bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Pharmacokinetics and Pharmacodynamics-Based Mathematical Modeling Identifies an Optimal Protocol for Metronomic Chemotherapy
Authors: Ciccolini Joseph , Barbolosi Dominique , Meille Christophe , Lombard Aurélie , Serdjebi Cindy , Giacometti Sarah , Padovani Laetitia , Pasquier Eddy , André Nicolas
Published: March 2023

Abstract
Metronomic chemotherapy is usually associated with better tolerance than conventional chemotherapy, and encouraging response rates have been reported in various settings. However, clinical development of metronomic chemotherapy has been hampered by a number of limitations, including the vagueness of its definition and the resulting empiricism in protocol design. In this study, we developed a pharmacokinetic/pharmacodynamic mathematical model that identifies in silico the most effective administration schedule for gemcitabine monotherapy. This model is based upon four biological assumptions regarding the mechanisms of action of metronomic chemotherapy, resulting in a set of 6 minimally parameterized differential equations. Simulations identified daily 0.5–1 mg/kg gemcitabine as an optimal protocol to maximize antitumor efficacy. Both metronomic protocols (0.5 and 1 mg/kg/day for 28 days) were evaluated in chemoresistant neuroblastoma-bearing mice and compared with the standard MTD protocol (100 mg/kg once a week for 4 weeks). Systemic exposure to gemcitabine was 14 times lower in the metronomic groups compared with the standard group. Despite this, metronomic gemcitabine significantly inhibited tumor angiogenesis and reduced tumor perfusion and inflammation in vivo, while standard gemcitabine did not. Furthermore, metronomic gemcitabine yielded a 40%–50% decrease in tumor mass at the end of treatment as compared with control mice (P = 0.002; ANOVA on ranks with Dunn test), while standard gemcitabine failed to significantly reduce tumor growth. Stable disease was maintained in the metronomic groups for up to 2 months after treatment completion (67%–72% reduction in tumor growth at study conclusion, P < 0.001; ANOVA on ranks with Dunn test). Collectively, our results confirmed the superiority of metronomic protocols in chemoresistant tumors in vivo. Cancer Res; 77(17); 4723–33. ©2017 AACR.
Data from HIF-2α Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1
Authors: Vandyke Kate , Zeissig Mara N. , Hewett Duncan R. , Martin Sally K. , Mrozik Krzysztof M. , Cheong Chee Man , Diamond Peter , To L. Bik , Gronthos Stan , Peet Daniel J. , Croucher Peter I. , Zannettino Andrew C.W.
Published: March 2023

Abstract
Disease progression and relapse in multiple myeloma is dependent on the ability of the multiple myeloma plasma cells (PC) to reenter the circulation and disseminate throughout the bone marrow. Increased bone marrow hypoxia is associated with increased recirculation of multiple myeloma PCs. Accordingly, we hypothesized that during chronic hypoxia, activation of HIF-2α may overcome the bone marrow retention signal provided by stromal-derived CXCL12, thereby enabling dissemination of multiple myeloma PCs. Here we demonstrate that HIF-2α upregulates multiple myeloma PC CXCL12 expression, decreasing migration toward CXCL12 and reducing adhesion to mesenchymal stromal cells in vitro. We also found that HIF-2α strongly induced expression of the chemokine receptor CCR1 in multiple myeloma PCs. CCR1 activation potently induces multiple myeloma PC migration toward CCL3 while abrogating the multiple myeloma PC migratory response to CXCL12. In addition, increased CCR1 expression by multiple myeloma PCs conferred poor prognosis in newly diagnosed multiple myeloma patients and was associated with an increase in circulating multiple myeloma PCs in these patients. Taken together, our results suggest a role for hypoxia-mediated CCR1 upregulation in driving the egress of multiple myeloma PCs from the bone marrow. Targeting CCR1 may represent a novel strategy to prevent dissemination and overt relapse in multiple myeloma. Cancer Res; 77(20); 5452–63. ©2017 AACR.
Data from Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity
Authors: Zheng Shunsheng , Koh Xin Yu , Goh Hui Chin , Rahmat Siti Aishah B. , Hwang Le-Ann , Lane David P.
Published: March 2023

Abstract
Chemotoxicity due to unwanted p53 activation in the bone marrow remains an unmet clinical challenge. Doxorubicin, a first-line chemotherapy drug, often causes myelosuppression in patients, thus limiting its effectiveness. In this study, we discovered that C646, a reversible p300 inhibitor, downregulates p53 transcription and selectively protects noncancerous cells from p53-dependent apoptosis. C646 treatment blocked acetylation of specific lysine residues that regulate p53 activity. Exploitation of differential p53 genetic backgrounds between human hematopoietic and colorectal cancer cells improved the therapeutic index of doxorubicin with C646 cotreatment. C646 administration in mice afflicted with p53-mutant tumors protected them from doxorubicin-induced neutropenia and anemia while retaining antitumor efficacy. We deduce that temporary and reversible inhibition of p53 acetylation in cancer subjects, especially those with p53-mutant tumors, may protect them from severe chemotoxicity while allowing treatment regimens to effectively proceed. Cancer Res; 77(16); 4342–54. ©2017 AACR.
Data from STRAP Promotes Stemness of Human Colorectal Cancer via Epigenetic Regulation of the NOTCH Pathway
Authors: Jin Lin , Vu Trung , Yuan Guandou , Datta Pran K.
Published: March 2023

Abstract
NOTCH signaling exerts essential roles in normal and malignant intestinal physiology and the homeostasis of cancer stem-like cells (CSC), but the basis for this latter role remains obscure. The signaling scaffold protein STRAP is upregulated in several cancers, where it promotes tumorigenicity and metastasis. Here we report a novel oncogenic function for STRAP in maintaining CSC subpopulations in a heterogeneous mixture by antagonizing formation of the chromatin modifier PRC2 and by epigenetically activating NOTCH signals in human colorectal cancer. Silencing STRAP sensitized colorectal cancer cells to chemotherapeutic drugs in vitro and in vivo. STRAP depletion also contributed to a reduced stem-like phenotype of colorectal cancer cells, as indicated by reduced expression of the CSC signature and NOTCH signaling regulators in vitro and by diminished tumorigenesis in vivo. Genes encoding some upstream activators of NOTCH were highly enriched for H3K27me3, which forms repressive chromatin domains upon STRAP silencing. Mechanistically, STRAP competitively disrupted association of the PRC2 subunits EZH2 and SUZ12, thereby inhibiting PRC2 assembly. Restoring the NOTCH pathway by lentiviral expression of NICD1 or HES1 in STRAP-depleted tumor cells reversed the CSC phenotype. In 90 colorectal cancer clinical specimens, a significant positive correlation was documented between the expression of STRAP and HES1. Overall, our findings illuminated a novel STRAP–NOTCH1–HES1 molecular axis as a CSC regulator in colorectal cancer, with potential implications to improve treatment of this disease. Cancer Res; 77(20); 5464–78. ©2017 AACR.
Data from EGFR Mediates Responses to Small-Molecule Drugs Targeting Oncogenic Fusion Kinases
Authors: Vaishnavi Aria , Schubert Laura , Rix Uwe , Marek Lindsay A. , Le Anh T. , Keysar Stephen B. , Glogowska Magdalena J. , Smith Matthew A. , Kako Severine , Sumi Natalia J. , Davies Kurtis D. , Ware Kathryn E. , Varella-Garcia Marileila , Haura Eric B. , Jimeno Antonio , Heasley Lynn E. , Aisner Dara L. , Doebele Robert C.
Published: March 2023

Abstract
Oncogenic kinase fusions of ALK, ROS1, RET, and NTRK1 act as drivers in human lung and other cancers. Residual tumor burden following treatment of ALK or ROS1+ lung cancer patients with oncogene-targeted therapy ultimately enables the emergence of drug-resistant clones, limiting the long-term effectiveness of these therapies. To determine the signaling mechanisms underlying incomplete tumor cell killing in oncogene-addicted cancer cells, we investigated the role of EGFR signaling in drug-naïve cancer cells harboring these oncogene fusions. We defined three distinct roles for EGFR in the response to oncogene-specific therapies. First, EGF-mediated activation of EGFR blunted fusion kinase inhibitor binding and restored fusion kinase signaling complexes. Second, fusion kinase inhibition shifted adaptor protein binding from the fusion oncoprotein to EGFR. Third, EGFR enabled bypass signaling to critical downstream pathways such as MAPK. While evidence of EGFR-mediated bypass signaling has been reported after ALK and ROS1 blockade, our results extended this effect to RET and NTRK1 blockade and uncovered the other additional mechanisms in gene fusion–positive lung cancer cells, mouse models, and human clinical specimens before the onset of acquired drug resistance. Collectively, our findings show how EGFR signaling can provide a critical adaptive survival mechanism that allows cancer cells to evade oncogene-specific inhibitors, providing a rationale to cotarget EGFR to reduce the risks of developing drug resistance. Cancer Res; 77(13); 3551–63. ©2017 AACR.
Data from Nicotinic Acid Phosphoribosyltransferase Regulates Cancer Cell Metabolism, Susceptibility to NAMPT Inhibitors, and DNA Repair
Authors: Piacente Francesco , Caffa Irene , Ravera Silvia , Sociali Giovanna , Passalacqua Mario , Vellone Valerio G. , Becherini Pamela , Reverberi Daniele , Monacelli Fiammetta , Ballestrero Alberto , Odetti Patrizio , Cagnetta Antonia , Cea Michele , Nahimana Aimable , Duchosal Michel , Bruzzone Santina , Nencioni Alessio
Published: March 2023

Abstract
In the last decade, substantial efforts have been made to identify NAD+ biosynthesis inhibitors, specifically against nicotinamide phosphoribosyltransferase (NAMPT), as preclinical studies indicate their potential efficacy as cancer drugs. However, the clinical activity of NAMPT inhibitors has proven limited, suggesting that alternative NAD+ production routes exploited by tumors confer resistance. Here, we show the gene encoding nicotinic acid phosphoribosyltransferase (NAPRT), a second NAD+-producing enzyme, is amplified and overexpressed in a subset of common types of cancer, including ovarian cancer, where NAPRT expression correlates with a BRCAness gene expression signature. Both NAPRT and NAMPT increased intracellular NAD+ levels. NAPRT silencing reduced energy status, protein synthesis, and cell size in ovarian and pancreatic cancer cells. NAPRT silencing sensitized cells to NAMPT inhibitors both in vitro and in vivo; similar results were obtained with the NAPRT inhibitor 2-hydroxynicotinic acid. Reducing NAPRT levels in a BRCA2-deficient cancer cell line exacerbated DNA damage in response to chemotherapeutics. In conclusion, NAPRT-dependent NAD+ biosynthesis contributes to cell metabolism and to the DNA repair process in a subset of tumors. This knowledge could be used to increase the efficacy of NAMPT inhibitors and chemotherapy. Cancer Res; 77(14); 3857–69. ©2017 AACR.
Data from Transglutaminase 2 Inhibition Reverses Mesenchymal Transdifferentiation of Glioma Stem Cells by Regulating C/EBPβ Signaling
Authors: Yin Jinlong , Oh Young Taek , Kim Jeong-Yub , Kim Sung Soo , Choi Eunji , Kim Tae Hoon , Hong Jun Hee , Chang Nakho , Cho Hee Jin , Sa Jason K. , Kim Jeong Cheol , Kwon Hyung Joon , Park Saewhan , Lin Weiwei , Nakano Ichiro , Gwak Ho-Shin , Yoo Heon , Lee Seung-Hoon , Lee Jeongwu , Kim Jong Heon , Kim Soo-Youl , Nam Do-Hyun , Park Myung-Jin , Park Jong Bae
Published: March 2023

Abstract
Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPβ, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NF-κB activation and further degraded DNA damage–inducible transcript 3 (GADD153) to induce C/EBPβ expression, resulting in expression of the MES transcriptome. Downregulation of TGM2 decreased sphere-forming ability, tumor size, and radioresistance and survival in a xenograft mouse model through a loss of the MES signature. A TGM2-specific inhibitor GK921 blocked MES transdifferentiation and showed significant therapeutic efficacy in mouse models of GSC. Moreover, TGM2 expression was significantly increased in recurrent MES patients and inversely correlated with patient prognosis. Collectively, our results indicate that TGM2 is a key molecular switch of necrosis-induced MES transdifferentiation and an important therapeutic target for MES GBM. Cancer Res; 77(18); 4973–84. ©2017 AACR.
Data from Plk4 Promotes Cancer Invasion and Metastasis through Arp2/3 Complex Regulation of the Actin Cytoskeleton
Authors: Kazazian Karineh , Go Christopher , Wu Hannah , Brashavitskaya Olga , Xu Roland , Dennis James W. , Gingras Anne-Claude , Swallow Carol J.
Published: March 2023

Abstract
The polo family serine threonine kinase Plk4 has been proposed as a therapeutic target in advanced cancers based on increased expression in primary human cancers, facilitation of tumor growth in murine xenograft models, and centrosomal amplification induced by its overexpression. However, both the causal link between these phenomena and the feasibility of selective Plk4 inhibition remain unclear. Here we characterize Plk4-dependent cancer cell migration and invasion as well as local invasion and metastasis of cancer xenografts. Plk4 depletion suppressed cancer invasion and induced an epithelial phenotype in poorly differentiated breast cancer cells. In an unbiased BioID screen for Plk4 interactors, we identified members of the Arp2/3 complex and confirmed a physical and functional interaction between Plk4 and Arp2 in mediating Plk4-driven cancer cell movement. This interaction is mediated through the Plk4 Polo-box 1-Polo-box 2 domain and results in phosphorylation of Arp2 at the T237/T238 activation site, which is required for Plk4-driven cell movement. Our results validate Plk4 as a therapeutic target in cancer patients and reveal a new role for Plk4 in regulating Arp2/3-mediated actin cytoskeletal rearrangement. Cancer Res; 77(2); 434–47. ©2016 AACR.
Data from Cellular Model of Colon Cancer Progression Reveals Signatures of mRNAs, miRNA, lncRNAs, and Epigenetic Modifications Associated with Metastasis
Authors: Rokavec Matjaz , Horst David , Hermeking Heiko
Published: March 2023

Abstract
Here, we developed and comprehensively characterized a cellular model of colon cancer progression consisting of four defined derivatives of a colon cancer cell line that resulted from consecutive epithelial–mesenchymal and mesenchymal–epithelial transitions (EMT/MET) and phenotypically recapitulate the metastatic cascade. Initial EMT was induced by prolonged exposure to IL6, a cytokine also generated by the tumor-stroma. Genome-wide characterization of transcriptional (mRNA, miRNA, and lncRNA) and epigenetic (DNA methylation, H3K4me3, H3K79me3, and H3K27me3 histone modifications) profiles of the cell derivatives, combined with correlative analyses of expression, methylation, and clinical data from the TCGA-COAD database gave insights into the molecular basis of their phenotypic changes. The signatures characterizing invasive, mesenchymal-like cell states as well as the metastases-derived epithelial-like state showed significant association with metastasis, positive nodal status, and poor survival of colon cancer patients. Global hypomethylation of gene-regulatory regions was observed during tumor progression, with the lowest degree of methylation present in cells isolated from metastases. Upregulation of an axon-guidance–related gene signature was the most significant feature of metastatic tumor cells and was also found in primary tumors from colon cancer patients with distant metastases. Furthermore, the microRNAs miR-99a, miR-100, and miR-125b showed elevated expression in mesenchymal-like cells, associated with poor survival, and promoted migration and invasion. Finally, elevated expression of H19 lncRNA due to promoter demethylation was observed in cells isolated from metastases and was associated with poor survival of colon cancer patients. In the future, our results may be further exploited for the discovery and evaluation of novel metastasis-associated mechanisms and biomarkers. Cancer Res; 77(8); 1854–67. ©2017 AACR.
Data from MALT1 Inhibition Is Efficacious in Both Naïve and Ibrutinib-Resistant Chronic Lymphocytic Leukemia
Authors: Saba Nakhle S. , Wong Deanna H. , Tanios Georges , Iyer Jessica R. , Lobelle-Rich Patricia , Dadashian Eman L. , Liu Delong , Fontan Lorena , Flemington Erik K. , Nichols Cydney M. , Underbayev Chingiz , Safah Hana , Melnick Ari , Wiestner Adrian , Herman Sarah E. M.
Published: March 2023

Abstract
The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B-cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2, a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway–dependent lymphoma. We therefore studied the activity of MI-2 against CLL and ibrutinib-resistant CLL. Treatment of CLL cells in vitro with MI-2 inhibited MALT1 proteolytic activity reduced BCR and NF-κB signaling, inhibited nuclear translocation of RelB and p50, and decreased Bcl-xL levels. MI-2 selectively induced dose and time-dependent apoptosis in CLL cells, sparing normal B lymphocytes. Furthermore, MI-2 abrogated survival signals provided by stromal cells and BCR cross-linking and was effective against CLL cells harboring features associated with poor outcomes, including 17p deletion and unmutated IGHV. Notably, MI-2 was effective against CLL cells collected from patients harboring mutations conferring resistance to ibrutinib. Overall, our findings provide a preclinical rationale for the clinical development of MALT1 inhibitors in CLL, in particular for ibrutinib-resistant forms of this disease. Cancer Res; 77(24); 7038–48. ©2017 AACR.
Data from A Transposon-based Analysis Reveals RASA1 Is Involved in Triple-Negative Breast Cancer
Authors: Suárez-Cabrera Cristian , Quintana Rita M. , Bravo Ana , Casanova M. Llanos , Page Angustias , Alameda Josefa P. , Paramio Jesús M. , Maroto Alicia , Salamanca Javier , Dupuy Adam J. , Ramírez Angel , Navarro Manuel
Published: March 2023

Abstract
RAS genes are mutated in 20% of human tumors, but these mutations are very rare in breast cancer. Here, we used a mouse model to generate tumors upon activation of a mutagenic T2Onc2 transposon via expression of a transposase driven by the keratin K5 promoter in a p53+/− background. These animals mainly developed mammary tumors, most of which had transposon insertions in one of two RASGAP genes, neurofibromin1 (Nf1) and RAS p21 protein activator (Rasa1). Immunohistochemical analysis of a collection of human breast tumors confirmed that low expression of RASA1 is frequent in basal (triple-negative) and estrogen receptor negative tumors. Bioinformatic analysis of human breast tumors in The Cancer Genome Atlas database showed that although RASA1 mutations are rare, allelic loss is frequent, particularly in basal tumors (80%) and in association with TP53 mutation. Inactivation of RASA1 in MCF10A cells resulted in the appearance of a malignant phenotype in the context of mutated p53. Our results suggest that alterations in the Ras pathway due to the loss of negative regulators of RAS may be a common event in basal breast cancer. Cancer Res; 77(6); 1357–68. ©2017 AACR.
Data from The Blebbishield Emergency Program Overrides Chromosomal Instability and Phagocytosis Checkpoints in Cancer Stem Cells
Authors: Jinesh Goodwin G. , Kamat Ashish M.
Published: March 2023

Abstract
Genomic instability and immune evasion are hallmarks of cancer. Apoptotic cancer stem cells can evade cell death by undergoing cellular transformation by constructing “blebbishields” from apoptotic bodies. In this study, we report a novel linkage between genomic instability and phagocytosis evasion that is coordinated by the blebbishield emergency program. Blebbishield emergency program evaded genomic instability checkpoint, expressed genomic instability–associated genes at distinct phases of cellular transformation, exhibited chromosomal instability, and promoted increase in nuclear size. Blebbishields fused with immune cells to evade phagocytosis, and the resultant hybrid cells exhibited increased migration, tumorigenesis, metastasis, red blood cell recruitment to tumors, and induced hepatosplenomegaly with signatures of genomic instability, blebbishield emergency program, and phagocytosis evasion to offer poor prognosis. Overall, our data demonstrate that the blebbishield emergency program drives evasion of chromosomal instability and phagocytosis checkpoints by apoptotic cancer stem cells. Cancer Res; 77(22); 6144–56. ©2017 AACR.
Data from CTLA4 Promotes Tyk2-STAT3–Dependent B-cell Oncogenicity
Authors: Herrmann Andreas , Lahtz Christoph , Nagao Toshikage , Song Joo Y. , Chan Wing C. , Lee Heehyoung , Yue Chanyu , Look Thomas , Mülfarth Ronja , Li Wenzhao , Jenkins Kurt , Williams John , Budde Lihua E. , Forman Stephen , Kwak Larry , Blankenstein Thomas , Yu Hua
Published: March 2023

Abstract
CTL–associated antigen 4 (CTLA4) is a well-established immune checkpoint for antitumor immune responses. The protumorigenic function of CTLA4 is believed to be limited to T-cell inhibition by countering the activity of the T-cell costimulating receptor CD28. However, as we demonstrate here, there are two additional roles for CTLA4 in cancer, including via CTLA4 overexpression in diverse B-cell lymphomas and in melanoma-associated B cells. CTLA4-CD86 ligation recruited and activated the JAK family member Tyk2, resulting in STAT3 activation and expression of genes critical for cancer immunosuppression and tumor growth and survival. CTLA4 activation resulted in lymphoma cell proliferation and tumor growth, whereas silencing or antibody-blockade of CTLA4 in B-cell lymphoma tumor cells in the absence of T cells inhibits tumor growth. This inhibition was accompanied by reduction of Tyk2/STAT3 activity, tumor cell proliferation, and induction of tumor cell apoptosis. The CTLA4–Tyk2–STAT3 signal pathway was also active in tumor-associated nonmalignant B cells in mouse models of melanoma and lymphoma. Overall, our results show how CTLA4-induced immune suppression occurs primarily via an intrinsic STAT3 pathway and that CTLA4 is critical for B-cell lymphoma proliferation and survival. Cancer Res; 77(18); 5118–28. ©2017 AACR.
Data from Broad and Conserved Immune Regulation by Genetically Heterogeneous Melanoma Cells
Authors: Neubert Natalie J. , Tillé Laure , Barras David , Soneson Charlotte , Baumgaertner Petra , Rimoldi Donata , Gfeller David , Delorenzi Mauro , Fuertes Marraco Silvia A. , Speiser Daniel E.
Published: March 2023

Abstract
Although mutations drive cancer, it is less clear to what extent genetic defects control immune mechanisms and confer resistance to T-cell-based immunotherapy. Here, we studied the reactions of malignant and benign melanocyte lines to cytotoxic CD8+ T cells (CTL) using flow cytometry and gene expression analyses. We found rapid and broad upregulation of immune-regulatory genes, essentially triggered by CTL-derived IFNγ and augmented by TNFα. These reactions were predominantly homogenous, independent of oncogenic driver mutations, and similar in benign and malignant cells. The reactions exhibited both pro- and antitumorigenic potential and primarily corresponded to mechanisms that were conserved, rather than acquired, by mutations. Similar results were obtained from direct ex vivo analysis of the tumor microenvironment. Thus, immune regulation in the tumor landscape may often be driven by conserved mechanisms, which may explain why T-cell–based immunotherapy can provide durable benefits with relatively infrequent escape. Cancer Res; 77(7); 1623–36. ©2017 AACR.
Data from Tumorigenic and Antiproliferative Properties of the TALE-Transcription Factors MEIS2D and MEIS2A in Neuroblastoma
Authors: Groß Anja , Schulz Catrine , Kolb Jasmine , Koster Jan , Wehner Sibylle , Czaplinski Sebastian , Khilan Abdulghani , Rohrer Hermann , Harter Patrick N. , Klingebiel Thomas , Langer Julian D. , Geerts Dirk , Schulte Dorothea
Published: March 2023

Abstract
Neuroblastoma is one of only a few human cancers that can spontaneously regress even after extensive dissemination, a poorly understood phenomenon that occurs in as many as 10% of patients. In this study, we identify the TALE-homeodomain transcription factor MEIS2 as a key contributor to this phenomenon. We identified MEIS2 as a MYCN-independent factor in neuroblastoma and showed that in this setting the alternatively spliced isoforms MEIS2A and MEIS2D exert antagonistic functions. Specifically, expression of MEIS2A was low in aggressive stage 4 neuroblastoma but high in spontaneously regressing stage 4S neuroblastoma. Moderate elevation of MEIS2A expression reduced proliferation of MYCN-amplified human neuroblastoma cells, induced neuronal differentiation and impaired the ability of these cells to form tumors in mice. In contrast, MEIS2A silencing or MEIS2D upregulation enhanced the aggressiveness of the tumor phenotype. Mechanistically, MEIS2A uncoupled a negative feedback loop that restricts accumulation of cellular retinoic acid, an effective agent in neuroblastoma treatment. Overall, our results illuminate the basis for spontaneous regression in neuroblastoma and identify an MEIS2A-specific signaling network as a potential therapeutic target in this common pediatric malignancy.

Significance: This study illuminates the basis for spontaneous regressions that can occur in a common pediatric tumor, with implications for the development of new treatment strategies. Cancer Res; 78(8); 1935–47. ©2018 AACR.
Data from Cistrome Cancer: A Web Resource for Integrative Gene Regulation Modeling in Cancer
Authors: Mei Shenglin , Meyer Clifford A. , Zheng Rongbin , Qin Qian , Wu Qiu , Jiang Peng , Li Bo , Shi Xiaohui , Wang Binbin , Fan Jingyu , Shih Celina , Brown Myles , Zang Chongzhi , Liu X. Shirley
Published: March 2023

Abstract
Cancer results from a breakdown of normal gene expression control, so the study of gene regulation is critical to cancer research. To gain insight into the transcriptional and epigenetic factors regulating abnormal gene expression patterns in cancers, we developed the Cistrome Cancer web resource (http://cistrome.org/CistromeCancer/). We conducted the systematic integration and modeling of over 10,000 tumor molecular profiles from The Cancer Genome Atlas (TCGA) with over 23,000 ChIP-seq and chromatin accessibility profiles from our Cistrome collection. The results include reconstruction of functional enhancer profiles, “super-enhancer” target genes, as well as predictions of active transcription factors and their target genes for each TCGA cancer type. Cistrome Cancer reveals novel insights from integrative analyses combining chromatin profiles with tumor molecular profiles and will be a useful resource to the cancer gene regulation community. Cancer Res; 77(21); e19–22. ©2017 AACR.
Data from Transplantation of iPS-Derived Tumor Cells with a Homozygous MHC Haplotype Induces GRP94 Antibody Production in MHC-Matched Macaques
Authors: Ishigaki Hirohito , Maeda Toshinaga , Inoue Hirokazu , Akagi Tsuyoshi , Sasamura Takako , Ishida Hideaki , Inubushi Toshiro , Okahara Junko , Shiina Takashi , Nakayama Misako , Itoh Yasushi , Ogasawara Kazumasa
Published: March 2023

Abstract
Immune surveillance is a critical component of the antitumor response in vivo, yet the specific components of the immune system involved in this regulatory response remain unclear. In this study, we demonstrate that autoantibodies can mitigate tumor growth in vitro and in vivo. We generated two cancer cell lines, embryonal carcinoma and glioblastoma cell lines, from monkey-induced pluripotent stem cells (iPSC) carrying a homozygous haplotype of major histocompatibility complex (MHC, Mafa in Macaca fascicularis). To establish a monkey cancer model, we transplanted these cells into monkeys carrying the matched Mafa haplotype in one of the chromosomes. Neither Mafa-homozygous cancer cell line grew in monkeys carrying the matched Mafa haplotype heterozygously. We detected in the plasma of these monkeys an IgG autoantibody against GRP94, a heat shock protein. Injection of the plasma prevented growth of the tumor cells in immunodeficient mice, whereas plasma IgG depleted of GRP94 IgG exhibited reduced killing activity against cancer cells in vitro. These results indicate that humoral immunity, including autoantibodies against GRP94, plays a role in cancer immune surveillance. Cancer Res; 77(21); 6001–10. ©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 2023

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 PDX-MI: Minimal Information for Patient-Derived Tumor Xenograft Models
Authors: Meehan Terrence F. , Conte Nathalie , Goldstein Theodore , Inghirami Giorgio , Murakami Mark A. , Brabetz Sebastian , Gu Zhiping , Wiser Jeffrey A. , Dunn Patrick , Begley Dale A. , Krupke Debra M. , Bertotti Andrea , Bruna Alejandra , Brush Matthew H. , Byrne Annette T. , Caldas Carlos , Christie Amanda L. , Clark Dominic A. , Dowst Heidi , Dry Jonathan R. , Doroshow James H. , Duchamp Olivier , Evrard Yvonne A. , Ferretti Stephane , Frese Kristopher K. , Goodwin Neal C. , Greenawalt Danielle , Haendel Melissa A. , Hermans Els , Houghton Peter J. , Jonkers Jos , Kemper Kristel , Khor Tin O. , Lewis Michael T. , Lloyd K.C. Kent , Mason Jeremy , Medico Enzo , Neuhauser Steven B. , Olson James M. , Peeper Daniel S. , Rueda Oscar M. , Seong Je Kyung , Trusolino Livio , Vinolo Emilie , Wechsler-Reya Robert J. , Weinstock David M. , Welm Alana , Weroha S. John , Amant Frédéric , Pfister Stefan M. , Kool Marcel , Parkinson Helen , Butte Atul J. , Bult Carol J.
Published: March 2023

Abstract
Patient-derived tumor xenograft (PDX) mouse models have emerged as an important oncology research platform to study tumor evolution, mechanisms of drug response and resistance, and tailoring chemotherapeutic approaches for individual patients. The lack of robust standards for reporting on PDX models has hampered the ability of researchers to find relevant PDX models and associated data. Here we present the PDX models minimal information standard (PDX-MI) for reporting on the generation, quality assurance, and use of PDX models. PDX-MI defines the minimal information for describing the clinical attributes of a patient's tumor, the processes of implantation and passaging of tumors in a host mouse strain, quality assurance methods, and the use of PDX models in cancer research. Adherence to PDX-MI standards will facilitate accurate search results for oncology models and their associated data across distributed repository databases and promote reproducibility in research studies using these models. Cancer Res; 77(21); e62–66. ©2017 AACR.
Data from Actin Cytoskeleton Remodeling Drives Breast Cancer Cell Escape from Natural Killer–Mediated Cytotoxicity
Authors: Al Absi Antoun , Wurzer Hannah , Guerin Coralie , Hoffmann Celine , Moreau Flora , Mao Xianqing , Brown-Clay Joshua , Petrolli Rémi , Casellas Carla Pou , Dieterle Monika , Thiery Jean-Paul , Chouaib Salem , Berchem Guy , Janji Bassam , Thomas Clément
Published: March 2023

Abstract
Elucidation of the underlying molecular mechanisms of immune evasion in cancer is critical for the development of immunotherapies aimed to restore and stimulate effective antitumor immunity. Here, we evaluate the role of the actin cytoskeleton in breast cancer cell resistance to cytotoxic natural killer (NK) cells. A significant fraction of breast cancer cells responded to NK-cell attack via a surprisingly rapid and massive accumulation of F-actin near the immunologic synapse, a process we termed “actin response.” Live-cell imaging provided direct evidence that the actin response is associated with tumor cell resistance to NK-cell–mediated cell death. High-throughput imaging flow cytometry analyses showed that breast cancer cell lines highly resistant to NK cells were significantly enriched in actin response-competent cells as compared with susceptible cell lines. The actin response was not associated with a defect in NK-cell activation but correlated with reduced intracellular levels of the cytotoxic protease granzyme B and a lower rate of apoptosis in target cells. Inhibition of the actin response by knocking down CDC42 or N-WASP led to a significant increase in granzyme B levels in target cells and was sufficient to convert resistant breast cancer cell lines into a highly susceptible phenotype. The actin response and its protective effects were fully recapitulated using donor-derived primary NK cells as effector cells. Together, these findings establish the pivotal role of actin remodeling in breast cancer cell resistance to NK-cell–mediated killing.

Significance: These findings establish the pivotal role of the actin cytoskeleton in driving breast cancer cell resistance to natural killer cells, a subset of cytotoxic lymphocytes with important roles in innate antitumor immunity. Cancer Res; 78(19); 5631–43. ©2018 AACR.
Data from HORMAD1 Is a Negative Prognostic Indicator in Lung Adenocarcinoma and Specifies Resistance to Oxidative and Genotoxic Stress
Authors: Nichols Brandt A. , Oswald Nathaniel W. , McMillan Elizabeth A. , McGlynn Kathleen , Yan Jingsheng , Kim Min S. , Saha Janapriya , Mallipeddi Prema L. , LaDuke Sydnie A. , Villalobos Pamela A. , Rodriguez-Canales Jaime , Wistuba Ignacio I. , Posner Bruce A. , Davis Anthony J. , Minna John D. , MacMillan John B. , Whitehurst Angelique W.
Published: March 2023

Abstract
Cancer testis antigens (CTA) are expressed in testis and placenta and anomalously activated in a variety of tumors. The mechanistic contribution of CTAs to neoplastic phenotypes remains largely unknown. Using a chemigenomics approach, we find that the CTA HORMAD1 correlates with resistance to the mitochondrial complex I inhibitor piericidin A in non–small cell lung cancer (NSCLC). Resistance was due to a reductive intracellular environment that attenuated the accumulation of free radicals. In human lung adenocarcinoma (LUAD) tumors, patients expressing high HORMAD1 exhibited elevated mutational burden and reduced survival. HORMAD1 tumors were enriched for genes essential for homologous recombination (HR), and HORMAD1 promoted RAD51-filament formation, but not DNA resection, during HR. Accordingly, HORMAD1 loss enhanced sensitivity to γ-irradiation and PARP inhibition, and HORMAD1 depletion significantly reduced tumor growth in vivo. These results suggest that HORMAD1 expression specifies a novel subtype of LUAD, which has adapted to mitigate DNA damage. In this setting, HORMAD1 could represent a direct target for intervention to enhance sensitivity to DNA-damaging agents or as an immunotherapeutic target in patients.

Significance: This study uses a chemigenomics approach to demonstrate that anomalous expression of the CTA HORMAD1 specifies resistance to oxidative stress and promotes HR to support tumor cell survival in NSCLC. Cancer Res; 78(21); 6196–208. ©2018 AACR.
Data from TRPM2 Mediates Neutrophil Killing of Disseminated Tumor Cells
Authors: Gershkovitz Maya , Caspi Yaki , Fainsod-Levi Tanya , Katz Ben , Michaeli Janna , Khawaled Saleh , Lev Shaya , Polyansky Lola , Shaul Merav E. , Sionov Ronit V. , Cohen-Daniel Leonor , Aqeilan Rami I. , Shaul Yoav D. , Mori Yasuo , Karni Rotem , Fridlender Zvi G. , Binshtok Alexander M. , Granot Zvi
Published: March 2023

Abstract
Neutrophils play a critical role in cancer, with both protumor and antitumor neutrophil subpopulations reported. The antitumor neutrophil subpopulation has the capacity to kill tumor cells and limit metastatic spread, yet not all tumor cells are equally susceptible to neutrophil cytotoxicity. Because cells that evade neutrophils have greater chances of forming metastases, we explored the mechanism neutrophils use to kill tumor cells. Neutrophil cytotoxicity was previously shown to be mediated by secretion of H2O2. We report here that neutrophil cytotoxicity is Ca2+ dependent and is mediated by TRPM2, a ubiquitously expressed H2O2-dependent Ca2+ channel. Perturbing TRPM2 expression limited tumor cell proliferation, leading to attenuated tumor growth. Concomitantly, cells expressing reduced levels of TRPM2 were protected from neutrophil cytotoxicity and seeded more efficiently in the premetastatic lung.

Significance: These findings identify the mechanism utilized by neutrophils to kill disseminated tumor cells and to limit metastatic spread. Cancer Res; 78(10); 2680–90. ©2018 AACR.
Data from Therapeutic Targeting of Sunitinib-Induced AR Phosphorylation in Renal Cell Carcinoma
Authors: Adelaiye-Ogala Remi , Damayanti Nur P. , Orillion Ashley R. , Arisa Sreevani , Chintala Sreenivasulu , Titus Mark A. , Kao Chinghai , Pili Roberto
Published: March 2023

Abstract
Androgen receptor (AR) plays a crucial role in the development and progression of prostate cancer. AR expression has also been reported in other solid tumors, including renal cell carcinoma (RCC), but its biological role here remains unclear. Through integrative analysis of a reverse phase protein array, we discovered increased expression of AR in an RCC patient–derived xenograft model of acquired resistance to the receptor tyrosine kinase inhibitor (RTKi) sunitinib. AR expression was increased in RCC cell lines with either acquired or intrinsic sunitinib resistance in vitro. An AR signaling gene array profiler indicated elevated levels of AR target genes in sunitinib-resistant cells. Sunitinib-induced AR transcriptional activity was associated with increased phosphorylation of serine 81 (pS81) on AR. Additionally, AR overexpression resulted in acquired sunitinib resistance and the AR antagonist enzalutamide-induced AR degradation and attenuated AR downstream activity in sunitinib-resistant cells, also indicated by decreased secretion of human kallikrein 2. Enzalutamide-induced AR degradation was rescued by either proteasome inhibition or by knockdown of the AR ubiquitin ligase speckle-type POZ protein (SPOP). In vivo treatment with enzalutamide and sunitinib demonstrated that this combination efficiently induced tumor regression in a RCC model following acquired sunitinib resistance. Overall, our results suggest the potential role of AR as a target for therapeutic interventions, in combination with RTKi, to overcome drug resistance in RCC.

Significance: These findings highlight the therapeutic potential of targeting the androgen receptor to overcome RCC resistance to receptor tyrosine kinase inhibitors. Cancer Res; 78(11); 2886–96. ©2018 AACR.
Data from Tobacco Carcinogen–Induced Production of GM-CSF Activates CREB to Promote Pancreatic Cancer
Authors: Srinivasan Supriya , Totiger Tulasigeri , Shi Chanjuan , Castellanos Jason , Lamichhane Purushottam , Dosch Austin R. , Messaggio Fanuel , Kashikar Nilesh , Honnenahally Kumaraswamy , Ban Yuguang , Merchant Nipun B. , VanSaun Michael , Nagathihalli Nagaraj S.
Published: March 2023

Abstract
Although smoking is a significant risk factor for pancreatic ductal adenocarcinoma (PDAC), the molecular mechanisms underlying PDAC development and progression in smokers are still unclear. Here, we show the role of cyclic AMP response element-binding protein (CREB) in the pathogenesis of smoking-induced PDAC. Smokers had significantly higher levels of activated CREB when compared with nonsmokers. Cell lines derived from normal pancreas and pancreatic intraepithelial neoplasm (PanIN) exhibited low baseline pCREB levels compared with PDAC cell lines. Furthermore, elevated CREB expression correlated with reduced survival in patients with PDAC. Depletion of CREB significantly reduced tumor burden after tobacco-specific nitrosamine 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) treatment, suggesting a CREB-dependent contribution to PDAC growth and progression in smokers. Conversely, NNK accelerated PanIN lesion and PDAC formation via GM-CSF–mediated activation of CREB in a PDAC mouse model. CREB inhibition (CREBi) in mice more effectively reduced primary tumor burden compared with control or GM-CSF blockade alone following NNK exposure. GM-CSF played a role in the recruitment of tumor-associated macrophages (TAM) and regulatory T cell (Treg) expansion and promotion, whereas CREBi significantly reduced TAM and Treg populations in NNK-exposed mice. Overall, these results suggest that NNK exposure leads to activation of CREB through GM-CSF, promoting inflammatory and Akt pathways. Direct inhibition of CREB, but not GM-CSF, effectively abrogates these effects and inhibits tumor progression, offering a viable therapeutic strategy for patients with PDAC.

Significance: These findings identify GM-CSF-induced CREB as a driver of pancreatic cancer in smokers and demonstrate the therapeutic potential of targeting CREB to reduce PDAC tumor growth.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/21/6146/F1.large.jpg. Cancer Res; 78(21); 6146–58. ©2018 AACR.
Data from Long Noncoding RNA MIR17HG Promotes Colorectal Cancer Progression via miR-17-5p
Authors: Xu Jie , Meng Qingtao , Li Xiaobo , Yang Hongbao , Xu Jin , Gao Na , Sun Hao , Wu Shenshen , Familiari Giuseppe , Relucenti Michela , Zhu Haitao , Wu Jiong , Chen Rui
Published: March 2023

Abstract
Immune dysregulation plays a vital role in colorectal cancer initiation and progression. Long noncoding RNAs (lncRNA) exhibit multiple functions including regulation of gene expression. Here, we identified an immune-related lncRNA, MIR17HG, whose expression was gradually upregulated in adjacent, adenoma, and colorectal cancer tissue. MIR17HG promoted tumorigenesis and metastasis in colorectal cancer cells both in vitro and in vivo. Mechanistically, MIR17HG increased the expression of NF-κB/RELA by competitively sponging the microRNA miR-375. In addition, RELA transcriptionally activated MIR17HG in a positive feedback loop by directly binding to its promoter region. Moreover, miR-17-5p, one of the transcribed miRNAs from MIR17HG, reduced the expression of the tumor suppressor B-cell linker (BLNK), resulting in increased migration and invasion of colorectal cancer cells. MIR17HG also upregulated PD-L1, indicating its potential role in immunotherapy. Overall, these findings demonstrate that MIR17HG plays an oncogenic role in colorectal cancer and may serve as a promising therapeutic target.
Significance:
These findings provide mechanistic insight into the role of the lncRNA MIR17HG and its miRNA members in regulating colorectal cancer carcinogenesis and progression.
Data from MRI Imaging of the Hemodynamic Vasculature of Neuroblastoma Predicts Response to Antiangiogenic Treatment
Authors: Zormpas-Petridis Konstantinos , Jerome Neil P. , Blackledge Matthew D. , Carceller Fernando , Poon Evon , Clarke Matthew , McErlean Ciara M. , Barone Giuseppe , Koers Alexander , Vaidya Sucheta J. , Marshall Lynley V. , Pearson Andrew D.J. , Moreno Lucas , Anderson John , Sebire Neil , McHugh Kieran , Koh Dow-Mu , Yuan Yinyin , Chesler Louis , Robinson Simon P. , Jamin Yann
Published: March 2023

Abstract
Childhood neuroblastoma is a hypervascular tumor of neural origin, for which antiangiogenic drugs are currently being evaluated; however, predictive biomarkers of treatment response, crucial for successful delivery of precision therapeutics, are lacking. We describe an MRI-pathologic cross-correlative approach using intrinsic susceptibility (IS) and susceptibility contrast (SC) MRI to noninvasively map the vascular phenotype in neuroblastoma Th-MYCN transgenic mice treated with the vascular endothelial growth factor receptor inhibitor cediranib. We showed that the transverse MRI relaxation rate R2* (second−1) and fractional blood volume (fBV, %) were sensitive imaging biomarkers of hemorrhage and vascular density, respectively, and were also predictive biomarkers of response to cediranib. Comparison with MRI and pathology from patients with MYCN-amplified neuroblastoma confirmed the high degree to which the Th-MYCN model vascular phenotype recapitulated that of the clinical phenotype, thereby supporting further evaluation of IS- and SC-MRI in the clinic. This study reinforces the potential role of functional MRI in delivering precision medicine to children with neuroblastoma.
Significance:
This study shows that functional MRI predicts response to vascular-targeted therapy in a genetically engineered murine model of neuroblastoma.
Data from Src-Dependent DBL Family Members Drive Resistance to Vemurafenib in Human Melanoma
Authors: Feddersen Charlotte R. , Schillo Jacob L. , Varzavand Afshin , Vaughn Hayley R. , Wadsworth Lexy S. , Voigt Andrew P. , Zhu Eliot Y. , Jennings Brooke M. , Mullen Sarah A. , Bobera Jeremy , Riordan Jesse D. , Stipp Christopher S. , Dupuy Adam J.
Published: March 2023

Abstract
The use of selective BRAF inhibitors (BRAFi) has produced remarkable outcomes for patients with advanced cutaneous melanoma harboring a BRAFV600E mutation. Unfortunately, the majority of patients eventually develop drug-resistant disease. We employed a genetic screening approach to identify gain-of-function mechanisms of BRAFi resistance in two independent melanoma cell lines. Our screens identified both known and unappreciated drivers of BRAFi resistance, including multiple members of the DBL family. Mechanistic studies identified a DBL/RAC1/PAK signaling axis capable of driving resistance to both current and next-generation BRAFis. However, we show that the SRC inhibitor, saracatinib, can block the DBL-driven resistance. Our work highlights the utility of our straightforward genetic screening method in identifying new drug combinations to combat acquired BRAFi resistance.
Significance:
A simple, rapid, and flexible genetic screening approach identifies genes that drive resistance to MAPK inhibitors when overexpressed in human melanoma cells.