bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Aberrant Notch Signaling in the Bone Marrow Microenvironment of Acute Lymphoid Leukemia Suppresses Osteoblast-Mediated Support of Hematopoietic Niche Function
Authors: Wang Weihuan , Zimmerman Grant , Huang Xiaoran , Yu Shuiliang , Myers Jay , Wang Yiwei , Moreton Stephen , Nthale Joseph , Awadallah Amad , Beck Rose , Xin Wei , Wald David , Huang Alex Y. , Zhou Lan
Published: April 2023

Abstract
More than half of T-cell acute lymphoblastic leukemia (T-ALL) patients harbor gain-of-function mutations in the intracellular domain of Notch1. Diffuse infiltration of the bone marrow commonly occurs in T-ALL and relapsed B-cell acute lymphoblastic leukemia patients, and is associated with worse prognosis. However, the mechanism of leukemia outgrowth in the marrow and the resulting biologic impact on hematopoiesis are poorly understood. Here, we investigated targetable cellular and molecular abnormalities in leukemia marrow stroma responsible for the suppression of normal hematopoiesis using a T-ALL mouse model and human T-ALL xenografts. We found that actively proliferating leukemia cells inhibited normal hematopoietic stem and progenitor cell (HSPC) proliferation and homing to the perivascular region. In addition, leukemia development was accompanied by the suppression of the endosteum-lining osteoblast population. We further demonstrated that aberrant Notch activation in the stroma plays an important role in negatively regulating the expression of CXLC12 on osteoblasts and their differentiation. Notch blockade reversed attenuated HSPC cycling, leukemia-associated abnormal blood lineage distribution, and thrombocytopenia as well as recovered osteoblast and HSPC abundance and improved the hematopoietic-supportive functions of osteoblasts. Finally, we confirmed that reduced osteoblast frequency and enhanced Notch signaling were also features of the marrow stroma of human ALL tissues. Collectively, our findings suggest that therapeutically targeting the leukemia-infiltrated hematopoietic niche may restore HSPC homeostasis and improve the outcome of ALL patients. Cancer Res; 76(6); 1641–52. ©2016 AACR.
Data from PDLIM1 Stabilizes the E-Cadherin/β-Catenin Complex to Prevent Epithelial–Mesenchymal Transition and Metastatic Potential of Colorectal Cancer Cells
Authors: Chen Hai-Ning , Yuan Kefei , Xie Na , Wang Kui , Huang Zhao , Chen Yan , Dou Qianhui , Wu Min , Nice Edouard C. , Zhou Zong-Guang , Huang Canhua
Published: April 2023

Abstract
Metastasis is a major cause of death in patients with colorectal cancer, and increasing evidence supports the contribution of the epithelial–mesenchymal transition (EMT) to cancer progression. The dissociation of the E-cadherin/β-catenin adhesion complex represents a key step in EMT and promotes cancer invasion and metastasis, but the upstream signaling pathways regulating this interaction are poorly understood. Here, we show that PDLIM1, a member of the PDZ and LIM protein family, was downregulated in highly metastatic colorectal cancer cells and liver metastases from colorectal cancer patients. We found that loss of PDLIM1 promoted the expression of EMT markers and increased the invasive and migratory properties of multiple colorectal cancer cell lines. Furthermore, PDLIM1 knockdown increased colon-derived liver metastasis in an orthotopic colorectal cancer model and promoted distant metastatic colonization in an experimental lung metastasis model. Mechanistic investigations revealed that PDLIM1 interacted with and stabilized the E-cadherin/β-catenin complex, thereby inhibiting the transcriptional activity of β-catenin and preventing EMT. Accordingly, PDLIM1 overexpression attenuated EMT of colorectal cancer cells. Moreover, the downregulation of PDLIM1 in colorectal cancer samples correlated with reduced E-cadherin and membrane β-catenin levels, and was associated with shorter overall survival. In conclusion, our study demonstrates that PDLIM1 suppresses EMT and metastatic potential of colorectal cancer cells by stabilizing β-catenin at cell–cell junctions, and its loss in metastatic tissues may represent a potential prognostic marker of aggressive disease. Cancer Res; 76(5); 1122–34. ©2015 AACR.
Data from Herbacetin Is a Novel Allosteric Inhibitor of Ornithine Decarboxylase with Antitumor Activity
Authors: Kim Dong Joon , Roh Eunmiri , Lee Mee-Hyun , Oi Naomi , Lim Do Young , Kim Myoung Ok , Cho Yong-Yeon , Pugliese Angelo , Shim Jung-Hyun , Chen Hanyong , Cho Eun Jin , Kim Jong-Eun , Kang Sun Chul , Paul Souren , Kang Hee Eun , Jung Ji Won , Lee Sung-Young , Kim Sung-Hyun , Reddy Kanamata , Yeom Young Il , Bode Ann M. , Dong Zigang
Published: April 2023

Abstract
Ornithine decarboxylase (ODC) is a rate-limiting enzyme in the first step of polyamine biosynthesis that is associated with cell growth and tumor formation. Existing catalytic inhibitors of ODC have lacked efficacy in clinical testing or displayed unacceptable toxicity. In this study, we report the identification of an effective and nontoxic allosteric inhibitor of ODC. Using computer docking simulation and an in vitro ODC enzyme assay, we identified herbacetin, a natural compound found in flax and other plants, as a novel ODC inhibitor. Mechanistic investigations defined aspartate 44 in ODC as critical for binding. Herbacetin exhibited potent anticancer activity in colon cancer cell lines expressing high levels of ODC. Intraperitoneal or oral administration of herbacetin effectively suppressed HCT116 xenograft tumor growth and also reduced the number and size of polyps in a mouse model of APC-driven colon cancer (ApcMin/+). Unlike the well-established ODC inhibitor DFMO, herbacetin treatment was not associated with hearing loss. Taken together, our findings defined the natural product herbacetin as an allosteric inhibitor of ODC with chemopreventive and antitumor activity in preclinical models of colon cancer, prompting its further investigation in clinical trials. Cancer Res; 76(5); 1146–57. ©2015 AACR.
Data from Lysine Demethylase LSD1 Coordinates Glycolytic and Mitochondrial Metabolism in Hepatocellular Carcinoma Cells
Authors: Sakamoto Akihisa , Hino Shinjiro , Nagaoka Katsuya , Anan Kotaro , Takase Ryuta , Matsumori Haruka , Ojima Hidenori , Kanai Yae , Arita Kazunori , Nakao Mitsuyoshi
Published: April 2023

Abstract
The hallmark of most cancer cells is the metabolic shift from mitochondrial to glycolytic metabolism for adapting to the surrounding environment. Although epigenetic modification is intimately linked to cancer, the molecular mechanism, by which epigenetic factors regulate cancer metabolism, is poorly understood. Here, we show that lysine-specific demethylase-1 (LSD1, KDM1A) has an essential role in maintaining the metabolic shift in human hepatocellular carcinoma cells. Inhibition of LSD1 reduced glucose uptake and glycolytic activity, with a concurrent activation of mitochondrial respiration. These metabolic changes coexisted with the inactivation of the hypoxia-inducible factor HIF1α, resulting in a decreased expression of GLUT1 and glycolytic enzymes. In contrast, during LSD1 inhibition, a set of mitochondrial metabolism genes was activated with the concomitant increase of methylated histone H3 at lysine 4 in the promoter regions. Consistently, both LSD1 and GLUT1 were significantly overexpressed in carcinoma tissues. These findings demonstrate the epigenetic plasticity of cancer cell metabolism, which involves an LSD1-mediated mechanism. Cancer Res; 75(7); 1445–56. ©2015 AACR.
Data from Cancer Cell Dissemination and Homing to the Bone Marrow in a Zebrafish Model
Authors: Sacco Antonio , Roccaro Aldo M. , Ma Dongdong , Shi Jiantao , Mishima Yuji , Moschetta Michele , Chiarini Marco , Munshi Nikhil , Handin Robert I. , Ghobrial Irene M.
Published: April 2023

Abstract
Advancement of many solid tumors and hematologic malignancies is frequently characterized by dissemination and homing of cancer cells to the bone marrow (BM). Methods to quantitatively characterize these key steps of the metastatic cascade in mammalian models are currently limited and do not offer opportunities to perform rapid, large-scale genomic, or drug screening. Because of their optical clarity, we used zebrafish to develop an in vivo model of cancer cell dissemination and homing to the BM. We performed intracardiac injection of multiple myeloma (MM) cells derived from human BM or cell lines and monitored their migration to the caudal hematopoietic tissue (CHT), the region where hematopoiesis occurs in the zebrafish embryo, which recapitulates a BM-like niche. Transcriptomic analyses confirmed that MM cells homing to the CHT displayed gene-expression differences compared with MM cells outside of the CHT, including significant enrichment for genes known to regulate interleukin-6 (IL6) signaling, cell adhesion, and angiogenesis. Collectively, our findings point to the zebrafish as a valuable model in which to study cancer cell homing to the hematopoietic niche and to establish a screening platform for the identification of factors and mechanisms contributing to the early steps of bone metastasis. Cancer Res; 76(2); 463–71. ©2016 AACR.
Data from Targeting the WASF3–CYFIP1 Complex Using Stapled Peptides Suppresses Cancer Cell Invasion
Authors: Teng Yong , Bahassan Abdulaziz , Dong Dayong , Hanold Laura E. , Ren Xiaoou , Kennedy Eileen J. , Cowell John K.
Published: April 2023

Abstract
Activation of the WASF3 protein by extracellular stimuli promotes actin cytoskeleton reorganization and facilitates cancer cell invasion, whereas WASF3 depletion suppresses invasion and metastasis. In quiescent cells, the interaction between WASF3 and a complex of proteins, including CYFIP1, acts as a conformational restraint to prevent WASF3 activation. Therefore, we took advantage of this endogenous regulatory mechanism to investigate potential sites that disrupt WASF3 function. Here, we show that genetic knockdown of CYFIP1 in cancer cells led to the destabilization of the WASF3 complex, loss of WASF3 function, and suppressed invasion. Based on existing crystallographic data, we developed stapled peptides, referred to as WASF Helix Mimics (WAHM), that target an α-helical interface between WASF3 and CYFIP1. Treatment of highly invasive breast and prostate cancer cells with WAHM inhibitor peptides significantly reduced motility and invasion in vitro. Mechanistic investigations revealed that these inhibitors suppressed the interaction between Rac and the WASF3 complex, which has been shown to promote cell migration. Furthermore, peptide-mediated inhibition of WASF3 also resulted in the dysregulation of known downstream targets such as MMP-9 and KISS1. Finally, we demonstrate that this invasive phenotype is specific to WASF3 as depletion of WASF1 and WASF2, which can also bind to CYFIP1, did not affect invasion. Collectively, our findings suggest that targeting WASF3 function with WAHM peptides could represent a promising therapeutic strategy for preventing tumor invasion and metastasis. Cancer Res; 76(4); 965–73. ©2015 AACR.
Data from Breast Tumor Kinase (Brk/PTK6) Is Induced by HIF, Glucocorticoid Receptor, and PELP1-Mediated Stress Signaling in Triple-Negative Breast Cancer
Authors: Regan Anderson Tarah M. , Ma Shi Hong , Raj Ganesh V. , Cidlowski John A. , Helle Taylor M. , Knutson Todd P. , Krutilina Raisa I. , Seagroves Tiffany N. , Lange Carol A.
Published: April 2023

Abstract
Cancer cells use stress response pathways to sustain their pathogenic behavior. In breast cancer, stress response–associated phenotypes are mediated by the breast tumor kinase, Brk (PTK6), via the hypoxia-inducible factors HIF-1α and HIF-2α. Given that glucocorticoid receptor (GR) is highly expressed in triple-negative breast cancer (TNBC), we investigated cross-talk between stress hormone–driven GR signaling and HIF-regulated physiologic stress. Primary TNBC tumor explants or cell lines treated with the GR ligand dexamethasone exhibited robust induction of Brk mRNA and protein that was HIF1/2–dependent. HIF and GR coassembled on the BRK promoter in response to either hypoxia or dexamethasone, indicating that Brk is a direct GR/HIF target. Notably, HIF-2α, not HIF-1α, expression was induced by GR signaling, and the important steroid receptor coactivator PELP1 was also found to be induced in a HIF-dependent manner. Mechanistic investigations showed how PELP1 interacted with GR to activate Brk expression and demonstrated that physiologic cell stress, including hypoxia, promoted phosphorylation of GR serine 134, initiating a feed-forward signaling loop that contributed significantly to Brk upregulation. Collectively, our findings linked cellular stress (HIF) and stress hormone (cortisol) signaling in TNBC, identifying the phospho-GR/HIF/PELP1 complex as a potential therapeutic target to limit Brk-driven progression and metastasis in TNBC patients. Cancer Res; 76(6); 1653–63. ©2016 AACR.
Data from Small-Molecule Prodigiosin Restores p53 Tumor Suppressor Activity in Chemoresistant Colorectal Cancer Stem Cells via c-Jun-Mediated ΔNp73 Inhibition and p73 Activation
Authors: Prabhu Varun V. , Hong Bo , Allen Joshua E. , Zhang Shengliang , Lulla Amriti R. , Dicker David T. , El-Deiry Wafik S.
Published: April 2023

Abstract
Tumor suppressor p53 is frequently mutated or inactivated in colorectal cancer. In contrast, p53 family member p73 is rarely mutated in colorectal cancer and p73 activation elicits p53-like tumor suppression. Colorectal cancer stem cells (CRCSC) comprise a rare self-renewing subpopulation that contributes to tumor maintenance and chemoresistance. p53 restoration is known to target CRCSCs, but p73 restoration in CRCSCs has not been examined. In this study, we investigated the effects of the small-molecule prodigiosin, which restores the p53 pathway in tumor cells via p73 activation, on CRCSCs in vitro and in vivo. Prodigiosin prevented colonosphere formation independent of p53 status and reduced the viability of self-renewing, 5-fluorouracil-resistant Aldefluor positive [Aldefluor(+)] CRCSCs in vitro. Furthermore, prodigiosin inhibited the growth of xenograft tumors initiated with Aldefluor+ cells without toxic effects and limited the tumorigenic potential of these cells. Consistently, prodigiosin induced activation of a p53-responsive luciferase reporter in colonospheres, Aldefluor(+) cells, and tumor xenografts. Mechanistic studies revealed that prodigiosin increased the levels of p73 and reduced levels of the oncogenic N-terminally truncated isoform ΔNp73 in Aldefluor(+) cells. Accordingly, p73 knockdown or ΔNp73 overexpression suppressed prodigiosin-mediated inhibition of colonosphere formation. Moreover, prodigiosin increased levels of the transcription factor c-Jun, a regulator of p73 and ΔNp73, in both the cytoplasm and nucleus. c-Jun knockdown attenuated prodigiosin-mediated p53-reporter activation, ΔNp73 downregulation, p73 activation, and cell death. Collectively, our findings highlight the previously uncharacterized use of p73-activating therapeutics to target CRCSCs. Cancer Res; 76(7); 1989–99. ©2016 AACR.
Data from SSBP1 Suppresses TGFβ-Driven Epithelial-to-Mesenchymal Transition and Metastasis in Triple-Negative Breast Cancer by Regulating Mitochondrial Retrograde Signaling
Authors: Jiang Hong-Lin , Sun He-Fen , Gao Shui-Ping , Li Liang-Dong , Huang Sheng , Hu Xin , Liu Sheng , Wu Jiong , Shao Zhi-Ming , Jin Wei
Published: April 2023

Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive tumor subtype lacking effective prognostic indicators or therapeutic targets. Mitochondrial function is dysregulated frequently in cancer cells to allow for adaptation to a harsh tumor microenvironment. Targeting mitochondrial biogenesis and bioenergetics is, therefore, an attractive therapeutic strategy. In this study, we performed quantitative proteomic analyses in human parental and metastatic breast cancer cell lines to identify mitochondrial proteins involved in TNBC metastasis. We found that single-strand DNA-binding protein 1 (SSBP1) was downregulated in highly metastatic breast cancer cells. Moreover, SSBP1 downregulation promoted TNBC cell metastasis in vitro and in vivo. Mechanistically, SSBP1 loss decreased mitochondrial DNA copy number, thereby potentiating calcineurin-mediated mitochondrial retrograde signaling that induced c-Rel/p50 nuclear localization, activated TGFβ promoter activity, and TGFβ-driven epithelial-to-mesenchymal transition. Low SSBP1 expression correlated with tumor progression and poor prognosis in patients. Collectively, our findings identified SSBP1 as a novel metastasis suppressor and elucidated the mechanisms by which dysregulated mitochondrial signaling contributes to metastatic potential, providing potential new prognostic indicators for patients with TNBC. Cancer Res; 76(4); 952–64. ©2015 AACR.
Data from Myeloid-Derived Suppressor Cells Endow Stem-like Qualities to Breast Cancer Cells through IL6/STAT3 and NO/NOTCH Cross-talk Signaling
Authors: Peng Dongjun , Tanikawa Takashi , Li Wei , Zhao Lili , Vatan Linda , Szeliga Wojciech , Wan Shanshan , Wei Shuang , Wang Yin , Liu Yan , Staroslawska Elzbieta , Szubstarski Franciszek , Rolinski Jacek , Grywalska Ewelina , Stanisławek Andrzej , Polkowski Wojciech , Kurylcio Andrzej , Kleer Celina , Chang Alfred E. , Wicha Max , Sabel Michael , Zou Weiping , Kryczek Ilona
Published: April 2023

Abstract
Myeloid-derived suppressor cells (MDSC) contribute to immune suppression in cancer, but the mechanisms through which they drive metastatic progression are not fully understood. In this study, we show how MDSC convey stem-like qualities to breast cancer cells that coordinately help enable immune suppression and escape. We found that MDSC promoted tumor formation by enhancing breast cancer cell stem-like properties as well as by suppressing T-cell activation. Mechanistic investigations indicated that these effects relied upon cross-talk between the STAT3 and NOTCH pathways in cancer cells, with MDSC inducing IL6-dependent phosphorylation of STAT3 and activating NOTCH through nitric oxide leading to prolonged STAT3 activation. In clinical specimens of breast cancer, the presence of MDSC correlated with the presence of cancer stem-like cells (CSC) and independently predicted poor survival outcomes. Collectively, our work revealed an immune-associated mechanism that extrinsically confers cancer cell stemness properties and affects patient outcome. We suggest that targeting STAT3-NOTCH cross-talk between MDSC and CSC could offer a unique locus to improve cancer treatment, by coordinately targeting a coupled mechanism that enables cancer stemness and immune escape. Cancer Res; 76(11); 3156–65. ©2016 AACR.
Data from An Anti-EGFR IgA That Displays Improved Pharmacokinetics and Myeloid Effector Cell Engagement In Vivo
Authors: Lohse Stefan , Meyer Saskia , Meulenbroek Laura A.P.M. , Jansen J.H. Marco , Nederend Maaike , Kretschmer Anna , Klausz Katja , Möginger Uwe , Derer Stefanie , Rösner Thies , Kellner Christian , Schewe Denis , Sondermann Peter , Tiwari Sanjay , Kolarich Daniel , Peipp Matthias , Leusen Jeanette H.W. , Valerius Thomas
Published: April 2023

Abstract
Antibodies of IgA isotype effectively engage myeloid effector cells for cancer immunotherapy. Here, we describe preclinical studies with an Fc engineered IgA2m(1) antibody containing the variable regions of the EGFR antibody cetuximab. Compared with wild-type IgA2m(1), the engineered molecule lacked two N-glycosylation sites (N166 and N337), two free cysteines (C311 and C472), and contained a stabilized heavy and light chain linkage (P221R mutation). This novel molecule displayed improved production rates and biochemical properties compared with wild-type IgA. In vitro, Fab- and Fc-mediated effector functions, such as inhibition of ligand binding, receptor modulation, and engagement of myeloid effector cells for antibody-dependent cell-mediated cytotoxicity, were similar between wild-type and engineered IgA2. The engineered antibody displayed lower levels of terminal galactosylation leading to reduced asialoglycoprotein-receptor binding and to improved pharmacokinetic properties. In a long-term in vivo model against EGFR-positive cancer cells, improved serum half-life translated into higher efficacy of the engineered molecule, which required myeloid cells expressing human FcαRI for its full efficacy. However, Fab-mediated effector functions contributed to the in vivo efficacy because the novel IgA antibody demonstrated therapeutic activity also in non-FcαRI transgenic mice. Together, these results demonstrate that engineering of an IgA antibody can significantly improve its pharmacokinetics and its therapeutic efficacy to inhibit tumor growth in vivo. Cancer Res; 76(2); 403–17. ©2015 AACR.
Data from In Situ Tumor Vaccination by Combining Local Radiation and Tumor-Specific Antibody or Immunocytokine Treatments
Authors: Morris Zachary S. , Guy Emily I. , Francis David M. , Gressett Monica M. , Werner Lauryn R. , Carmichael Lakeesha L. , Yang Richard K. , Armstrong Eric A. , Huang Shyhmin , Navid Fariba , Gillies Stephen D. , Korman Alan , Hank Jacquelyn A. , Rakhmilevich Alexander L. , Harari Paul M. , Sondel Paul M.
Published: April 2023

Abstract
Interest in combining radiotherapy and immune checkpoint therapy is growing rapidly. In this study, we explored a novel combination of this type to augment antitumor immune responses in preclinical murine models of melanoma, neuroblastoma, and head and neck squamous cell carcinoma. Cooperative effects were observed with local radiotherapy and intratumoral injection of tumor-specific antibodies, arising in part from enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). We could improve this response by combining radiation with intratumoral injection of an IL2-linked tumor-specific antibody (termed here an immunocytokine), resulting in complete regression of established tumors in most animals associated with a tumor-specific memory T-cell response. Given the T-cell response elicited by combined local radiation and intratumoral immunocytokine, we tested the potential benefit of adding this treatment to immune checkpoint blockade. In mice bearing large primary tumors or disseminated metastases, the triple-combination of intratumoral immunocytokine, radiation, and systemic anti–CTLA-4 improved primary tumor response and animal survival compared with combinations of any two of these three interventions. Taken together, our results show how combining radiation and intratumoral immunocytokine in murine tumor models can eradicate large tumors and metastases, eliciting an in situ vaccination effect that can be leveraged further by T-cell checkpoint blockade, with immediate implications for clinical evaluation. Cancer Res; 76(13); 3929–41. ©2016 AACR.
Data from Combined Inhibition of DNMT and HDAC Blocks the Tumorigenicity of Cancer Stem-like Cells and Attenuates Mammary Tumor Growth
Authors: Pathania Rajneesh , Ramachandran Sabarish , Mariappan Gurusamy , Thakur Priyanka , Shi Huidong , Choi Jeong-Hyeon , Manicassamy Santhakumar , Kolhe Ravindra , Prasad Puttur D. , Sharma Suash , Lokeshwar Bal L. , Ganapathy Vadivel , Thangaraju Muthusamy
Published: April 2023

Abstract
Recently, impressive technical advancements have been made in the isolation and validation of mammary stem cells and cancer stem cells (CSC), but the signaling pathways that regulate stem cell self-renewal are largely unknown. Furthermore, CSCs are believed to contribute to chemo- and radioresistance. In this study, we used the MMTV-Neu-Tg mouse mammary tumor model to identify potential new strategies for eliminating CSCs. We found that both luminal progenitor and basal stem cells are susceptible to genetic and epigenetic modifications, which facilitate oncogenic transformation and tumorigenic potential. A combination of the DNMT inhibitor 5-azacytidine and the HDAC inhibitor butyrate markedly reduced CSC abundance and increased the overall survival in this mouse model. RNA-seq analysis of CSCs treated with 5-azacytidine plus butyrate provided evidence that inhibition of chromatin modifiers blocks growth-promoting signaling molecules such as RAD51AP1 and SPC25, which play key roles in DNA damage repair and kinetochore assembly. Moreover, RAD51AP1 and SPC25 were significantly overexpressed in human breast tumor tissues and were associated with reduced overall patient survival. In conclusion, our studies suggest that breast CSCs are intrinsically sensitive to genetic and epigenetic modifications and can therefore be significantly affected by epigenetic-based therapies, warranting further investigation of combined DNMT and HDAC inhibition in refractory or drug-resistant breast cancer. Cancer Res; 76(11); 3224–35. ©2016 AACR.
Data 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

Abstract
c-Myc is regarded as a transcription factor, but the basis for its function remains unclear. Here, we define a long noncoding RNA (lncRNA)/protein complex that mediates the transcriptional activation by c-Myc in breast cancer cells. Among 388 c-Myc target genes in human MCF-7 breast cancer cells, we found that their promoters could be occupied by the oncoprotein HBXIP. We confirmed that the HBXIP expression correlated with expression of the c-Myc target genes cyclin A, eIF4E, and LDHA. RNAi-mediated silencing of HBXIP abolished c-Myc–mediated upregulation of these target genes. Mechanistically, HBXIP interacted directly with c-Myc through the leucine zippers and recruited the lncRNA Hotair along with the histone demethylase LSD1, for which Hotair serves as a scaffold. Silencing of HBXIP, Hotair, or LSD1 was sufficient to block c-Myc–enhanced cancer cell growth in vitro and in vivo. Taken together, our results support a model in which the HBXIP/Hotair/LSD1 complex serves as a critical effector of c-Myc in activating transcription of its target genes, illuminating long-standing questions on how c-Myc drives carcinogenesis. Cancer Res; 76(2); 293–304. ©2015 AACR.
Data from Hypoxia-Induced Epithelial-to-Mesenchymal Transition in Hepatocellular Carcinoma Induces an Immunosuppressive Tumor Microenvironment to Promote Metastasis
Authors: Ye Long-Yun , Chen Wei , Bai Xue-Li , Xu Xing-Yuan , Zhang Qi , Xia Xue-Feng , Sun Xu , Li Guo-Gang , Hu Qi-Da , Fu Qi-Han , Liang Ting-Bo
Published: April 2023

Abstract
Portal vein tumor thrombosis (PVTT) is a significant risk factor for metastasis in hepatocellular carcinoma (HCC) patients and is therefore associated with poor prognosis. The presence of PVTT frequently accompanies substantial hypoxia within the tumor microenvironment, which is suggested to accelerate tumor metastasis, but it is unclear how this occurs. Recent evidence has shown that the hypoxia-inducible factor HIF-1α induces epithelial-to-mesenchymal transition (EMT) in tumor cells to facilitate metastasis. In this study, we investigated whether hypoxia-induced EMT in cancer cells also affects immune cells in the tumor microenvironment to promote immunosuppression. We found that hypoxia-induced EMT increased the expression of the CCL20 cytokine in hepatoma cells. Furthermore, coculture of monocyte-derived macrophages with hypoxic hepatoma cells revealed that the expression of indoleamine 2, 3-dioxygenase (IDO) was induced in monocyte-derived macrophages in a CCL20-dependent manner. In turn, these IDO-expressing monocyte-derived macrophages suppressed T-cell proliferation and promoted the expansion of immunosuppressive regulatory T cells. Moreover, high CCL20 expression in HCC specimens was associated with PVTT and poor patient survival. Collectively, our findings suggest that the HIF-1α/CCL20/IDO axis in hepatocellular carcinoma is important for accelerating tumor metastasis through both the induction of EMT and the establishment of an immunosuppressive tumor microenvironment, warranting further investigation into the therapeutic effects of blocking specific nodes of this signaling network. Cancer Res; 76(4); 818–30. ©2016 AACR.
Data from MYC-Driven Neuroblastomas Are Addicted to a Telomerase-Independent Function of Dyskerin
Authors: O'Brien Rosemary , Tran Sieu L. , Maritz Michelle F. , Liu Bing , Kong Cheng Fei , Purgato Stefania , Yang Chen , Murray Jayne , Russell Amanda J. , Flemming Claudia L. , von Jonquieres Georg , Pickett Hilda A. , London Wendy B. , Haber Michelle , Gunaratne Preethi H. , Norris Murray D. , Perini Giovanni , Fletcher Jamie I. , MacKenzie Karen L.
Published: April 2023

Abstract
The RNA-binding protein dyskerin, encoded by the DKC1 gene, functions as a core component of the telomerase holoenzyme as well as ribonuclear protein complexes involved in RNA processing and ribosome biogenesis. The diverse roles of dyskerin across many facets of RNA biology implicate its potential contribution to malignancy. In this study, we examined the expression and function of dyskerin in neuroblastoma. We show that DKC1 mRNA levels were elevated relative to normal cells across a panel of 15 neuroblastoma cell lines, where both N-Myc and c-Myc directly targeted the DKC1 promoter. Upregulation of MYCN was shown to dramatically increase DKC1 expression. In two independent neuroblastoma patient cohorts, high DKC1 expression correlated strongly with poor event-free and overall survival (P < 0.0001), independently of established prognostic factors. RNAi-mediated depletion of dyskerin inhibited neuroblastoma cell proliferation, including cells immortalized via the telomerase-independent ALT mechanism. Furthermore, dyskerin attenuation impaired anchorage-independent proliferation and tumor growth. Overexpression of the telomerase RNA component, hTR, demonstrated that this proliferative impairment was not a consequence of telomerase suppression. Instead, ribosomal stress, evidenced by depletion of small nucleolar RNAs and nuclear dispersal of ribosomal proteins, was the likely cause of the proliferative impairment in dyskerin-depleted cells. Accordingly, dyskerin suppression caused p53-dependent G1 cell-cycle arrest in p53 wild-type cells, and a p53-independent pathway impaired proliferation in cells with p53 dysfunction. Together, our findings highlight dyskerin as a new therapeutic target in neuroblastoma with crucial telomerase-independent functions and broader implications for the spectrum of malignancies driven by MYC family oncogenes. Cancer Res; 76(12); 3604–17. ©2016 AACR.
Data from DNMT1 Inhibition Reprograms Pancreatic Cancer Stem Cells via Upregulation of the miR-17-92 Cluster
Authors: Zagorac Sladjana , Alcala Sonia , Fernandez Bayon Gustavo , Bou Kheir Tony , Schoenhals Matthieu , González-Neira Anna , Fernandez Fraga Mario , Aicher Alexandra , Heeschen Christopher , Sainz Bruno
Published: April 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) and other carcinomas are hierarchically organized, with cancer stem cells (CSC) residing at the top of the hierarchy, where they drive tumor progression, metastasis, and chemoresistance. As CSC and non-CSC share an identical genetic background, we hypothesize that differences in epigenetics account for the striking functional differences between these two cell populations. Epigenetic mechanisms, such as DNA methylation, play an important role in maintaining pluripotency and regulating the differentiation of stem cells, but the role of DNA methylation in pancreatic CSC is obscure. In this study, we investigated the genome-wide DNA methylation profile of PDAC CSC, and we determined the importance of DNA methyltransferases for CSC maintenance and tumorigenicity. Using high-throughput methylation analysis, we discovered that sorted CSCs have a higher level of DNA methylation, regardless of the heterogeneity or polyclonality of the CSC populations present in the tumors analyzed. Mechanistically, CSC expressed higher DNMT1 levels than non-CSC. Pharmacologic or genetic targeting of DNMT1 in CSCs reduced their self-renewal and in vivo tumorigenic potential, defining DNMT1 as a candidate CSC therapeutic target. The inhibitory effect we observed was mediated in part through epigenetic reactivation of previously silenced miRNAs, in particular the miR-17-92 cluster. Together, our findings indicate that DNA methylation plays an important role in CSC biology and also provide a rationale to develop epigenetic modulators to target CSC plasticity and improve the poor outcome of PDAC patients. Cancer Res; 76(15); 4546–58. ©2016 AACR.
Data from Computational Analysis of Cholangiocarcinoma Phosphoproteomes Identifies Patient-Specific Drug Targets
Authors: Khorsandi Shirin Elizabeth , Dokal Arran D. , Rajeeve Vinothini , Britton David J. , Illingworth Megan S. , Heaton Nigel , Cutillas Pedro R.
Published: April 2023

Abstract
Cholangiocarcinoma is a form of hepatobiliary cancer with an abysmal prognosis. Despite advances in our understanding of cholangiocarcinoma pathophysiology and its genomic landscape, targeted therapies have not yet made a significant impact on its clinical management. The low response rates of targeted therapies in cholangiocarcinoma suggest that patient heterogeneity contributes to poor clinical outcome. Here we used mass spectrometry–based phosphoproteomics and computational methods to identify patient-specific drug targets in patient tumors and cholangiocarcinoma-derived cell lines. We analyzed 13 primary tumors of patients with cholangiocarcinoma with matched nonmalignant tissue and 7 different cholangiocarcinoma cell lines, leading to the identification and quantification of more than 13,000 phosphorylation sites. The phosphoproteomes of cholangiocarcinoma cell lines and patient tumors were significantly correlated. MEK1, KIT, ERK1/2, and several cyclin-dependent kinases were among the protein kinases most frequently showing increased activity in cholangiocarcinoma relative to nonmalignant tissue. Application of the Drug Ranking Using Machine Learning (DRUML) algorithm selected inhibitors of histone deacetylase (HDAC; belinostat and CAY10603) and PI3K pathway members as high-ranking therapies to use in primary cholangiocarcinoma. The accuracy of the computational drug rankings based on predicted responses was confirmed in cell-line models of cholangiocarcinoma. Together, this study uncovers frequently activated biochemical pathways in cholangiocarcinoma and provides a proof of concept for the application of computational methodology to rank drugs based on efficacy in individual patients.
Significance:
Phosphoproteomic and computational analyses identify patient-specific drug targets in cholangiocarcinoma, supporting the potential of a machine learning method to predict personalized therapies.
Supplementary Figure 8 from Collaborative Cancer Epidemiology in the 21st Century: The Model of Cancer Consortia
Authors: Burgio Michael R. , Ioannidis John P.A. , Kaminski Brett M. , DeRycke Eric , Rogers Scott , Khoury Muin J. , Seminara Daniela
Published: April 2023

PDF - 27KB, Percentage of CEC papers published each year that are linkage studies or GWAS.
Supplementary Figure 4 from Collaborative Cancer Epidemiology in the 21st Century: The Model of Cancer Consortia
Authors: Burgio Michael R. , Ioannidis John P.A. , Kaminski Brett M. , DeRycke Eric , Rogers Scott , Khoury Muin J. , Seminara Daniela
Published: April 2023

PDF - 132KB, Fraction of small and large CEC and non-CEC associated grants by year.
Supplemental Figure 5 from Medical Care Cost of Oropharyngeal Cancer among Texas Patients
Authors: Lairson David R. , Wu Chi-Fang , Chan Wenyaw , Dahlstrom Kristina R. , Tam Samantha , Sturgis Erich M.
Published: April 2023

The adjusted 2-year cost distributions between case and controls
Supplemental Figure 1 from Medical Care Cost of Oropharyngeal Cancer among Texas Patients
Authors: Lairson David R. , Wu Chi-Fang , Chan Wenyaw , Dahlstrom Kristina R. , Tam Samantha , Sturgis Erich M.
Published: April 2023

Patient selection flowchart
Supplementary Figure Legend from Sex Disparities in Cancer Mortality and Survival
Authors: Cook Michael B. , McGlynn Katherine A. , Devesa Susan S. , Freedman Neal D. , Anderson William F.
Published: April 2023

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Supplementary Figure 4 from Sex Disparities in Cancer Mortality and Survival
Authors: Cook Michael B. , McGlynn Katherine A. , Devesa Susan S. , Freedman Neal D. , Anderson William F.
Published: April 2023

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Supplementary Figure 32 from Sex Disparities in Cancer Mortality and Survival
Authors: Cook Michael B. , McGlynn Katherine A. , Devesa Susan S. , Freedman Neal D. , Anderson William F.
Published: April 2023

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Supplementary Figure 30 from Sex Disparities in Cancer Mortality and Survival
Authors: Cook Michael B. , McGlynn Katherine A. , Devesa Susan S. , Freedman Neal D. , Anderson William F.
Published: April 2023

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Supplementary Figure 3 from Sex Disparities in Cancer Mortality and Survival
Authors: Cook Michael B. , McGlynn Katherine A. , Devesa Susan S. , Freedman Neal D. , Anderson William F.
Published: April 2023

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Supplementary Figure Legends from Epstein–Barr Virus Serology as a Potential Screening Marker for Nasopharyngeal Carcinoma among High-Risk Individuals from Multiplex Families in Taiwan
Authors: Coghill Anna E. , Hsu Wan-Lun , Pfeiffer Ruth M. , Juwana Hedy , Yu Kelly J. , Lou Pei-Jen , Wang Cheng-Ping , Chen Jen-Yang , Chen Chien-Jen , Middeldorp Jaap M. , Hildesheim Allan
Published: April 2023

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Supplementary Figure 24 from Sex Disparities in Cancer Mortality and Survival
Authors: Cook Michael B. , McGlynn Katherine A. , Devesa Susan S. , Freedman Neal D. , Anderson William F.
Published: April 2023

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Supplementary Figure 23 from Sex Disparities in Cancer Mortality and Survival
Authors: Cook Michael B. , McGlynn Katherine A. , Devesa Susan S. , Freedman Neal D. , Anderson William F.
Published: April 2023

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Supplementary Figure 22 from Sex Disparities in Cancer Mortality and Survival
Authors: Cook Michael B. , McGlynn Katherine A. , Devesa Susan S. , Freedman Neal D. , Anderson William F.
Published: April 2023

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FHPP Baseline Survey from A Randomized Trial to Increase Colonoscopy Screening in Members of High-Risk Families in the Colorectal Cancer Family Registry and Cancer Genetics Network
Authors: Lowery Jan T. , Horick Nora , Kinney Anita Y. , Finkelstein Dianne M. , Garrett Kathleen , Haile Robert W. , Lindor Noralane M. , Newcomb Polly A. , Sandler Robert S. , Burke Carol , Hill Deirdre A. , Ahnen Dennis J.
Published: April 2023

PDF - 80K, Family Health Promotion Project: Baseline Questionnaire used in trial.
Supplementary Figure 2 from Sex Disparities in Cancer Mortality and Survival
Authors: Cook Michael B. , McGlynn Katherine A. , Devesa Susan S. , Freedman Neal D. , Anderson William F.
Published: April 2023

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Supplementary Figures 1 - 4 from Risk of Precancer Determined by HPV Genotype Combinations in Women with Minor Cytologic Abnormalities
Authors: Gage Julia C. , Schiffman Mark , Solomon Diane , Wheeler Cosette M. , Gravitt Patti E. , Castle Philip E. , Wentzensen Nicolas
Published: April 2023

PDF file - 116K, Among women aged <30 with carcinogenic HPV infection, absolute risks of CIN2+ (left panel) and CIN3+ (right panel) at enrollment given category of HPV genotyping results by referral cytology.
Supplementary Figure 2 from Pectoral Muscle Attenuation as a Marker for Breast Cancer Risk in Full-Field Digital Mammography
Authors: Cheddad Abbas , Czene Kamila , Hall Per , Humphreys Keith
Published: April 2023

Supplementary Figure 2: Area density distributions (APD) across the different machine types reported in this study.
Supplementary Figure 1 from Circulating Biomarkers of Tryptophan and the Kynurenine Pathway and Lung Cancer Risk
Authors: Chuang Shu-Chun , Fanidi Anouar , Ueland Per Magne , Relton Caroline , Midttun Øivind , Vollset Stein Emil , Gunter Marc J. , Seckl Michael J. , Travis Ruth C. , Wareham Nicholas , Trichopoulou Antonia , Lagiou Pagona , Trichopoulos Dimitrios , Peeters Petra H.M. , Bueno-de-Mesquita H. Bas , Boeing Heiner , Wientzek Angelika , Kuehn Tilman , Kaaks Rudolf , Tumino Rosario , Agnoli Claudia , Palli Domenico , Naccarati Alessio , Aicua Eva Ardanaz , Sánchez María-José , Quirós José Ramón , Chirlaque María-Dolores , Agudo Antonio , Johansson Mikael , Grankvist Kjell , Boutron-Ruault Marie-Christine , Clavel-Chapelon Françoise , Fagherazzi Guy , Weiderpass Elisabete , Riboli Elio , Brennan Paul J. , Vineis Paolo , Johansson Mattias
Published: April 2023

PDF file - 71K, Spearman partial correlation coefficients between biomarkers among controls of a nested case-control study in the EPIC cohort.
Supplemental Materials and Methods, Table 1 from Pectoral Muscle Attenuation as a Marker for Breast Cancer Risk in Full-Field Digital Mammography
Authors: Cheddad Abbas , Czene Kamila , Hall Per , Humphreys Keith
Published: April 2023

Supplemental Materials and Methods, Table 1. Supplementary Table 1- Residual deviance tests to select the most relevant acquisition parameters combination that can explain MIP. The residual deviances correspond to fitted linear regression models with MIP as an outcome variable and the acquisition parameters as covariates, adjusting for VPD.
Supplementary Table S1 from Messages to Motivate Human Papillomavirus Vaccination: National Studies of Parents and Physicians
Authors: Malo Teri L. , Gilkey Melissa B. , Hall Megan E. , Shah Parth D. , Brewer Noel T.
Published: April 2023

Message length and average readability grade level.
Supplementary Tables 1 - 8 from Single-Nucleotide Polymorphisms in Nucleotide Excision Repair Genes, Cigarette Smoking, and the Risk of Head and Neck Cancer
Authors: Wyss Annah B. , Herring Amy H. , Avery Christy L. , Weissler Mark C. , Bensen Jeannette T. , Barnholtz-Sloan Jill S. , Funkhouser William K. , Olshan Andrew F.
Published: April 2023

PDF file - 195K, Table 1S. Single Nucleotide Polymorphisms (SNPs) in Nucleotide Excision Repair (NER) Genes Inclusion and Exclusion Criteria, Carolina Head and Neck Cancer Epidemiology (CHANCE) Study.: Table 2S. Odds Ratios for Environmental Tobacco Smoke and Head and Neck Cancer in the Carolina Head and Neck Cancer Epidemiology (CHANCE) Study.: Table 3S. Odds Ratios for Single Nucleotide Polymorphisms (SNPs) in ERCC3 and Head and Neck Cancer Tumor Sites Using Hierarchical Regression, the Carolina Head and Neck Cancer Epidemiology (CHANCE) Study, Whites.: Table 4S. Odds Ratios for Single Nucleotide Polymorphisms (SNPs) in ERCC6 Genes and Laryngeal Cancer Using Hierarchical Regression, the Carolina Head and Neck Cancer Epidemiology (CHANCE) Study, African Americans.: Table 5S. Odds Ratios for Single Nucleotide Polymorphisms (SNPs) in Nucleotide Excision Repair (NER) Genes and Head and Neck Cancer Using Conventional Logistic Regression, the Carolina Head and Neck Cancer Epidemiology (CHANCE) Study, Whites.: Table 6S. Odds Ratios for Single Nucleotide Polymorphisms (SNPs) in Nucleotide Excision Repair (NER) Genes and Head and Neck Cancer Using Conventional Logistic Regression, the Carolina Head and Neck Cancer Epidemiology (CHANCE) Study, African Americans.: Table 7S. Odds Ratios and Relative Excess Risk Due to Interaction Estimates for Joint Effects of Single Nucleotide Polymorphisms (SNPs) in Nucleotide Excision Repair (NER) Genes and Former/Current Cigarette Smoking on Head and Neck Cancer Risk Using Conventional Logistic Regression, the Carolina Head and Neck Cancer Epidemiology (CHANCE) Study, Whites.: Table 8S. Odds Ratios and Relative Excess Risk Due to Interaction Estimates for Joint Effects of Single Nucleotide Polymorphisms (SNPs) in Nucleotide Excision Repair (NER) Genes and Ever Environmental Tobacco Smoke on Head and Neck Cancer Risk Using Conventional Logistic Regression, the Carolina Head and Neck Cancer Epidemiology (CHANCE) Study, Whites.
Supplementary Appendix from Contribution of Screening and Survival Differences to Racial Disparities in Colorectal Cancer Rates
Authors: Lansdorp-Vogelaar Iris , Kuntz Karen M. , Knudsen Amy B. , van Ballegooijen Marjolein , Zauber Ann G. , Jemal Ahmedin
Published: April 2023

PDF file - 149K, Appendix containing detailed model description, estimates of survival by race, age and gender over time and Formulas for Calculation of Disparities and Proportion of Disparities Explained by Screening and Survival
Supplementary Table 3 from A Pooled Analysis of Alcohol Consumption and Risk of Multiple Myeloma in the International Multiple Myeloma Consortium
Authors: Andreotti Gabriella , Birmann Brenda , De Roos Anneclaire J. , Spinelli John , Cozen Wendy , Camp Nicola J. , Moysich Kirsten , Chiu Brian , Steplowski Emily , Krzystan Joseph , Boffetta Paolo , Benhaim-Luzon Véronique , Brennan Paul , de Sanjosé Silvia , Costas Laura , Costantini Adele Seniori , Miligi Lucia , Cocco Pierluigi , Becker Nikolaus , Foretová Lenka , Maynadié Marc , Nieters Alexandra , Staines Anthony , Tricot Guido , Milliken Kevin , Weisenburger Dennis , Zheng Tongzhang , Baris Dalsu , Purdue Mark P.
Published: April 2023

PDF - 64KB, Risk of Multiple Myeloma associated with beer, wine, liquor consumption in pooled study population by gender.
Data from Circadian Variation of Melatonin, Light Exposure, and Diurnal Preference in Day and Night Shift Workers of Both Sexes
Authors: Papantoniou Kyriaki , Pozo Oscar J. , Espinosa Ana , Marcos Josep , Castaño-Vinyals Gemma , Basagaña Xavier , Ribas Ferran Calduch , Mirabent Joan , Martín Jordi , Carenys Gemma , Martín Celia Reyes , Middleton Benita , Skene Debra J. , Kogevinas Manolis
Published: April 2023

Abstract
Background: Light-at-night has been shown in experimental studies to disrupt melatonin production but this has only partly been confirmed in studies of night shift workers. In this cross-sectional study, we examined the circadian variation of melatonin in relation to shift status, individual levels of light-at-night exposure, and diurnal preference, an attribute reflecting personal preference for activity in the morning or evening.

Methods: One hundred and seventeen workers (75 night and 42 day) of both sexes, ages 22 to 64 years, were recruited from four companies. Participants collected urine samples from all voids over 24 hours and wore a data logger continuously recording their light exposure. Sociodemographic, occupational, lifestyle, and diurnal preference information were collected by interview. Concentrations of urinary 6-sulfatoxymelatonin (aMT6s), the main melatonin metabolite, were measured.

Results: Mean aMT6s levels were lower in night [10.9 ng/mg creatinine/hour; 95% confidence interval (CI), 9.5–12.6] compared with day workers (15.4; 95% CI, 12.3–19.3). The lowest aMT6s levels were observed in night workers with morning preference (6.4; 95% CI, 3.0–13.6). Peak time of aMT6s production occurred 3 hours later in night (08:42 hour, 95% CI, 07:48–09:42) compared with day workers (05:36 hour, 95% CI, 05:06–06:12). Phase delay was stronger among subjects with higher light-at-night exposure and number of nights worked.

Conclusions: Night shift workers had lower levels and a delay in peak time of aMT6s production over a 24-hour period. Differences were modified by diurnal preference and intensity of light-at-night exposure.

Impact: Night shift work affects levels and timing of melatonin production and both parameters may relate to future cancer risk. Cancer Epidemiol Biomarkers Prev; 23(7); 1176–86. ©2014 AACR.