bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Cyclin E Associates with the Lipogenic Enzyme ATP-Citrate Lyase to Enable Malignant Growth of Breast Cancer Cells
Authors: Lucenay Kimberly S. , Doostan Iman , Karakas Cansu , Bui Tuyen , Ding Zhiyong , Mills Gordon B. , Hunt Kelly K. , Keyomarsi Khandan
Published: March 2023

Abstract
Cyclin E is altered in nearly a third of invasive breast cancers where it is a powerful independent predictor of survival in women with stage I–III disease. Full-length cyclin E is posttranslationally cleaved into low molecular weight (LMW-E) isoforms, which are tumor-specific and accumulate in the cytoplasm because they lack a nuclear localization sequence. We hypothesized that aberrant localization of cytosolic LMW-E isoforms alters target binding and activation ultimately contributing to LMW-E–induced tumorigenicity. To address this hypothesis, we used a retrovirus-based protein complementation assay to find LMW-E binding proteins in breast cancer, identifying ATP-citrate lyase (ACLY), an enzyme in the de novo lipogenesis pathway, as a novel LMW-E–interacting protein in the cytoplasm. LMW-E upregulated ACLY enzymatic activity, subsequently increasing lipid droplet formation, thereby providing cells with essential building blocks to support growth. ACLY was also required for LMW-E–mediated transformation, migration, and invasion of breast cancer cells in vitro along with tumor growth in vivo. In clinical specimens of breast cancer, the absence of LMW-E and low expression of adipophilin (PLIN2), a marker of lipid droplet formation, associated with favorable prognosis, whereas overexpression of both proteins correlated with a markedly worse prognosis. Taken together, our findings establish a novel relationship between LMW-E isoforms of cyclin E and aberrant lipid metabolism pathways in breast cancer tumorigenesis, warranting further investigation in additional malignancies exhibiting their expression. Cancer Res; 76(8); 2406–18. ©2016 AACR.
Data from CCR2 Influences T Regulatory Cell Migration to Tumors and Serves as a Biomarker of Cyclophosphamide Sensitivity
Authors: Loyher Pierre-Louis , Rochefort Juliette , Baudesson de Chanville Camille , Hamon Pauline , Lescaille Géraldine , Bertolus Chloé , Guillot-Delost Maude , Krummel Matthew F. , Lemoine François M. , Combadière Christophe , Boissonnas Alexandre
Published: March 2023

Abstract
The CCL2 chemokine receptor CCR2 drives cancer by mediating the recruitment of monocytes and myeloid-derived suppressor cells to the tumor microenvironment. In this study, we extend the significance of CCR2 in this setting by identifying a new role for it in mediating recruitment of CD4+ T regulatory cells (Treg). Following tumor initiation, an expanded population of CCR2+ Tregs required CCR2 expression to traffic between draining lymph nodes (dLN) and the tumor. This Treg subset was enriched in the fraction of tumor antigen–specific cells in the dLN, where they displayed an activated immunosuppressive phenotype. Notably, in mouse models, low-dose cyclophosphamide treatment preferentially depleted CCR2+ Treg, enhancing priming of tumor-specific CD8+ T cells. In the MMTV-PyMT transgenic mouse model of breast cancer and in oral squamous cell carcinoma patients, tumor development was associated with decreased blood frequency and inversely increased tumor frequency of CCR2+ Tregs. Our results define a novel subset of CCR2+ Treg involved in tumoral immune escape, and they offer evidence that this Treg subset may be preferentially eradicated by low-dose cyclophosphamide treatment. Cancer Res; 76(22); 6483–94. ©2016 AACR.
Data from In Vivo Imaging of Tumor Metabolism and Acidosis by Combining PET and MRI-CEST pH Imaging
Authors: Longo Dario L. , Bartoli Antonietta , Consolino Lorena , Bardini Paola , Arena Francesca , Schwaiger Markus , Aime Silvio
Published: March 2023

Abstract
The vast majority of cancers exhibit increased glucose uptake and glycolysis regardless of oxygen availability. This metabolic shift leads to an enhanced production of lactic acid that decreases extracellular pH (pHe), a hallmark of the tumor microenvironment. In this way, dysregulated tumor pHe and upregulated glucose metabolism are linked tightly and their relative assessment may be useful to gain understanding of the underlying biology. Here we investigated noninvasively the in vivo correlation between tumor 18F-FDG uptake and extracellular pH values in a murine model of HER2+ breast cancer. Tumor extracellular pH and perfusion were assessed by acquiring MRI-CEST (chemical exchange saturation transfer) images on a 3T scanner after intravenous administration of a pH-responsive contrast agent (iopamidol). Static PET images were recorded immediately after MRI acquisitions to quantify the extent of 18F-FDG uptake. We demonstrated the occurrence of tumor pHe changes that report on acidification of the interstitial fluid caused by an accelerated glycolysis. Combined PET and MRI-CEST images reported complementary spatial information of the altered glucose metabolism. Notably, a significant inverse correlation was found between extracellular tumor pH and 18F-FDG uptake, as a high 18F-FDG uptake corresponds to lower extracellular pH values. These results show how merging the information from 18F-FDG-uptake and extracellular pH measurements can improve characterization of the tumor microenvironment. Cancer Res; 76(22); 6463–70. ©2016 AACR.
Data from Inhibiting Mitochondrial DNA Ligase IIIα Activates Caspase 1–Dependent Apoptosis in Cancer Cells
Authors: Sallmyr Annahita , Matsumoto Yoshihiro , Roginskaya Vera , Van Houten Bennett , Tomkinson Alan E.
Published: March 2023

Abstract
Elevated levels of DNA ligase IIIα (LigIIIα) have been identified as a biomarker of an alteration in DNA repair in cancer cells that confers hypersensitivity to a LigIIIα inhibitor, L67, in combination with a poly (ADP-ribose) polymerase inhibitor. Because LigIIIα functions in the nucleus and mitochondria, we examined the effect of L67 on these organelles. Here, we show that, although the DNA ligase inhibitor selectively targets mitochondria, cancer and nonmalignant cells respond differently to disruption of mitochondrial DNA metabolism. Inhibition of mitochondrial LigIIIα in cancer cells resulted in abnormal mitochondrial morphology, reduced levels of mitochondrial DNA, and increased levels of mitochondrially generated reactive oxygen species that caused nuclear DNA damage. In contrast, these effects did not occur in nonmalignant cells. Furthermore, inhibition of mitochondrial LigIIIα activated a caspase 1–dependent apoptotic pathway, which is known to be part of inflammatory responses induced by pathogenic microorganisms in cancer, but not nonmalignant cells. These results demonstrate that the disruption of mitochondrial DNA metabolism elicits different responses in nonmalignant and cancer cells and suggests that the abnormal response in cancer cells may be exploited in the development of novel therapeutic strategies that selectively target cancer cells. Cancer Res; 76(18); 5431–41. ©2016 AACR.
Data from NRF2 Induction Supporting Breast Cancer Cell Survival Is Enabled by Oxidative Stress–Induced DPP3–KEAP1 Interaction
Authors: Lu Kevin , Alcivar Allen L. , Ma Jianglin , Foo Tzeh Keong , Zywea Susan , Mahdi Amar , Huo Yanying , Kensler Thomas W. , Gatza Michael L. , Xia Bing
Published: March 2023

Abstract
NRF2 is a transcription factor serving as a master regulator of the expression of many genes involved in cellular responses to oxidative and other stresses. In the absence of stress, NRF2 is constantly synthesized but maintained at low levels as it is targeted by KEAP1 for ubiquitination and proteasome-mediated degradation. NRF2 binds KEAP1 mainly through a conserved “ETGE” motif that has also been found in several other proteins, such as DPP3, which has been shown to bind KEAP1 and enhance NRF2 function upon overexpression. Here we demonstrate the interaction between endogenous DPP3 and endogenous KEAP1. We further show that the DPP3–KEAP1 interaction is strongly induced by hydrogen peroxide and that DPP3 is required for timely NRF2 induction and nuclear accumulation in the estrogen receptor (ER)-positive MCF7 breast cancer cells. Moreover, we present evidence that the binding of DPP3 to KEAP1 stabilizes the latter. Finally, we show that DPP3 is overexpressed in breast cancer and that elevated levels of DPP3 mRNA correlate with increased NRF2 downstream gene expression and poor prognosis, particularly for ER-positive breast cancer. Our studies reveal novel insights into the regulation of NRF2 and identify DPP3 and an NRF2 transcriptional signature as potential biomarkers for breast cancer prognosis and treatment. Cancer Res; 77(11); 2881–92. ©2017 AACR.
Data from Development of a T-cell Receptor Mimic Antibody against Wild-Type p53 for Cancer Immunotherapy
Authors: Li Demin , Bentley Carol , Anderson Amanda , Wiblin Sarah , Cleary Kirstie L.S. , Koustoulidou Sofia , Hassanali Tasneem , Yates Jenna , Greig Jenny , Nordkamp Marloes Olde , Trenevska Iva , Ternette Nicola , Kessler Benedikt M. , Cornelissen Bart , Cragg Mark S. , Banham Alison H.
Published: March 2023

Abstract
The tumor suppressor p53 is widely dysregulated in cancer and represents an attractive target for immunotherapy. Because of its intracellular localization, p53 is inaccessible to classical therapeutic monoclonal antibodies, an increasingly successful class of anticancer drugs. However, peptides derived from intracellular antigens are presented on the cell surface in the context of MHC I and can be bound by T-cell receptors (TCR). Here, we report the development of a novel antibody, T1-116C, that acts as a TCR mimic to recognize an HLA-A*0201–presented wild-type p53 T-cell epitope, p5365–73(RMPEAAPPV). The antibody recognizes a wide range of cancers, does not bind normal peripheral blood mononuclear cells, and can activate immune effector functions to kill cancer cells in vitro. In vivo, the antibody targets p5365–73 peptide–expressing breast cancer xenografts, significantly inhibiting tumor growth. This represents a promising new agent for future cancer immunotherapy. Cancer Res; 77(10); 2699–711. ©2017 AACR.
Data from Preclinical Evidence That 3′-Deoxy-3′-[18F]Fluorothymidine PET Can Visualize Recovery of Hematopoiesis after Gemcitabine Chemotherapy
Authors: Schelhaas Sonja , Held Annelena , Bäumer Nicole , Viel Thomas , Hermann Sven , Müller-Tidow Carsten , Jacobs Andreas H.
Published: March 2023

Abstract
Molecular imaging with the PET tracer 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) allows assessment of the proliferative state of organs in vivo. Although used primarily in the oncology clinic, it can also shed light on the proliferation of other tissues, as demonstrated here for monitoring hematopoietic organs that recover after myelosuppressive chemotherapy. In the NMRI nude mouse model, we observed up to a 4.5-fold increase in [18F]FLT uptake in bone marrow and spleen on days 2, 3, and 5 after treatment with gemcitabine, a chemotherapeutic agent that is powerfully myelosuppressive in the model. Specifically, we observed (i) a reduced spleen weight; (ii) reduced bone marrow cell counts and proliferation (BrdUrd flow cytometry, spleen IHC; 6 hours/day 1); and (iii) reduced leukocytes in peripheral blood (day 5). In conclusion, our results show how [18F]FLT PET can provide a powerful tool to noninvasively visualize the proliferative status of hematopoietic organs after myelosuppressive therapy. Cancer Res; 76(24); 7089–95. ©2016 AACR.
Data from Agonistic CD40 mAb-Driven IL12 Reverses Resistance to Anti-PD1 in a T-cell–Rich Tumor
Authors: Ngiow Shin Foong , Young Arabella , Blake Stephen J. , Hill Geoffrey R. , Yagita Hideo , Teng Michele W. L. , Korman Alan J. , Smyth Mark J.
Published: March 2023

Abstract
The durability and efficacy of anti-human PD1 monoclonal antibodies (PD1 mAb) vary across different malignancies. Although an absence of tumor-infiltrating cytotoxic T lymphocytes has been identified as a cause for resistance to PD1 mAb, the presence of intratumor exhausted PD1hi T cells also contributes to insensitivity to this immune checkpoint therapy. In this study, we used mouse tumor models of PD1 mAb resistance that harbored PD1hi T cells and flow cytometry analysis of tumor-infiltrating leukocytes immediately post-therapy as a screening platform to identify agents that could resensitize T cells to PD1 blockade. We showed that an agonistic anti-CD40 mAb converted PD1hi T cells into PD1lo T cells, reversing phenotypic T-cell exhaustion and allowing the anti-PD1 refractory tumors to respond to anti-PD1 therapy. PD1 downmodulation by anti-CD40 mAb relied upon IL12 but not IL23, CD80/CD86/CD28, or CD70/CD27. Consistent with a role for regulatory T cells (Treg) in promoting T-cell exhaustion, we also showed that intratumor Treg presented with a less activated and attenuated suppressive phenotype, marked by reductions in CTLA4 and PD1. Similar to anti-CD40 mAb, anti-CTLA4 mAb also lowered intratumor T-cell PD1 expression. Our study provides a proof-of-principle framework to systematically identify immune conditioning agents able to convert PD1hi T cells to PD1lo T cells, with clinical implications in the management of anti-PD1 refractory patients. Cancer Res; 76(21); 6266–77. ©2016 AACR.
Data from Transcription Factor ZBP-89 Drives a Feedforward Loop of β-Catenin Expression in Colorectal Cancer
Authors: Essien Bryan E. , Sundaresan Sinju , Ocadiz-Ruiz Ramon , Chavis Aaron , Tsao Amy C. , Tessier Arthur J. , Hayes Michael M. , Photenhauer Amanda , Saqui-Salces Milena , Kang Anthony J. , Shah Yatrik M. , Győrffy Balazs , Merchant Juanita L.
Published: March 2023

Abstract
In colorectal cancer, APC-mediated induction of unregulated cell growth involves posttranslational mechanisms that prevent proteasomal degradation of proto-oncogene β-catenin (CTNNB1) and its eventual translocation to the nucleus. However, about 10% of colorectal tumors also exhibit increased CTNNB1 mRNA. Here, we show in colorectal cancer that increased expression of ZNF148, the gene coding for transcription factor ZBP-89, correlated with reduced patient survival. Tissue arrays showed that ZBP-89 protein was overexpressed in the early stages of colorectal cancer. Conditional deletion of Zfp148 in a mouse model of Apc-mediated intestinal polyps demonstrated that ZBP-89 was required for polyp formation due to induction of Ctnnb1 gene expression. Chromatin immunoprecipitation (ChIP) and EMSA identified a ZBP-89–binding site in the proximal promoter of CTNNB1. Reciprocally, siRNA-mediated reduction of CTNNB1 expression also decreased ZBP-89 protein. ChIP identified TCF DNA binding sites in the ZNF148 promoter through which Wnt signaling regulates ZNF148 gene expression. Suppression of either ZNF148 or CTNNB1 reduced colony formation in WNT-dependent, but not WNT-independent cell lines. Therefore, the increase in intracellular β-catenin protein initiated by APC mutations is sustained by ZBP-89–mediated feedforward induction of CTNNB1 mRNA. Cancer Res; 76(23); 6877–87. ©2016 AACR.
Data from DNA Repair Capacity in Multiple Pathways Predicts Chemoresistance in Glioblastoma Multiforme
Authors: Nagel Zachary D. , Kitange Gaspar J. , Gupta Shiv K. , Joughin Brian A. , Chaim Isaac A. , Mazzucato Patrizia , Lauffenburger Douglas A. , Sarkaria Jann N. , Samson Leona D.
Published: March 2023

Abstract
Cancer cells can resist the effects of DNA-damaging therapeutic agents via utilization of DNA repair pathways, suggesting that DNA repair capacity (DRC) measurements in cancer cells could be used to identify patients most likely to respond to treatment. However, the limitations of available technologies have so far precluded adoption of this approach in the clinic. We recently developed fluorescence-based multiplexed host cell reactivation (FM-HCR) assays to measure DRC in multiple pathways. Here we apply a mathematical model that uses DRC in multiple pathways to predict cellular resistance to killing by DNA-damaging agents. This model, developed using FM-HCR and drug sensitivity measurements in 24 human lymphoblastoid cell lines, was applied to a panel of 12 patient-derived xenograft (PDX) models of glioblastoma to predict glioblastoma response to treatment with the chemotherapeutic DNA-damaging agent temozolomide. This work showed that, in addition to changes in O6-methylguanine DNA methyltransferase (MGMT) activity, small changes in mismatch repair (MMR), nucleotide excision repair (NER), and homologous recombination (HR) capacity contributed to acquired temozolomide resistance in PDX models and led to reduced relative survival prolongation following temozolomide treatment of orthotopic mouse models in vivo. Our data indicate that measuring the combined status of MMR, HR, NER, and MGMT provided a more robust prediction of temozolomide resistance than assessments of MGMT activity alone. Cancer Res; 77(1); 198–206. ©2016 AACR.
Data from v-Src Oncogene Induces Trop2 Proteolytic Activation via Cyclin D1
Authors: Ju Xiaoming , Jiao Xuanmao , Ertel Adam , Casimiro Mathew C. , Di Sante Gabriele , Deng Shengqiong , Li Zhiping , Di Rocco Agnese , Zhan Tingting , Hawkins Adam , Stoyanova Tanya , Andò Sebastiano , Fatatis Alessandro , Lisanti Michael P. , Gomella Leonard G. , Languino Lucia R. , Pestell Richard G.
Published: March 2023

Abstract
Proteomic analysis of castration-resistant prostate cancer demonstrated the enrichment of Src tyrosine kinase activity in approximately 90% of patients. Src is known to induce cyclin D1, and a cyclin D1–regulated gene expression module predicts poor outcome in human prostate cancer. The tumor-associated calcium signal transducer 2 (TACSTD2/Trop2/M1S1) is enriched in the prostate, promoting prostate stem cell self-renewal upon proteolytic activation via a γ-secretase cleavage complex (PS1, PS2) and TACE (ADAM17), which releases the Trop2 intracellular domain (Trop2 ICD). Herein, v-Src transformation of primary murine prostate epithelial cells increased the proportion of prostate cancer stem cells as characterized by gene expression, epitope characteristics, and prostatosphere formation. Cyclin D1 was induced by v-Src, and Src kinase induction of Trop2 ICD nuclear accumulation required cyclin D1. Cyclin D1 induced abundance of the Trop2 proteolytic cleavage activation components (PS2, TACE) and restrained expression of the inhibitory component of the Trop2 proteolytic complex (Numb). Patients with prostate cancer with increased nuclear Trop2 ICD and cyclin D1, and reduced Numb, had reduced recurrence-free survival probability (HR = 4.35). Cyclin D1, therefore, serves as a transducer of v-Src–mediated induction of Trop2 ICD by enhancing abundance of the Trop2 proteolytic activation complex. Cancer Res; 76(22); 6723–34. ©2016 AACR.
Data from Assessment of Breast Cancer Risk Factors Reveals Subtype Heterogeneity
Authors: Holm Johanna , Eriksson Louise , Ploner Alexander , Eriksson Mikael , Rantalainen Mattias , Li Jingmei , Hall Per , Czene Kamila
Published: March 2023

Abstract
Subtype heterogeneity for breast cancer risk factors has been suspected, potentially reflecting etiologic differences and implicating risk prediction. However, reports are conflicting regarding the presence of heterogeneity for many exposures. To examine subtype heterogeneity across known breast cancer risk factors, we conducted a case–control analysis of 2,632 breast cancers and 15,945 controls in Sweden. Molecular subtype was predicted from pathology record–derived IHC markers by a classifier trained on PAM50 subtyping. Multinomial logistic regression estimated separate ORs for each subtype by the exposures parity, age at first birth, breastfeeding, menarche, hormone replacement therapy use, somatotype at age 18, benign breast disease, mammographic density, polygenic risk score, family history of breast cancer, and BRCA mutations. We found clear subtype heterogeneity for genetic factors and breastfeeding. Polygenic risk score was associated with all subtypes except for the basal-like (Pheterogeneity < 0.0001). “Never breastfeeding” was associated with increased risk of basal-like subtype [OR 4.17; 95% confidence interval (CI) 1.89–9.21] compared with both nulliparity (reference) and breastfeeding. Breastfeeding was not associated with risk of HER2-overexpressing type, but protective for all other subtypes. The observed heterogeneity in risk of distinct breast cancer subtypes for germline variants supports heterogeneity in etiology and has implications for their use in risk prediction. The association between basal-like subtype and breastfeeding merits more research into potential causal mechanisms and confounders. Cancer Res; 77(13); 3708–17. ©2017 AACR.
Data from Personalized Management of Pancreatic Ductal Adenocarcinoma Patients through Computational Modeling
Authors: Yamamoto Kimiyo N. , Yachida Shinichi , Nakamura Akira , Niida Atsushi , Oshima Minoru , De Subhajyoti , Rosati Lauren M. , Herman Joseph M. , Iacobuzio-Donahue Christine A. , Haeno Hiroshi
Published: March 2023

Abstract
Phenotypic diversity in pancreatic ductal adenocarcinoma (PDAC) results in a variety of treatment responses. Rapid autopsy studies have revealed a subgroup of PDAC patients with a lower propensity to develop metastatic disease, challenging the common perception that all patients die of widely metastatic disease, but questions remain about root causes of this difference and the potential impact on treatment strategies. In this study, we addressed these questions through the development of a mathematical model of PDAC progression that incorporates the major alteration status of specific genes with predictive utility. The model successfully reproduced clinical outcomes regarding metastatic patterns and the genetic alteration status of patients from two independent cohorts from the United States and Japan. Using this model, we defined a candidate predictive signature in patients with low metastatic propensity. If a primary tumor contained a small fraction of cells with KRAS and additional alterations to CDKN2A, TP53, or SMAD4 genes, the patient was likely to exhibit low metastatic propensity. By using this predictive signature, we computationally simulated a set of clinical trials to model whether this subgroup would benefit from locally intensive therapies such as surgery or radiation therapy. The largest overall survival benefit resulted from complete resection, followed by adjuvant chemoradiation therapy and salvage therapies for isolated recurrence. While requiring prospective validation in a clinical trial, our results suggest a new tool to help personalize care in PDAC patients in seeking the most effective therapeutic modality for each individual. Cancer Res; 77(12); 3325–35. ©2017 AACR.
Data from A Model-Based Personalized Cancer Screening Strategy for Detecting Early-Stage Tumors Using Blood-Borne Biomarkers
Authors: Hori Sharon Seiko , Lutz Amelie M. , Paulmurugan Ramasamy , Gambhir Sanjiv Sam
Published: March 2023

Abstract
An effective cancer blood biomarker screening strategy must distinguish aggressive from nonaggressive tumors at an early, intervenable time. However, for blood-based strategies to be useful, the quantity of biomarker shed into the blood and its relationship to tumor growth or progression must be validated. To study how blood biomarker levels correlate with early-stage viable tumor growth in a mouse model of human cancer, we monitored early tumor growth of engineered human ovarian cancer cells (A2780) implanted orthotopically into nude mice. Biomarker shedding was monitored by serial blood sampling, whereas tumor viability and volume were monitored by bioluminescence imaging and ultrasound imaging. From these metrics, we developed a mathematical model of cancer biomarker kinetics that accounts for biomarker shedding from tumor and healthy cells, biomarker entry into vasculature, biomarker elimination from plasma, and subject-specific tumor growth. We validated the model in a separate set of mice in which subject-specific tumor growth rates were accurately predicted. To illustrate clinical translation of this strategy, we allometrically scaled model parameters from mouse to human and used parameters for PSA shedding and prostate cancer. In this manner, we found that blood biomarker sampling data alone were capable of enabling the detection and discrimination of simulated aggressive (2-month tumor doubling time) and nonaggressive (18-month tumor doubling time) tumors as early as 7.2 months and 8.9 years before clinical imaging, respectively. Our model and screening strategy offers broad impact in their applicability to any solid cancer and associated biomarkers shed, thereby allowing a distinction between aggressive and nonaggressive tumors using blood biomarker sampling data alone. Cancer Res; 77(10); 2570–84. ©2017 AACR.
Data from Metabolic Markers and Statistical Prediction of Serous Ovarian Cancer Aggressiveness by Ambient Ionization Mass Spectrometry Imaging
Authors: Sans Marta , Gharpure Kshipra , Tibshirani Robert , Zhang Jialing , Liang Li , Liu Jinsong , Young Jonathan H. , Dood Robert L. , Sood Anil K. , Eberlin Livia S.
Published: March 2023

Abstract
Ovarian high-grade serous carcinoma (HGSC) results in the highest mortality among gynecological cancers, developing rapidly and aggressively. Dissimilarly, serous borderline ovarian tumors (BOT) can progress into low-grade serous carcinomas and have relatively indolent clinical behavior. The underlying biological differences between HGSC and BOT call for accurate diagnostic methodologies and tailored treatment options, and identification of molecular markers of aggressiveness could provide valuable biochemical insights and improve disease management. Here, we used desorption electrospray ionization (DESI) mass spectrometry (MS) to image and chemically characterize the metabolic profiles of HGSC, BOT, and normal ovarian tissue samples. DESI-MS imaging enabled clear visualization of fine papillary branches in serous BOT and allowed for characterization of spatial features of tumor heterogeneity such as adjacent necrosis and stroma in HGSC. Predictive markers of cancer aggressiveness were identified, including various free fatty acids, metabolites, and complex lipids such as ceramides, glycerophosphoglycerols, cardiolipins, and glycerophosphocholines. Classification models built from a total of 89,826 individual pixels, acquired in positive and negative ion modes from 78 different tissue samples, enabled diagnosis and prediction of HGSC and all tumor samples in comparison with normal tissues, with overall agreements of 96.4% and 96.2%, respectively. HGSC and BOT discrimination was achieved with an overall accuracy of 93.0%. Interestingly, our classification model allowed identification of three BOT samples presenting unusual histologic features that could be associated with the development of low-grade carcinomas. Our results suggest DESI-MS as a powerful approach for rapid serous ovarian cancer diagnosis based on altered metabolic signatures. Cancer Res; 77(11); 2903–13. ©2017 AACR.
Data from Mutational Landscape and Gene Expression Patterns in Adult Acute Myeloid Leukemias with Monosomy 7 as a Sole Abnormality
Authors: Eisfeld Ann-Kathrin , Kohlschmidt Jessica , Mrózek Krzysztof , Volinia Stefano , Blachly James S. , Nicolet Deedra , Oakes Christopher , Kroll Karl , Orwick Shelley , Carroll Andrew J. , Stone Richard M. , Byrd John C. , de la Chapelle Albert , Bloomfield Clara D.
Published: March 2023

Abstract
Monosomy of chromosome 7 is the most frequent autosomal monosomy in acute myeloid leukemia (AML), where it associates with poor clinical outcomes. However, molecular features associated with this sole monosomy subtype (-7 AML), which may give insights into the basis for its poor prognosis, have not been characterized. In this study, we analyzed 36 cases of -7 AML for mutations in 81 leukemia/cancer-associated genes using a customized targeted next-generation sequencing panel (Miseq). Global gene and miRNA expression profiles were also determined using paired RNA and small RNA sequencing data. Notably, gene mutations were detected in all the major AML-associated functional groups, which include activated signaling, chromatin remodeling, cohesin complex, methylation, NPM1, spliceosome, transcription factors, and tumor suppressors. Gene mutations in the chromatin remodeling groups were relatively more frequent in patients <60 years of age, who also had less mutations in the methylation and spliceosome groups compared with patients ≥60 years of age. Novel recurrent mutational events in AML were identified in the SMARCA2 gene. In patients ≥60 years of age, the presence of spliceosome mutations associated with a lower complete remission rate (P = 0.03). RNA sequencing revealed distinct gene and miRNA expression patterns between the sole -7 and non -7 AML cases, with reduced expression, as expected, of many genes and miRNAs mapped to chromosome 7, and overexpression of ID1, MECOM, and PTPRM, among others. Overall, our findings illuminate a number of molecular features of the underlying aggressive pathobiology in -7 AML patients. Cancer Res; 77(1); 207–18. ©2016 AACR.
Data from Western Diet Deregulates Bile Acid Homeostasis, Cell Proliferation, and Tumorigenesis in Colon
Authors: Dermadi Denis , Valo Satu , Ollila Saara , Soliymani Rabah , Sipari Nina , Pussila Marjaana , Sarantaus Laura , Linden Jere , Baumann Marc , Nyström Minna
Published: March 2023

Abstract
Western-style diets (WD) high in fat and scarce in fiber and vitamin D increase risks of colorectal cancer. Here, we performed a long-term diet study in mice to follow tumorigenesis and characterize structural and metabolic changes in colon mucosa associated with WD and predisposition to colorectal cancer. WD increased colon tumor numbers, and mucosa proteomic analysis indicated severe deregulation of intracellular bile acid (BA) homeostasis and activation of cell proliferation. WD also increased crypt depth and colon cell proliferation. Despite increased luminal BA, colonocytes from WD-fed mice exhibited decreased expression of the BA transporters FABP6, OSTβ, and ASBT and decreased concentrations of secondary BA deoxycholic acid and lithocholic acid, indicating reduced activity of the nuclear BA receptor FXR. Overall, our results suggest that WD increases cancer risk by FXR inactivation, leading to BA deregulation and increased colon cell proliferation. Cancer Res; 77(12); 3352–63. ©2017 AACR.
Data from FGF2 from Marrow Microenvironment Promotes Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia
Authors: Traer Elie , Martinez Jacqueline , Javidi-Sharifi Nathalie , Agarwal Anupriya , Dunlap Jennifer , English Isabel , Kovacsovics Tibor , Tyner Jeffrey W. , Wong Melissa , Druker Brian J.
Published: March 2023

Abstract
Potent FLT3 inhibitors, such as quizartinib (AC220), have shown promise in treating acute myeloid leukemia (AML) containing FLT3 internal tandem duplication (ITD) mutations. However, responses are not durable and resistance develops within months. In this study, we outline a two-step model of resistance whereby extrinsic microenvironmental proteins FLT3 ligand (FL) and fibroblast growth factor 2 (FGF2) protect FLT3-ITD+ MOLM14 cells from AC220, providing time for subsequent accumulation of ligand-independent resistance mechanisms. FL directly attenuated AC220 inhibition of FLT3, consistent with previous reports. Conversely, FGF2 promoted resistance through activation of FGFR1 and downstream MAPK effectors; these resistant cells responded synergistically to combinatorial inhibition of FGFR1 and FLT3. Removing FL or FGF2 from ligand-dependent resistant cultures transiently restored sensitivity to AC220, but accelerated acquisition of secondary resistance via reactivation of FLT3 and RAS/MAPK signaling. FLT3-ITD AML patients treated with AC220 developed increased FGF2 expression in marrow stromal cells, which peaked prior to overt clinical relapse and detection of resistance mutations. Overall, these results support a strategy of early combination therapy to target early survival signals from the bone marrow microenvironment, in particular FGF2, to improve the depth of response in FLT3-ITD AML. Cancer Res; 76(22); 6471–82. ©2016 AACR.
Data from Merkel Cell Polyomavirus Small T Antigen Initiates Merkel Cell Carcinoma-like Tumor Development in Mice
Authors: Verhaegen Monique E. , Mangelberger Doris , Harms Paul W. , Eberl Markus , Wilbert Dawn M. , Meireles Julia , Bichakjian Christopher K. , Saunders Thomas L. , Wong Sunny Y. , Dlugosz Andrzej A.
Published: March 2023

Abstract
Merkel cell carcinoma (MCC) tumor cells express several markers detected in normal Merkel cells, a nonproliferative population of neuroendocrine cells that arise from epidermis. MCCs frequently contain Merkel cell polyomavirus (MCPyV) DNA and express viral transforming antigens, sT and tLT, but the role of these putative oncogenes in MCC development, and this tumor's cell of origin, are unknown. Using a panel of preterm transgenic mice, we show that epidermis-targeted coexpression of sT and the cell fate-determinant atonal bHLH transcription factor 1 (ATOH1) leads to development of widespread cellular aggregates, with histology and marker expression mimicking that of human intraepidermal MCC. The MCC-like tumor phenotype was dependent on the FBXW7-binding domain of sT, but not the sT-PP2A binding domain. Coexpression of MCPyV tLT did not appreciably alter the phenotype driven by either sT or sT combined with ATOH1. MCPyV sT, when coexpressed with ATOH1, is thus sufficient to initiate development of epidermis-derived MCC-like tumors in mice. Cancer Res; 77(12); 3151–7. ©2017 AACR.
Data from HDAC Inhibitor Panobinostat Engages Host Innate Immune Defenses to Promote the Tumoricidal Effects of Trastuzumab in HER2+ Tumors
Authors: Medon Mikolaj , Vidacs Eva , Vervoort Stephin J , Li Jason , Jenkins Misty R. , Ramsbottom Kelly M. , Trapani Joseph A. , Smyth Mark J. , Darcy Phillip K. , Atadja Peter W. , Henderson Michael A. , Johnstone Ricky W. , Haynes Nicole M.
Published: March 2023

Abstract
Histone deacetylase inhibitors (HDACi) may engage host immunity as one basis for their antitumor effects. Herein, we demonstrate an application of this concept using the HDACi panobinostat to augment the antitumor efficacy of trastuzumab (anti-HER2) therapy, through both tumor cell autonomous and nonautonomous mechanisms. In HER2+ tumors that are inherently sensitive to the cytostatic effects of trastuzumab, cotreatment with panobinostat abrogated AKT signaling and triggered tumor regression in mice that lacked innate and/or adaptive immune effector cells. However, the cooperative ability of panobinostat and trastuzumab to harness host anticancer immune defenses was essential for their curative activity in trastuzumab-refractory HER2+ tumors. In trastuzumab-resistant HER2+ AU565pv xenografts and BT474 tumors expressing constitutively active AKT, panobinostat enhanced the antibody-dependent cell-mediated cytotoxicity function of trastuzumab. IFNγ–mediated, CXCR3-dependent increases in tumor-associated NK cells underpinned the combined curative activity of panobinostat and trastuzumab in these tumors. These data highlight the immune-enhancing effects of panobinostat and provide compelling evidence that this HDACi can license trastuzumab to evoke NK-cell–mediated responses capable of eradicating trastuzumab-refractory HER2+ tumors. Cancer Res; 77(10); 2594–606. ©2017 AACR.
Data from A PET Imaging Strategy to Visualize Activated T Cells in Acute Graft-versus-Host Disease Elicited by Allogenic Hematopoietic Cell Transplant
Authors: Ronald John A. , Kim Byung-Su , Gowrishankar Gayatri , Namavari Mohammad , Alam Israt S. , D'Souza Aloma , Nishikii Hidekazu , Chuang Hui-Yen , Ilovich Ohad , Lin Chih-Feng , Reeves Robert , Shuhendler Adam , Hoehne Aileen , Chan Carmel T. , Baker Jeanette , Yaghoubi Shahriar S. , VanBrocklin Henry F. , Hawkins Randall , Franc Benjamin L. , Jivan Salma , Slater James B. , Verdin Emily F. , Gao Kenneth T. , Benjamin Jonathan , Negrin Robert , Gambhir Sanjiv Sam
Published: March 2023

Abstract
A major barrier to successful use of allogeneic hematopoietic cell transplantation is acute graft-versus-host disease (aGVHD), a devastating condition that arises when donor T cells attack host tissues. With current technologies, aGVHD diagnosis is typically made after end-organ injury and often requires invasive tests and tissue biopsies. This affects patient prognosis as treatments are dramatically less effective at late disease stages. Here, we show that a novel PET radiotracer, 2′-deoxy-2′-[18F]fluoro-9-β-D-arabinofuranosylguanine ([18F]F-AraG), targeted toward two salvage kinase pathways preferentially accumulates in activated primary T cells. [18F]F-AraG PET imaging of a murine aGVHD model enabled visualization of secondary lymphoid organs harboring activated donor T cells prior to clinical symptoms. Tracer biodistribution in healthy humans showed favorable kinetics. This new PET strategy has great potential for early aGVHD diagnosis, enabling timely treatments and improved patient outcomes. [18F]F-AraG may be useful for imaging activated T cells in various biomedical applications. Cancer Res; 77(11); 2893–902. ©2017 AACR.
Data from Oncogenic Role of SND1 in Development and Progression of Hepatocellular Carcinoma
Authors: Jariwala Nidhi , Rajasekaran Devaraja , Mendoza Rachel G. , Shen Xue-Ning , Siddiq Ayesha , Akiel Maaged A. , Robertson Chadia L. , Subler Mark A. , Windle Jolene J. , Fisher Paul B. , Sanyal Arun J. , Sarkar Devanand
Published: March 2023

Abstract
SND1, a subunit of the miRNA regulatory complex RISC, has been implicated as an oncogene in hepatocellular carcinoma (HCC). In this study, we show that hepatocyte-specific SND1 transgenic mice (Alb/SND1 mice) develop spontaneous HCC with partial penetrance and exhibit more highly aggressive HCC induced by chemical carcinogenesis. Livers from Alb/SND1 mice exhibited a relative increase in inflammatory markers and spheroid-generating tumor-initiating cells (TIC). Mechanistic investigations defined roles for Akt and NF-κB signaling pathways in promoting TIC formation in Alb/SND1 mice. In human xenograft models of subcutaneous or orthotopic HCC, administration of the selective SND1 inhibitor 3′, 5′-deoxythymidine bisphosphate (pdTp), inhibited tumor formation without effects on body weight or liver function. Our work establishes an oncogenic role for SND1 in promoting TIC formation and highlights pdTp as a highly selective SND1 inhibitor as a candidate therapeutic lead to treat advanced HCC. Cancer Res; 77(12); 3306–16. ©2017 AACR.
Data from Hypoxia-Induced Downregulation of DUSP-2 Phosphatase Drives Colon Cancer Stemness
Authors: Hou Pei-Chi , Li Yo-Hua , Lin Shih-Chieh , Lin Shau-Chieh , Lee Jenq-Chang , Lin Bo-Wen , Liou Jing-Ping , Chang Jang-Yang , Kuo Ching-Chuan , Liu Yi-Min , Sun H. Sunny , Tsai Shaw-Jenq
Published: March 2023

Abstract
Cancer stem-like cells (CSC) evolve to overcome the pressures of reduced oxygen, nutrients or chemically induced cell death, but the mechanisms driving this evolution are incompletely understood. Here, we report that hypoxia-mediated downregulation of the dual specificity phosphatase 2 (DUSP2) is critical for the accumulation of CSC in colorectal cancer. Reduced expression of DUSP2 led to overproduction of COX-2–derived prostaglandin E2, which promoted cancer stemness via the EP2/EP4 signaling pathways. Genetic and pharmacological inhibition of PGE2 biosynthesis or signal transduction ameliorated loss-of-DUSP2–induced tumor growth and cancer stemness. Genome-wide profile analysis revealed that genes regulated by DUSP2 were similar to those controlled by histone deacetylase. Indeed, treatment with novel histone deacetylase inhibitors abolished hypoxia-induced DUSP2 downregulation, COX-2 overexpression, cancer stemness, tumor growth, and drug resistance. Our findings illuminate mechanisms of cancer stemness and suggest new cancer therapy regimens. Cancer Res; 77(16); 4305–16. ©2017 AACR.
Data from Phosphoproteomic Profiling Reveals ALK and MET as Novel Actionable Targets across Synovial Sarcoma Subtypes
Authors: Fleuren Emmy D.G. , Vlenterie Myrella , van der Graaf Winette T.A. , Hillebrandt-Roeffen Melissa H.S. , Blackburn James , Ma Xiuquan , Chan Howard , Magias Mandy C. , van Erp Anke , van Houdt Laurens , Cebeci Sabri A.S. , van de Ven Amy , Flucke Uta E. , Heyer Erin E. , Thomas David M. , Lord Christopher J. , Marini Kieren D. , Vaghjiani Vijesh , Mercer Tim R. , Cain Jason E. , Wu Jianmin , Versleijen-Jonkers Yvonne M.H. , Daly Roger J.
Published: March 2023

Abstract
Despite intensive multimodal treatment of sarcomas, a heterogeneous group of malignant tumors arising from connective tissue, survival remains poor. Candidate-based targeted treatments have demonstrated limited clinical success, urging an unbiased and comprehensive analysis of oncogenic signaling networks to reveal therapeutic targets and personalized treatment strategies. Here we applied mass spectrometry–based phosphoproteomic profiling to the largest and most heterogeneous set of sarcoma cell lines characterized to date and identified novel tyrosine phosphorylation patterns, enhanced tyrosine kinases in specific subtypes, and potential driver kinases. ALK was identified as a novel driver in the Aska-SS synovial sarcoma (SS) cell line via expression of an ALK variant with a large extracellular domain deletion (ALKΔ2–17). Functional ALK dependency was confirmed in vitro and in vivo with selective inhibitors. Importantly, ALK immunopositivity was detected in 6 of 43 (14%) of SS patient specimens, one of which exhibited an ALK rearrangement. High PDGFRα phosphorylation also characterized SS cell lines, which was accompanied by enhanced MET activation in Yamato-SS cells. Although Yamato-SS cells were sensitive to crizotinib (ALK/MET-inhibitor) but not pazopanib (VEGFR/PDGFR-inhibitor) monotherapy in vitro, synergistic effects were observed upon drug combination. In vivo, both drugs were individually effective, with pazopanib efficacy likely attributable to reduced angiogenesis. MET or PDGFRα expression was detected in 58% and 84% of SS patients, respectively, with coexpression in 56%. Consequently, our integrated approach has led to the identification of ALK and MET as promising therapeutic targets in SS. Cancer Res; 77(16); 4279–92. ©2017 AACR.
Data from SOX5/6/21 Prevent Oncogene-Driven Transformation of Brain Stem Cells
Authors: Kurtsdotter Idha , Topcic Danijal , Karlén Alexandra , Singla Bhumica , Hagey Daniel W. , Bergsland Maria , Siesjö Peter , Nistér Monica , Carlson Joseph W. , Lefebvre Veronique , Persson Oscar , Holmberg Johan , Muhr Jonas
Published: March 2023

Abstract
Molecular mechanisms preventing self-renewing brain stem cells from oncogenic transformation are poorly defined. We show that the expression levels of SOX5, SOX6, and SOX21 (SOX5/6/21) transcription factors increase in stem cells of the subventricular zone (SVZ) upon oncogenic stress, whereas their expression in human glioma decreases during malignant progression. Elevated levels of SOX5/6/21 promoted SVZ cells to exit the cell cycle, whereas genetic ablation of SOX5/6/21 dramatically increased the capacity of these cells to form glioma-like tumors in an oncogene-driven mouse brain tumor model. Loss-of-function experiments revealed that SOX5/6/21 prevent detrimental hyperproliferation of oncogene expressing SVZ cells by facilitating an antiproliferative expression profile. Consistently, restoring high levels of SOX5/6/21 in human primary glioblastoma cells enabled expression of CDK inhibitors and decreased p53 protein turnover, which blocked their tumorigenic capacity through cellular senescence and apoptosis. Altogether, these results provide evidence that SOX5/6/21 play a central role in driving a tumor suppressor response in brain stem cells upon oncogenic insult. Cancer Res; 77(18); 4985–97. ©2017 AACR.
Data from The Alkylating Chemotherapeutic Temozolomide Induces Metabolic Stress in IDH1-Mutant Cancers and Potentiates NAD+ Depletion–Mediated Cytotoxicity
Authors: Tateishi Kensuke , Higuchi Fumi , Miller Julie J. , Koerner Mara V.A. , Lelic Nina , Shankar Ganesh M. , Tanaka Shota , Fisher David E. , Batchelor Tracy T. , Iafrate A. John , Wakimoto Hiroaki , Chi Andrew S. , Cahill Daniel P.
Published: March 2023

Abstract
IDH1-mutant gliomas are dependent upon the canonical coenzyme NAD+ for survival. It is known that PARP activation consumes NAD+ during base excision repair (BER) of chemotherapy-induced DNA damage. We therefore hypothesized that a strategy combining NAD+ biosynthesis inhibitors with the alkylating chemotherapeutic agent temozolomide could potentiate NAD+ depletion–mediated cytotoxicity in mutant IDH1 cancer cells. To investigate the impact of temozolomide on NAD+ metabolism, patient-derived xenografts and engineered mutant IDH1-expressing cell lines were exposed to temozolomide, in vitro and in vivo, both alone and in combination with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, which block NAD+ biosynthesis. The acute time period (<3 hours) after temozolomide treatment displayed a burst of NAD+ consumption driven by PARP activation. In IDH1-mutant–expressing cells, this consumption reduced further the abnormally lowered basal steady-state levels of NAD+, introducing a window of hypervulnerability to NAD+ biosynthesis inhibitors. This effect was selective for IDH1-mutant cells and independent of methylguanine methyltransferase or mismatch repair status, which are known rate-limiting mediators of adjuvant temozolomide genotoxic sensitivity. Combined temozolomide and NAMPT inhibition in an in vivo IDH1-mutant cancer model exhibited enhanced efficacy compared with each agent alone. Thus, we find IDH1-mutant cancers have distinct metabolic stress responses to chemotherapy-induced DNA damage and that combination regimens targeting nonredundant NAD+ pathways yield potent anticancer efficacy in vivo. Such targeting of convergent metabolic pathways in genetically selected cancers could minimize treatment toxicity and improve durability of response to therapy. Cancer Res; 77(15); 4102–15. ©2017 AACR.
Data from Vitamin D3 Prevents Calcium-Induced Progression of Early-Stage Prostate Tumors by Counteracting TRPC6 and Calcium Sensing Receptor Upregulation
Authors: Bernichtein Sophie , Pigat Natascha , Barry Delongchamps Nicolas , Boutillon Florence , Verkarre Virginie , Camparo Philippe , Reyes-Gomez Edouard , Méjean Arnaud , Oudard Stéphane M. , Lepicard Eve M. , Viltard Mélanie , Souberbielle Jean-Claude , Friedlander Gérard , Capiod Thierry , Goffin Vincent
Published: March 2023

Abstract
Active surveillance has emerged as an alternative to immediate treatment for men with low-risk prostate cancer. Accordingly, identification of environmental factors that facilitate progression to more aggressive stages is critical for disease prevention. Although calcium-enriched diets have been speculated to increase prostate cancer risk, their impact on early-stage tumors remains unexplored. In this study, we addressed this issue with a large interventional animal study. Mouse models of fully penetrant and slowly evolving prostate tumorigenesis showed that a high calcium diet dramatically accelerated the progression of prostate intraepithelial neoplasia, by promoting cell proliferation, micro-invasion, tissue inflammation, and expression of acknowledged prostate cancer markers. Strikingly, dietary vitamin D prevented these calcium-triggered tumorigenic effects. Expression profiling and in vitro mechanistic studies showed that stimulation of PC-3 cells with extracellular Ca2+ resulted in an increase in cell proliferation rate, store-operated calcium entry (SOCE) amplitude, cationic channel TRPC6, and calcium sensing receptor (CaSR) expression. Notably, administration of the active vitamin D metabolite calcitriol reversed all these effects. Silencing CaSR or TRPC6 expression in calcium-stimulated PC3 cells decreased cell proliferation and SOCE. Overall, our results demonstrate the protective effects of vitamin D supplementation in blocking the progression of early-stage prostate lesions induced by a calcium-rich diet. Cancer Res; 77(2); 355–65. ©2016 AACR.