the nuclear orphan receptor family and performs critical regulatory functions in cell proliferation, metastasis, and chemoresistance in various types of malignant tumors. Here we showed that expression of RORC is lost in tumor tissues of bladder cancer patients. Enhanced expression of RORC suppressed cell proliferation and glucose metabolism and increased cisplatin-induced apoptosis in vitro and in vivo. RORC bound the promoter region of programmed death ligand-1 (PD-L1) and negatively regulated PD-L1 expression. PD-L1 directly interacted with integrin β6 (ITGB6) and activated the ITGB6/FAK signaling pathway. RORC prevented the nuclear translocation of STAT3 via suppression of the PD-L1/ITGB6 signaling pathway, which further inhibited bladder cell proliferation and glucose metabolism and increased cisplatin-induced apoptosis. These findings reveal that RORC regulates bladder cancer cell proliferation, glucose metabolism, and chemoresistance by participating in the PD-L1/ITGB6/STAT3 signaling axis. Moreover, this new understanding of PD-L1 signaling may guide the selection of therapeutic targets to prevent tumor recurrence.
Significance:
These findings suggest that RORC-mediated regulation of a PD-L1/ITGB6/FAK/STAT3 signaling axis in bladder cancer provides several potential therapeutic targets to prevent tumor progression.
Data from A Containerized Software System for Generation, Management, and Exploration of Features from Whole Slide Tissue Images
Authors: Saltz Joel , Sharma Ashish , Iyer Ganesh , Bremer Erich , Wang Feiqiao , Jasniewski Alina , DiPrima Tammy , Almeida Jonas S. , Gao Yi , Zhao Tianhao , Saltz Mary , Kurc Tahsin
Published: March 2024

Abstract
Well-curated sets of pathology image features will be critical to clinical studies that aim to evaluate and predict treatment responses. Researchers require information synthesized across multiple biological scales, from the patient to the molecular scale, to more effectively study cancer. This article describes a suite of services and web applications that allow users to select regions of interest in whole slide tissue images, run a segmentation pipeline on the selected regions to extract nuclei and compute shape, size, intensity, and texture features, store and index images and analysis results, and visualize and explore images and computed features. All the services are deployed as containers and the user-facing interfaces as web-based applications. The set of containers and web applications presented in this article is used in cancer research studies of morphologic characteristics of tumor tissues. The software is free and open source. Cancer Res; 77(21); e79–82. ©2017 AACR.
Data from KDM4 Inhibition Targets Breast Cancer Stem–like Cells
Authors: Metzger Eric , Stepputtis Stella S. , Strietz Juliane , Preca Bogdan-Tiberius , Urban Sylvia , Willmann Dominica , Allen Anita , Zenk Fides , Iovino Nicola , Bronsert Peter , Proske Amelie , Follo Marie , Boerries Melanie , Stickeler Elmar , Xu Jiangchun , Wallace Michael B. , Stafford Jeffrey A. , Kanouni Toufike , Maurer Jochen , Schüle Roland
Published: March 2024

Abstract
Traditional treatments for breast cancer fail to address therapy-resistant cancer stem–like cells that have been characterized by changes in epigenetic regulators such as the lysine demethylase KDM4. Here, we describe an orally available, selective and potent KDM4 inhibitor (QC6352) with unique preclinical characteristics. To assess the antitumor properties of QC6352, we established a method to isolate and propagate breast cancer stem–like cells (BCSC) from individual triple-negative tumors resected from patients after neoadjuvant chemotherapy. Limiting-dilution orthotopic xenografts of these BCSCs regenerated original patient tumor histology and gene expression. QC6352 blocked BCSC proliferation, sphere formation, and xenograft tumor formation. QC6352 also abrogated expression of EGFR, which drives the growth of therapy-resistant triple-negative breast cancer cells. Our findings validate a unique BCSC culture system for drug screening and offer preclinical proof of concept for KDM4 inhibition as a new strategy to treat triple-negative breast cancer. Cancer Res; 77(21); 5900–12. ©2017 AACR.
Data from A Convolutional Neural Network Uses Microscopic Images to Differentiate between Mouse and Human Cell Lines and Their Radioresistant Clones
Authors: Toratani Masayasu , Konno Masamitsu , Asai Ayumu , Koseki Jun , Kawamoto Koichi , Tamari Keisuke , Li Zhihao , Sakai Daisuke , Kudo Toshihiro , Satoh Taroh , Sato Katsutoshi , Motooka Daisuke , Okuzaki Daisuke , Doki Yuichiro , Mori Masaki , Ogawa Kazuhiko , Ishii Hideshi
Published: March 2024

Abstract
Artificial intelligence (AI) trained with a convolutional neural network (CNN) is a recent technological advancement. Previously, several attempts have been made to train AI using medical images for clinical applications. However, whether AI can distinguish microscopic images of mammalian cells has remained debatable. This study assesses the accuracy of image recognition techniques using the CNN to identify microscopic images. We also attempted to distinguish between mouse and human cells and their radioresistant clones. We used phase-contrast microscopic images of radioresistant clones from two cell lines, mouse squamous cell carcinoma NR-S1, and human cervical carcinoma ME-180. We obtained 10,000 images of each of the parental NR-S1 and ME-180 controls as well as radioresistant clones. We trained the CNN called VGG16 using these images and obtained an accuracy of 96%. Features extracted by the trained CNN were plotted using t-distributed stochastic neighbor embedding, and images of each cell line were well clustered. Overall, these findings suggest the utility of image recognition using AI for predicting minute differences among phase-contrast microscopic images of cancer cells and their radioresistant clones.
Significance:
This study demonstrates rapid and accurate identification of radioresistant tumor cells in culture using artifical intelligence; this should have applications in future preclinical cancer research.
Data 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: March 2024

Abstract
Sialic acid sugars on the surface of cancer cells have emerged as potent immune modulators that contribute to the immunosuppressive microenvironment and tumor immune evasion. However, the mechanisms by which these sugars modulate antitumor immunity as well as therapeutic strategies directed against them are limited. Here we report that intratumoral injections with a sialic acid mimetic Ac53FaxNeu5Ac block tumor sialic acid expression in vivo and suppress tumor growth in multiple tumor models. Sialic acid blockade had a major impact on the immune cell composition of the tumor, enhancing tumor-infiltrating natural killer cell and CD8+ T-cell numbers while reducing regulatory T-cell and myeloid regulatory cell numbers. Sialic acid blockade enhanced cytotoxic CD8+ T-cell–mediated killing of tumor cells in part by facilitating antigen-specific T-cell–tumor cell clustering. Sialic acid blockade also synergized with adoptive transfer of tumor-specific CD8+ T cells in vivo and enhanced CpG immune adjuvant therapy by increasing dendritic cell activation and subsequent CD8+ T-cell responses. Collectively, these data emphasize the crucial role of sialic acids in tumor immune evasion and provide proof of concept that sialic acid blockade creates an immune-permissive tumor microenvironment for CD8+ T-cell–mediated tumor immunity, either as single treatment or in combination with other immune-based intervention strategies.

Significance: Sialic acid sugars function as important modulators of the immunosuppressive tumor microenvironment that limit potent antitumor immunity.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3574/F1.large.jpg. Cancer Res; 78(13); 3574–88. ©2018 AACR.
Data from DDX3 Activates CBC-eIF3–Mediated Translation of uORF-Containing Oncogenic mRNAs to Promote Metastasis in HNSCC
Authors: Chen Hung-Hsi , Yu Hsin-I , Yang Muh-Hwa , Tarn Woan-Yuh
Published: March 2024

Abstract
Mutated or dysregulated DDX3 participates in the progression and metastasis of cancer via its multiple roles in regulating gene expression and cellular signaling. Here, we show that the high expression levels of DDX3 in head and neck squamous cell carcinoma (HNSCC) correlate with lymph node metastasis and poor prognosis and demonstrate that DDX3 is essential for the proliferation, invasion, and metastasis of oral squamous cell carcinoma (OSCC) cells. Microarray analyses revealed that DDX3 is required for the expression of a set of pro-metastatic genes, including ATF4-modulated genes in an aggressive OSCC cell line. DDX3 activated translation of ATF4 and a set of its downstream targets, all of which contain upstream open reading frames (uORF). DDX3 promoted translation of these targets, likely by skipping the inhibitory uORF. DDX3 specifically enhanced the association of the cap-binding complex (CBC) with uORF-containing mRNAs and facilitated recruitment of the eukaryotic initiation factor 3 (eIF3). CBC and certain eIF3 subunits contributed to the expression of metastatic-related gene expression. Taken together, our results indicate a role for the novel DDX3–CBC–eIF3 translational complex in promoting metastasis.

Significance: The discovery of DDX3-mediated expression of oncogenic uORF-containing genes expands knowledge on translational control mechanisms and provides potential targets for cancer therapy.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4512/F1.large.jpg Cancer Res; 78(16); 4512–23. ©2018 AACR.
Data from A Mutant p53-Dependent Embryonic Stem Cell Gene Signature Is Associated with Augmented Tumorigenesis of Stem Cells
Authors: Koifman Gabriela , Shetzer Yoav , Eizenberger Shay , Solomon Hilla , Rotkopf Ron , Molchadsky Alina , Lonetto Giuseppe , Goldfinger Naomi , Rotter Varda
Published: March 2024

Abstract
Mutations in the tumor suppressor p53 are the most frequent alterations in human cancer. These mutations include p53-inactivating mutations as well as oncogenic gain-of-function (GOF) mutations that endow p53 with capabilities to promote tumor progression. A primary challenge in cancer therapy is targeting stemness features and cancer stem cells (CSC) that account for tumor initiation, metastasis, and cancer relapse. Here we show that in vitro cultivation of tumors derived from mutant p53 murine bone marrow mesenchymal stem cells (MSC) gives rise to aggressive tumor lines (TL). These MSC-TLs exhibited CSC features as displayed by their augmented oncogenicity and high expression of CSC markers. Comparative analyses between MSC-TL with their parental mutant p53 MSC allowed for identification of the molecular events underlying their tumorigenic properties, including an embryonic stem cell (ESC) gene signature specifically expressed in MSC-TLs. Knockout of mutant p53 led to a reduction in tumor development and tumorigenic cell frequency, which was accompanied by reduced expression of CSC markers and the ESC MSC-TL signature. In human cancer, MSC-TL ESC signature–derived genes correlated with poor patient survival and were highly expressed in human tumors harboring p53 hotspot mutations. These data indicate that the ESC gene signature–derived genes may serve as new stemness-based prognostic biomarkers as well as novel cancer therapeutic targets.

Significance: Mesenchymal cancer stem cell-like cell lines express a mutant p53-dependent embryonic stem cell gene signature, which can serve as a potential prognostic biomarker and therapeutic target in cancer. Cancer Res; 78(20); 5833–47. ©2018 AACR.
Data from Epigenetic Regulation of CXCL12 Plays a Critical Role in Mediating Tumor Progression and the Immune Response In Osteosarcoma
Authors: Li Binghao , Wang Zhan , Wu Hao , Xue Mingfeng , Lin Peng , Wang Shengdong , Lin Nong , Huang Xin , Pan Weibo , Liu Meng , Yan Xiaobo , Qu Hao , Sun Lingling , Li Hengyuan , Wu Yan , Teng Wangsiyuan , Wang Zenan , Zhou Xingzhi , Chen Huabiao , Poznansky Mark C. , Ye Zhaoming
Published: March 2024

Abstract
The mechanism by which osteosarcomas metastasize is elusive, and challenges remain regarding its treatment with modalities including immunotherapy. CXCL12 is deeply involved in the process of tumor metastasis and T-cell homing, which is driven by a chemokine gradient, but healthy bones are supposed to preferentially express CXCL12. Here, we show for the first time that osteosarcomas epigenetically downregulate CXCL12 expression via DNA methyltransferase 1 (DNMT1) and consequently acquire the ability to metastasize and to impair cytotoxic T-cell homing to the tumor site. Analysis of human osteosarcoma cases further revealed that CXCL12 expression strongly correlated with overall survival. Evaluations on fresh human chemotherapy-free osteosarcoma samples also showed a positive correlation between CXCL12 concentration and the number of intratumoral lymphocytes. Critically, treatment targeting DNMT1 in immunocompetent mouse models significantly elevated expression of CXCL12 in tumors, resulting in a robust immune response and consequently eradicating early lung metastases in addition to suppressing subcutaneous tumor growth. These antitumor effects were abrogated by CXCL12–CXCR4 blockade or CD8+ T-cell depletion. Collectively, our data show that CXCL12 regulation plays a significant role in both tumor progression and immune response, and targeting CXCL12 is promising for therapeutics against osteosarcoma.

Significance: Epigenetic regulation of CXCL12 controls metastasis and immune response in osteosarcoma, suggesting epigenetic therapies or therapies targeting CXCL12 have potential for therapeutic intervention in osteosarcoma. Cancer Res; 78(14); 3938–53. ©2018 AACR.
Data from Targeting the Hsp40/Hsp70 Chaperone Axis as a Novel Strategy to Treat Castration-Resistant Prostate Cancer
Authors: Moses Michael A. , Kim Yeong Sang , Rivera-Marquez Genesis M. , Oshima Nobu , Watson Matthew J. , Beebe Kristin E. , Wells Catherine , Lee Sunmin , Zuehlke Abbey D. , Shao Hao , Bingman William E. , Kumar Vineet , Malhotra Sanjay V. , Weigel Nancy L. , Gestwicki Jason E. , Trepel Jane B. , Neckers Leonard M.
Published: March 2024

Abstract
Castration-resistant prostate cancer (CRPC) is characterized by reactivation of androgen receptor (AR) signaling, in part by elevated expression of AR splice variants (ARv) including ARv7, a constitutively active, ligand binding domain (LBD)-deficient variant whose expression has been correlated with therapeutic resistance and poor prognosis. In a screen to identify small-molecule dual inhibitors of both androgen-dependent and androgen-independent AR gene signatures, we identified the chalcone C86. Binding studies using purified proteins and CRPC cell lysates revealed C86 to interact with Hsp40. Pull-down studies using biotinylated-C86 found Hsp40 present in a multiprotein complex with full-length (FL-) AR, ARv7, and Hsp70 in CRPC cells. Treatment of CRPC cells with C86 or the allosteric Hsp70 inhibitor JG98 resulted in rapid protein destabilization of both FL-AR and ARv, including ARv7, concomitant with reduced FL-AR- and ARv7-mediated transcriptional activity. The glucocorticoid receptor, whose elevated expression in a subset of CRPC also leads to androgen-independent AR target gene transcription, was also destabilized by inhibition of Hsp40 or Hsp70. In vivo, Hsp40 or Hsp70 inhibition demonstrated single-agent and combinatorial activity in a 22Rv1 CRPC xenograft model. These data reveal that, in addition to recognized roles of Hsp40 and Hsp70 in FL-AR LBD remodeling, ARv lacking the LBD remain dependent on molecular chaperones for stability and function. Our findings highlight the feasibility and potential benefit of targeting the Hsp40/Hsp70 chaperone axis to treat prostate cancer that has become resistant to standard antiandrogen therapy.

Significance:These findings highlight the feasibility of targeting the Hsp40/Hsp70 chaperone axis to treat CRPC that has become resistant to standard antiandrogen therapy. Cancer Res; 78(14); 4022–35. ©2018 AACR.
Data from EGFR Cooperates with EGFRvIII to Recruit Macrophages in Glioblastoma
Authors: An Zhenyi , Knobbe-Thomsen Christiane B. , Wan Xiaohua , Fan Qi Wen , Reifenberger Guido , Weiss William A.
Published: March 2024

Abstract
Amplification of the EGFR gene and its truncation mutant EGFRvIII are hallmarks of glioblastoma. Although coexpression of EGFR and EGFRvIII confers a growth advantage, how EGFR and EGFRvIII influence the tumor microenvironment remains incompletely understood. Here, we show that EGFR and EGFRvIII cooperate to induce macrophage infiltration via upregulation of the chemokine CCL2. EGFRvIII was significantly enriched in glioblastoma patient samples with high CCL2, and knockout of CCL2 in tumors coexpressing EGFR and EGFRvIII led to decreased infiltration of macrophages. KRAS was a critical signaling intermediate for EGFR- and EGFRvIII-induced expression of CCL2. Our results illustrate how EGFR and EGFRvIII direct the microenvironment in glioblastoma.
Significance:
Full-length EGFR and truncated EGFRvIII work through KRAS to upregulate the chemokine CCL2 and drive macrophage infiltration in glioblastoma.
Data from RAS–MAPK Pathway-Driven Tumor Progression Is Associated with Loss of CIC and Other Genomic Aberrations in Neuroblastoma
Authors: Eleveld Thomas F. , Schild Linda , Koster Jan , Zwijnenburg Danny A. , Alles Lindy K. , Ebus Marli E. , Volckmann Richard , Tijtgat Godelieve A. , van Sluis Peter , Versteeg Rogier , Molenaar Jan J.
Published: March 2024

Abstract
Mutations affecting the RAS–MAPK pathway frequently occur in relapsed neuroblastoma tumors, which suggests that activation of this pathway is associated with a more aggressive phenotype. To explore this hypothesis, we generated several model systems to define a neuroblastoma RAS–MAPK pathway signature. Activation of this pathway in primary tumors indeed correlated with poor survival and was associated with known activating mutations in ALK and other RAS–MAPK pathway genes. Integrative analysis showed that mutations in PHOX2B, CIC, and DMD were also associated with an activated RAS–MAPK pathway. Mutation of PHOX2B and deletion of CIC in neuroblastoma cell lines induced activation of the RAS–MAPK pathway. This activation was independent of phosphorylated ERK in CIC knockout systems. Furthermore, deletion of CIC caused a significant increase in tumor growth in vivo. These results show that the RAS–MAPK pathway is involved in tumor progression and establish CIC as a powerful tumor suppressor that functions downstream of this pathway in neuroblastoma.

Significance: This work identifies CIC as a powerful tumor suppressor affecting the RAS-MAPK pathway in neuroblastoma and reinforces the importance of mutation-driven activation of this pathway in cancer. Cancer Res; 78(21); 6297–307. ©2018 AACR.
Data from Comutations in DNA Damage Response Pathways Serve as Potential Biomarkers for Immune Checkpoint Blockade
Authors: Wang Zhijie , Zhao Jing , Wang Guoqiang , Zhang Fan , Zhang Zemin , Zhang Yuzi , Dong Hua , Zhao Xiaochen , Duan Jianchun , Bai Hua , Tian Yanhua , Wan Rui , Han Miao , Cao Yan , Xiong Lei , Liu Li , Wang Shuhang , Cai Shangli , Mok Tony S.K. , Wang Jie
Published: March 2024

Abstract
Biomarkers such as programmed death receptor 1 ligand (PD-L1) expression, tumor mutational burden (TMB), and high microsatellite instability are potentially applicable to predict the efficacy of immune checkpoint blockade (ICB). However, several challenges such as defining the cut-off value, test platform uniformity, and low frequencies limit their broad clinical application. Here we identify comutations in the DNA damage response (DDR) pathways of homologous recombination repair and mismatch repair (HRR-MMR) or HRR and base excision repair (HRR-BER; defined as co-mut+) that are associated with increased TMB and neoantigen load and increased levels of immune gene expression signatures. In four public clinical cohorts, co-mut+ patients presented a higher objective response rate and a longer progression-free survival or overall survival than co-mut− patients. Overall, identification of DDR comutations in HRR-MMR or HRR-BER as predictors of response to ICB provides a potentially convenient approach for future clinical practice.

Significance: Identification of comutations in specific DDR pathways as predictors of superior survival outcomes in response to immune checkpoint blockade provide a clinically convenient approach for estimation of tumor mutational burden and delivery of ICB therapy. Cancer Res; 78(22); 6486–96. ©2018 AACR.
Data from IL1 Receptor Antagonist Controls Transcriptional Signature of Inflammation in Patients with Metastatic Breast Cancer
Authors: Wu Te-Chia , Xu Kangling , Martinek Jan , Young Robyn R. , Banchereau Romain , George Joshy , Turner Jacob , Kim Kyung In , Zurawski Sandra , Wang Xuan , Blankenship Derek , Brookes Hannah M. , Marches Florentina , Obermoser Gerlinde , Lavecchio Elizabeth , Levin Maren K. , Bae Sookyoung , Chung Cheng-Han , Smith Jennifer L. , Cepika Alma-Martina , Oxley Kyp L. , Snipes George J. , Banchereau Jacques , Pascual Virginia , O'Shaughnessy Joyce , Palucka A. Karolina
Published: March 2024

Abstract
Inflammation affects tumor immune surveillance and resistance to therapy. Here, we show that production of IL1β in primary breast cancer tumors is linked with advanced disease and originates from tumor-infiltrating CD11c+ myeloid cells. IL1β production is triggered by cancer cell membrane–derived TGFβ. Neutralizing TGFβ or IL1 receptor prevents breast cancer progression in humanized mouse model. Patients with metastatic HER2− breast cancer display a transcriptional signature of inflammation in the blood leukocytes, which is attenuated after IL1 blockade. When present in primary breast cancer tumors, this signature discriminates patients with poor clinical outcomes in two independent public datasets (TCGA and METABRIC).

Significance: IL1β orchestrates tumor-promoting inflammation in breast cancer and can be targeted in patients using an IL1 receptor antagonist. Cancer Res; 78(18); 5243–58. ©2018 AACR.

See related commentary by Dinarello, p. 5200
Data from EGR1-Mediated Transcription of lncRNA-HNF1A-AS1 Promotes Cell-Cycle Progression in Gastric Cancer
Authors: Liu Hai-Ting , Liu Sen , Liu Lei , Ma Ran-Ran , Gao Peng
Published: March 2024

Abstract
Long noncoding RNAs (lncRNA) are dysregulated in various human cancers and control tumor development and progression. However, the upstream mechanisms underlying their dysregulation remain unclear. Here, we demonstrate that the expression of hepatocyte nuclear factor 1 homeobox A antisense RNA 1 (HNF1A-AS1) is significantly upregulated in gastric cancer tissues. Overexpression of HNF1A-AS1 enhanced cell proliferation and promoted cell-cycle progression, whereas knockdown of HNF1A-AS1 elicited the opposite effects. Early growth response protein 1 (EGR1) directly bound the HNF1A-AS1 promoter region and activated its transcription. Overexpression of EGR1 enhanced cell proliferation and promoted cell-cycle promotion, similar to the function of HNF1A-AS1. HNF1A-AS1 functioned as competing endogenous RNA (ceRNA) by binding to miR-661, upregulating the expression of cell division cycle 34 (CDC34), which is a direct target of miR-661. EGR1 and HNF1A-AS1 enhanced the expression of cyclin-dependent kinase 2 (CDK2), CDK4, and cyclin E1 but inhibited the expression of p21 by promoting CDC34-mediated ubiquitination and degradation of p21. Taken together, these findings suggest that EGR1-activated HNF1A-AS1 regulates various pro- and antigrowth factors to promote the development of gastric cancer, implicating it as a possible target for therapeutic intervention in this disease.

Significance: This study provides novel insights into mechanisms by which the noncoding RNA HNF1A-AS1 contributes to gastric cancer progression through modulation of the cell cycle. Cancer Res; 78(20); 5877–90. ©2018 AACR.
Data from CBP Modulates Sensitivity to Dasatinib in Pre-BCR+ Acute Lymphoblastic Leukemia
Authors: Duque-Afonso Jesús , Lin Chiou-Hong , Han Kyuho , Morgens David W. , Jeng Edwin E. , Weng Ziming , Jeong Johan , Wong Stephen Hon Kit , Zhu Li , Wei Michael C. , Chae Hee-Don , Schrappe Martin , Cario Gunnar , Duyster Justus , Xiao Xiangshu , Sakamoto Kathleen M. , Bassik Michael C. , Cleary Michael L.
Published: March 2024

Abstract
Dasatinib is a multi-tyrosine kinase inhibitor approved for treatment of Ph+ acute lymphoblastic leukemia (ALL), but its efficacy is limited by resistance. Recent preclinical studies suggest that dasatinib may be a candidate therapy in additional ALL subtypes including pre-BCR+ ALL. Here we utilized shRNA library screening and global transcriptomic analysis to identify several novel genes and pathways that may enhance dasatinib efficacy or mitigate potential resistance in human pre-BCR+ ALL. Depletion of the transcriptional coactivator CBP increased dasatinib sensitivity by downregulating transcription of the pre-BCR signaling pathway previously associated with dasatinib sensitivity. Acquired resistance was due, in part, to upregulation of alternative pathways including WNT through a mechanism, suggesting transcriptional plasticity. Small molecules that disrupt CBP interactions with the CREB KID domain or β-catenin showed promising preclinical efficacy in combination with dasatinib. These findings highlight novel modulators of sensitivity to targeted therapies in human pre-BCR+ ALL, which can be reversed by small-molecule inhibitors. They also identify promising therapeutic approaches to ameliorate dasatinib sensitivity and prevent resistance in ALL.

Significance: These findings reveal mechanisms that modulate sensitivity to dasatinib and suggest therapeutic strategies to improve the outcome of patients with acute lymphoblastic leukemia.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/22/6497/F1.large.jpg. Cancer Res; 78(22); 6497–508. ©2018 AACR.
Data from Dose and Schedule Determine Distinct Molecular Mechanisms Underlying the Efficacy of the p53–MDM2 Inhibitor HDM201
Authors: Jeay Sébastien , Ferretti Stéphane , Holzer Philipp , Fuchs Jeanette , Chapeau Emilie A. , Wartmann Markus , Sterker Dario , Romanet Vincent , Murakami Masato , Kerr Grainne , Durand Eric Y. , Gaulis Swann , Cortes-Cros Marta , Ruetz Stephan , Stachyra Therese-Marie , Kallen Joerg , Furet Pascal , Würthner Jens , Guerreiro Nelson , Halilovic Ensar , Jullion Astrid , Kauffmann Audrey , Kuriakose Emil , Wiesmann Marion , Jensen Michael R. , Hofmann Francesco , Sellers William R.
Published: March 2024

Abstract
Activation of p53 by inhibitors of the p53–MDM2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. Here, we report distinct mechanisms by which the novel, potent, and selective inhibitor of the p53–MDM2 interaction HDM201 elicits therapeutic efficacy when applied at various doses and schedules. Continuous exposure of HDM201 led to induction of p21 and delayed accumulation of apoptotic cells. By comparison, high-dose pulses of HDM201 were associated with marked induction of PUMA and a rapid onset of apoptosis. shRNA screens identified PUMA as a mediator of the p53 response specifically in the pulsed regimen. Consistent with this, the single high-dose HDM201 regimen resulted in rapid and marked induction of PUMA expression and apoptosis together with downregulation of Bcl-xL in vivo. Knockdown of Bcl-xL was identified as the top sensitizer to HDM201 in vitro, and Bcl-xL was enriched in relapsing tumors from mice treated with intermittent high doses of HDM201. These findings define a regimen-dependent mechanism by which disruption of MDM2–p53 elicits therapeutic efficacy when given with infrequent dosing. In an ongoing HDM201 trial, the observed exposure–response relationship indicates that the molecular mechanism elicited by pulse dosing is likely reproducible in patients. These data support the clinical comparison of daily and intermittent regimens of p53–MDM2 inhibitors.

Significance: Pulsed high doses versus sustained low doses of the p53-MDM2 inhibitor HDM201 elicit a proapoptotic response from wild-type p53 cancer cells, offering guidance to current clinical trials with this and other drugs that exploit the activity of p53. Cancer Res; 78(21); 6257–67. ©2018 AACR.