bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Assessing Immune-Related Adverse Events of Efficacious Combination Immunotherapies in Preclinical Models of Cancer
Authors: Liu Jing , Blake Stephen J. , Harjunpää Heidi , Fairfax Kirsten A. , Yong Michelle C.R. , Allen Stacey , Kohrt Holbrook E. , Takeda Kazuyoshi , Smyth Mark J. , Teng Michele W.L.
Published: March 2023

Abstract
New combination immunotherapies are displaying both efficacy and immune-related adverse events (irAE) in humans. However, grade 3/4 irAEs occur in a high proportion, which can lead to discontinuation of treatment and can result in fatalities if not promptly treated. Prolonged T regulatory cell (Treg) depletion in tumor-bearing Foxp3-DTR mice using diphtheria toxin (DT) mirrored the spectrum of antitumor responses and severity of irAEs that can occur in ipilimumab/nivolumab-treated patients. In contrast, transient Treg depletion or anti-CTLA-4/PD-1 therapy had equivalent effects in mice, lowering the immune tolerance threshold and allowing irAEs to be more easily induced following treatment with additional immunomodulatory antibodies. Transient Treg depletion of DT in combination with anti-PD-1 or anti-TIM-3 monoclonal antibodies had a high therapeutic window compared with DT plus anti-CD137. In contrast, DT plus anti-CD137–treated mice developed severe irAEs similar to grade 3/4 clinical symptoms. These irAEs appeared because of an infiltration of activated proliferating effector T cells in the tissues producing IFNγ and TNF; however, TNF blockade decreased irAEs severity without impacting on tumor growth. Cancer Res; 76(18); 5288–301. ©2016 AACR.
Data from Phospholipase D1 Acts through Akt/TopBP1 and RB1 to Regulate the E2F1-Dependent Apoptotic Program in Cancer Cells
Authors: Kang Dong Woo , Lee Shin Wha , Hwang Won Chan , Lee Bo Hui , Choi Yong-Seok , Suh Young-Ah , Choi Kang-Yell , Min Do Sik
Published: March 2023

Abstract
The RB1/E2F1 signaling pathway is frequently deregulated in colorectal cancer and has been suggested to intersect with Wnt/β-catenin and PI3K/Akt pathways, but molecular evidence for this link is lacking. In this study, we demonstrate that phospholipase D1 (PLD1), a transcriptional target of β-catenin/TCF4, orchestrates functional interactions between these pathways during intestinal tumor development. Overexpression of PLD1 in intestinal epithelial cells protected cells from apoptosis induced by PLD1 ablation in the Apcmin/+ mouse model of intestinal tumorigenesis. Mechanistic investigations revealed that genetic and pharmacologic targeting of PLD1 promote the E2F1-dependent apoptotic program via both miR-192/4465–mediated downregulation of RB1 and inhibition of Akt–TopBP1 pathways. Moreover, the miRNA–RB1 axis and Akt pathway also contributed to the PLD1-mediated self-renewal capacity of colon cancer–initiating cells. Finally, PLD1-driven E2F1 target gene expression positively correlated with tumor stage in patients with colorectal cancer. Overall, our findings suggest that PLD1 mediates cross-talk between multiple major signaling pathways to promote the survival and malignancy of colon cancer cells and may therefore represent an ideal signaling node for therapeutic targeting. Cancer Res; 77(1); 142–52. ©2016 AACR.
Data from Destabilization of Fatty Acid Synthase by Acetylation Inhibits De Novo Lipogenesis and Tumor Cell Growth
Authors: Lin Huai-Peng , Cheng Zhou-Li , He Ruo-Yu , Song Lei , Tian Meng-Xin , Zhou Li-Sha , Groh Beezly S. , Liu Wei-Ren , Ji Min-Biao , Ding Chen , Shi Ying-Hong , Guan Kun-Liang , Ye Dan , Xiong Yue
Published: March 2023

Abstract
Fatty acid synthase (FASN) is the terminal enzyme in de novo lipogenesis and plays a key role in cell proliferation. Pharmacologic inhibitors of FASN are being evaluated in clinical trials for treatment of cancer, obesity, and other diseases. Here, we report a previously unknown mechanism of FASN regulation involving its acetylation by KAT8 and its deacetylation by HDAC3. FASN acetylation promoted its degradation via the ubiquitin–proteasome pathway. FASN acetylation enhanced its association with the E3 ubiquitin ligase TRIM21. Acetylation destabilized FASN and resulted in decreased de novo lipogenesis and tumor cell growth. FASN acetylation was frequently reduced in human hepatocellular carcinoma samples, which correlated with increased HDAC3 expression and FASN protein levels. Our results suggest opportunities to target FASN acetylation as an anticancer strategy. Cancer Res; 76(23); 6924–36. ©2016 AACR.
Data from Targeting Vascular Endothelial-Cadherin in Tumor-Associated Blood Vessels Promotes T-cell–Mediated Immunotherapy
Authors: Zhao Yang , Ting Ka Ka , Li Jia , Cogger Victoria C. , Chen Jinbiao , Johansson-Percival Anna , Ngiow Shin Foong , Holst Jeff , Grau Georges , Goel Shom , Muller Thorleif , Dejana Elisabetta , McCaughan Geoff , Smyth Mark J. , Ganss Ruth , Vadas Mathew A. , Gamble Jennifer R.
Published: March 2023

Abstract
T-cell infiltration of solid tumors is associated with improved prognosis and favorable responses to immunotherapy. Mechanisms that enable tumor infiltration of CD8+ T cells have not been defined, nor have drugs that assist this process been discovered. Here we address these issues with a focus on VE-cadherin, a major endothelial cell–specific junctional protein that controls vascular integrity. A decrease in VE-cadherin expression is associated with tumor pathology. We developed an oligonucleotide-based inhibitor (CD5-2), which disrupted the interaction of VE-cadherin with its regulator miR-27a, resulting in increased VE-cadherin expression. Administration of CD5-2 in tumor-bearing mice enhanced expression of VE-cadherin in tumor endothelium, activating TIE-2 and tight junction pathways and normalizing vessel structure and function. CD5-2 administration also enhanced tumor-specific T-cell infiltration and spatially redistributed CD8+ T cells within the tumor parenchyma. Finally, CD5-2 treatment enhanced the efficacy of anti-PD-1 blocking antibody. Our work establishes a role for VE-cadherin in T-cell infiltration in tumors and offers a preclinical proof of concept for CD5-2 as a therapeutic modifier of cancer immunotherapy via effects on the tumor vasculature. Cancer Res; 77(16); 4434–47. ©2017 AACR.
Data from Raman-Encoded Molecular Imaging with Topically Applied SERS Nanoparticles for Intraoperative Guidance of Lumpectomy
Authors: Wang Yu “Winston” , Reder Nicholas P. , Kang Soyoung , Glaser Adam K. , Yang Qian , Wall Matthew A. , Javid Sara H. , Dintzis Suzanne M. , Liu Jonathan T.C.
Published: March 2023

Abstract
Intraoperative identification of carcinoma at lumpectomy margins would enable reduced re-excision rates, which are currently as high as 20% to 50%. Although imaging of disease-associated biomarkers can identify malignancies with high specificity, multiplexed imaging of such biomarkers is necessary to detect molecularly heterogeneous carcinomas with high sensitivity. We have developed a Raman-encoded molecular imaging (REMI) technique in which targeted nanoparticles are topically applied on excised tissues to enable rapid visualization of a multiplexed panel of cell surface biomarkers at surgical margin surfaces. A first-ever clinical study was performed in which 57 fresh specimens were imaged with REMI to simultaneously quantify the expression of four biomarkers HER2, ER, EGFR, and CD44. Combined detection of these biomarkers enabled REMI to achieve 89.3% sensitivity and 92.1% specificity for the detection of breast carcinoma. These results highlight the sensitivity and specificity of REMI to detect biomarkers in freshly resected tissue, which has the potential to reduce the rate of re-excision procedures in cancer patients. Cancer Res; 77(16); 4506–16. ©2017 AACR.
Data from De Novo Lipid Synthesis Facilitates Gemcitabine Resistance through Endoplasmic Reticulum Stress in Pancreatic Cancer
Authors: Tadros Saber , Shukla Surendra K. , King Ryan J. , Gunda Venugopal , Vernucci Enza , Abrego Jaime , Chaika Nina V. , Yu Fang , Lazenby Audrey J. , Berim Lyudmyla , Grem Jean , Sasson Aaron R. , Singh Pankaj K.
Published: March 2023

Abstract
Pancreatic adenocarcinoma is moderately responsive to gemcitabine-based chemotherapy, the most widely used single-agent therapy for pancreatic cancer. Although the prognosis in pancreatic cancer remains grim in part due to poor response to therapy, previous attempts at identifying and targeting the resistance mechanisms have not been very successful. By leveraging The Cancer Genome Atlas dataset, we identified lipid metabolism as the metabolic pathway that most significantly correlated with poor gemcitabine response in pancreatic cancer patients. Furthermore, we investigated the relationship between alterations in lipogenesis pathway and gemcitabine resistance by utilizing tissues from the genetically engineered mouse model and human pancreatic cancer patients. We observed a significant increase in fatty acid synthase (FASN) expression with increasing disease progression in spontaneous pancreatic cancer mouse model, and a correlation of high FASN expression with poor survival in patients and poor gemcitabine responsiveness in cell lines. We observed a synergistic effect of FASN inhibitors with gemcitabine in pancreatic cancer cells in culture and orthotopic implantation models. Combination of gemcitabine and the FASN inhibitor orlistat significantly diminished stemness, in part due to induction of endoplasmic reticulum (ER) stress that resulted in apoptosis. Moreover, direct induction of ER stress with thapsigargin caused a similar decrease in stemness and showed synergistic activity with gemcitabine. Our in vivo studies with orthotopic implantation models demonstrated a robust increase in gemcitabine responsiveness upon inhibition of fatty acid biosynthesis with orlistat. Altogether, we demonstrate that fatty acid biosynthesis pathway manipulation can help overcome the gemcitabine resistance in pancreatic cancer by regulating ER stress and stemness. Cancer Res; 77(20); 5503–17. ©2017 AACR.
Data from HNF1B Loss Exacerbates the Development of Chromophobe Renal Cell Carcinomas
Authors: Sun Mianen , Tong Pan , Kong Wen , Dong Baijun , Huang Yiran , Park In Young , Zhou Lijun , Liu Xian-De , Ding Zhiyong , Zhang Xuesong , Bai Shanshan , German Peter , Powell Reid , Wang Quan , Tong Xuefei , Tannir Nizar M. , Matin Surena F. , Rathmell W. Kimryn , Fuller Gregory N. , McCutcheon Ian E. , Walker Cheryl L. , Wang Jing , Jonasch Eric
Published: March 2023

Abstract
Chromophobe renal cell carcinoma (ChRCC) is characterized by major changes in chromosomal copy number (CN). No model is available to precisely elucidate the molecular drivers of this tumor type. HNF1B is a master regulator of gene expression. Here, we report that the transcription factor HNF1B is downregulated in the majority of ChRCC and that the magnitude of HNF1B loss is unique to ChRCC. We also observed a strong correlation between reduced HNF1B expression and aneuploidy in ChRCC patients. In murine embryonic fibroblasts or ACHN cells, HNF1B deficiency reduced expression of the spindle checkpoint proteins MAD2L1 and BUB1B, and the cell-cycle checkpoint proteins RB1 and p27. Furthermore, it altered the chromatin accessibility of Mad2l1, Bub1b, and Rb1 genes and triggered aneuploidy development. Analysis of The Cancer Genome Atlas database revealed TP53 mutations in 33% of ChRCC where HNF1B expression was repressed. In clinical specimens, combining HNF1B loss with TP53 mutation produced an association with poor patient prognosis. In cells, combining HNF1B loss and TP53 mutation increased cell proliferation and aneuploidy. Our results show how HNF1B loss leads to abnormal mitotic protein regulation and induction of aneuploidy. We propose that coordinate loss of HNF1B and TP53 may enhance cellular survival and confer an aggressive phenotype in ChRCC. Cancer Res; 77(19); 5313–26. ©2017 AACR.
Data from JCAD Promotes Progression of Nonalcoholic Steatohepatitis to Liver Cancer by Inhibiting LATS2 Kinase Activity
Authors: Ye Juan , Li Tian-Sheng , Xu Gang , Zhao Yi-Ming , Zhang Ning-Ping , Fan Jia , Wu Jian
Published: March 2023

Abstract
Nonalcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) is a malignancy whose incidents are rapidly increasing. However, the mechanisms that drive development of HCC in a steatotic microenvironment remain unknown. Here we report that the obesity-associated protein JCAD is expressed at significantly higher levels in human NASH-HCC specimens compared with pericarcinoma specimens. High JCAD expression was verified in multiple hepatoma cell lines. Forced overexpression of JCAD in hepatoma cells promoted tumor growth and proliferation, whereas JCAD silencing yielded opposite effects. JCAD interacted with the kinase domain of the tumor suppressor kinase LATS2, a core component of the Hippo signaling pathway. JCAD overexpression inhibited the ability of LATS2 to phosphorylate YAP in this pathway, in turn upregulating CCND1 and GLI2 to promote hepatoma cell proliferation. JCAD was induced by fatty acid overload in hepatic cells and was highly expressed in a mouse model of NASH-precarcinoma lesions, where the ratio of phospho-YAP to YAP was decreased. In human NASH-HCC specimens, JCAD expression and YAP phosphorylation patterns paralleled with the mouse model. Our findings illuminate a new role for JCAD and its critical interplay in the Hippo signaling cascade during the transition of NASH to HCC, with potential implications for therapeutic development in this setting. Cancer Res; 77(19); 5287–300. ©2017 AACR.
Data from Competition between DNA Methylation, Nucleotide Synthesis, and Antioxidation in Cancer versus Normal Tissues
Authors: Cao Sha , Zhu Xiwen , Zhang Chi , Qian Hong , Schuttler Heinz-Bernd , Gong Jianping , Xu Ying
Published: March 2023

Abstract
Global DNA hypomethylation occurs in many cancer types, but there is no explanation for its differential occurrence or possible impact on cancer cell physiology. Here we address these issues with a computational study of genome-scale DNA methylation in 16 cancer types. Specifically, we identified (i) a possible determinant for global DNA methylation in cancer cells and (ii) a relationship between levels of DNA methylation, nucleotide synthesis, and intracellular oxidative stress in cells. We developed a system of kinetic equations to capture the metabolic relations among DNA methylation, nucleotide synthesis, and antioxidative stress response, including their competitions for methyl and sulfur groups, based on known information about one-carbon metabolism and trans-sulfuration pathways. We observed a kinetic-based regulatory mechanism that controls reaction rates of the three competing processes when their shared resources are limited, particularly when the nucleotide synthesis rates or oxidative states are high. The combination of this regulatory mechanism and the need for rapid nucleotide synthesis, as well as high production of glutathione dictated by cancer-driving forces, led to the nearly universal observations of reduced global DNA methylation in cancer. Our model provides a natural explanation for differential global DNA methylation levels across cancer types and supports the observation that more malignant cancers tend to exhibit reduced DNA methylation levels. Insights obtained from this work provide useful information about the complexities of cancer due to interplays among competing, dynamic biological processes. Cancer Res; 77(15); 4185–95. ©2017 AACR.
Data from ATOH1 Promotes Leptomeningeal Dissemination and Metastasis of Sonic Hedgehog Subgroup Medulloblastomas
Authors: Grausam Katie B. , Dooyema Samuel D.R. , Bihannic Laure , Premathilake Hasitha , Morrissy A. Sorana , Forget Antoine , Schaefer Amanda M. , Gundelach Justin H. , Macura Slobodan , Maher Diane M. , Wang Xin , Heglin Alex H. , Ge Xijin , Zeng Erliang , Puget Stephanie , Chandrasekar Indra , Surendran Kameswaran , Bram Richard J. , Schüller Ulrich , Talyor Michael D. , Ayrault Olivier , Zhao Haotian
Published: March 2023

Abstract
Medulloblastoma arising from the cerebellum is the most common pediatric brain malignancy, with leptomeningeal metastases often present at diagnosis and recurrence associated with poor clinical outcome. In this study, we used mouse medulloblastoma models to explore the relationship of tumor pathophysiology and dysregulated expression of the NOTCH pathway transcription factor ATOH1, which is present in aggressive medulloblastoma subtypes driven by aberrant Sonic Hedgehog/Patched (SHH/PTCH) signaling. In experiments with conditional ATOH1 mouse mutants crossed to Ptch1+/− mice, which develop SHH-driven medulloblastoma, animals with Atoh1 transgene expression developed highly penetrant medulloblastoma at a young age with extensive leptomeningeal disease and metastasis to the spinal cord and brain, resembling xenografts of human SHH medulloblastoma. Metastatic tumors retained abnormal SHH signaling like tumor xenografts. Conversely, ATOH1 expression was detected consistently in recurrent and metastatic SHH medulloblastoma. Chromatin immunoprecipitation sequencing and gene expression profiling identified candidate ATOH1 targets in tumor cells involved in development and tumorigenesis. Among these targets specific to metastatic tumors, there was an enrichment in those implicated in extracellular matrix remodeling activity, cytoskeletal network and interaction with microenvironment, indicating a shift in transcriptomic and epigenomic landscapes during metastasis. Treatment with bone morphogenetic protein or SHH pathway inhibitors decreased tumor cell proliferation and suppressed metastatic tumor growth, respectively. Our work reveals a dynamic ATOH1-driven molecular cascade underlying medulloblastoma metastasis that offers possible therapeutic opportunities. Cancer Res; 77(14); 3766–77. ©2017 AACR.
Data from Trastuzumab Increases HER2 Uptake and Cross-Presentation by Dendritic Cells
Authors: Gall Victor A. , Philips Anne V. , Qiao Na , Clise-Dwyer Karen , Perakis Alexander A. , Zhang Mao , Clifton Guy T. , Sukhumalchandra Pariya , Ma Qing , Reddy Sangeetha M. , Yu Dihua , Molldrem Jeffrey J. , Peoples George E. , Alatrash Gheath , Mittendorf Elizabeth A.
Published: March 2023

Abstract
Early-phase clinical trials evaluating CD8+ T cell–eliciting, HER2-derived peptide vaccines administered to HER2+ breast cancer patients in the adjuvant setting suggest synergy between the vaccines and trastuzumab, the mAb targeting the HER2 protein. Among 60 patients enrolled in clinical trials evaluating the E75 + GM-CSF and GP2 + GM-CSF vaccines, there have been no recurrences in patients vaccinated after receiving trastuzumab as part of standard therapy in the per treatment analyses conducted after a median follow-up of greater than 34 months. Here, we describe a mechanism by which this synergy may occur. Flow cytometry showed that trastuzumab facilitated uptake of HER2 by dendritic cells (DC), which was mediated by the Fc receptor and was specific to trastuzumab. In vitro, increased HER2 uptake by DC increased cross-presentation of E75, the immunodominant epitope derived from the HER2 protein, an observation confirmed in two in vivo mouse models. This increased E75 cross-presentation, mediated by trastuzumab treatment, enabled more efficient expansion of E75-specific cytotoxic T cells (E75-CTL). These results demonstrate a mechanism by which trastuzumab links innate and adaptive immunity by facilitating activation of antigen-specific T cells. On the basis of these data, we conclude that HER2-positive breast cancer patients that have been treated with trastuzumab may experience a more robust antitumor immune response by restimulation of T cells with the E75 peptide vaccine, thereby accounting for the improved disease-free survival observed with combination therapy. Cancer Res; 77(19); 5374–83. ©2017 AACR.
Data from Loss of Igf2 Gene Imprinting in Murine Prostate Promotes Widespread Neoplastic Growth
Authors: Damaschke Nathan A. , Yang Bing , Bhusari Sachin , Avilla Mele , Zhong Weixiong , Blute Michael L. , Huang Wei , Jarrard David F.
Published: March 2023

Abstract
Loss of imprinting (LOI) is an epigenetic event that relaxes an allele-specific restriction on gene expression. One gene that experiences LOI is the paracrine insulin-like growth factor IGF2, which occurs commonly in human prostate tissues during aging and tumorigenesis. However, the relationship between IGF2 LOI and prostate tumorigenesis has not been established functionally. In this study, we created a mouse model with CTCF-binding site mutations at the Igf2-H19 imprint control region that abolishes CTCF insulator activity, resulting in biallelic Igf2 expression that mimics increased levels seen with aging-induced LOI. We found that Igf2 LOI increased the prevalence and severity of prostatic intraepithelial neoplasia (PIN), a premalignant lesion. Engineering Nkx3.1 deficiency into our model increased the frequency of PIN lesions in an additive fashion. Prostates harboring LOI displayed increased MAPK signaling and epithelial proliferation. In human prostate tissue arrays, we documented a positive correlation in benign tissues of IGF2 levels with phospho-ERK and phospho-AKT levels. Overall, our results establish that Igf2 LOI is sufficient on its own to increase rates of neoplastic development in the prostate by upregulating critical cancer-associated signaling pathways. Cancer Res; 77(19); 5236–47. ©2017 AACR.
Data from MET Exon 14 Mutation Encodes an Actionable Therapeutic Target in Lung Adenocarcinoma
Authors: Lu Xinyuan , Peled Nir , Greer John , Wu Wei , Choi Peter , Berger Alice H. , Wong Sergio , Jen Kuang-Yu , Seo Youngho , Hann Byron , Brooks Angela , Meyerson Matthew , Collisson Eric A.
Published: March 2023

Abstract
Targeting somatically activated oncogenes has revolutionized the treatment of non–small cell lung cancer (NSCLC). Mutations in the gene mesenchymal–epithelial transition (MET) near the exon 14 splice sites are recurrent in lung adenocarcinoma and cause exon skipping (METΔ14). Here, we analyzed 4,422 samples from 12 different malignancies to estimate the rate of said exon skipping. METΔ14 mutation and transcript were most common in lung adenocarcinoma. Endogenously expressed levels of METΔ14 transformed human epithelial lung cells in a hepatocyte growth factor–dependent manner. In addition, overexpression of the orthologous mouse allele induced lung adenocarcinoma in a novel, immunocompetent mouse model. Met inhibition showed clinical benefit in this model. In addition, we observed a clinical response to crizotinib in a patient with METΔ14-driven NSCLC, only to observe new missense mutations in the MET activation loop, critical for binding to crizotinib, upon clinical progression. These findings support genomically selected clinical trials directed toward METΔ14 in a fraction of NSCLC patients, confirm second-site mutations for further therapeutic targeting prior to and beyond acquired resistance, and provide an in vivo system for the study of METΔ14 in an immunocompetent host. Cancer Res; 77(16); 4498–505. ©2017 AACR.
Data from Cic Loss Promotes Gliomagenesis via Aberrant Neural Stem Cell Proliferation and Differentiation
Authors: Yang Rui , Chen Lee H. , Hansen Landon J. , Carpenter Austin B. , Moure Casey J. , Liu Heng , Pirozzi Christopher J. , Diplas Bill H. , Waitkus Matthew S. , Greer Paula K. , Zhu Huishan , McLendon Roger E. , Bigner Darell D. , He Yiping , Yan Hai
Published: March 2023

Abstract
Inactivating mutations in the transcriptional repression factor Capicua (CIC) occur in approximately 50% of human oligodendrogliomas, but mechanistic links to pathogenesis are unclear. To address this question, we generated Cic-deficient mice and human oligodendroglioma cell models. Genetic deficiency in mice resulted in a partially penetrant embryonic or perinatal lethal phenotype, with the production of an aberrant proliferative neural population in surviving animals. In vitro cultured neural stem cells derived from Cic conditional knockout mice bypassed an EGF requirement for proliferation and displayed a defect in their potential for oligodendrocyte differentiation. Cic is known to participate in gene suppression that can be relieved by EGFR signal, but we found that cic also activated expression of a broad range of EGFR-independent genes. In an orthotopic mouse model of glioma, we found that Cic loss potentiated the formation and reduced the latency in tumor development. Collectively, our results define an important role for Cic in regulating neural cell proliferation and lineage specification, and suggest mechanistic explanations for how CIC mutations may impact the pathogenesis and therapeutic targeting of oligodendroglioma. Cancer Res; 77(22); 6097–108. ©2017 AACR.
Data from Prominent Oncogenic Roles of EVI1 in Breast Carcinoma
Authors: Wang Hui , Schaefer Thorsten , Konantz Martina , Braun Martin , Varga Zsuzsanna , Paczulla Anna M. , Reich Selina , Jacob Francis , Perner Sven , Moch Holger , Fehm Tanja N. , Kanz Lothar , Schulze-Osthoff Klaus , Lengerke Claudia
Published: March 2023

Abstract
Overexpression of the EVI1 oncogene is associated typically with aggressive myeloid leukemia, but is also detectable in breast carcinoma where its contributions are unexplored. Analyzing a tissue microarray of 608 breast carcinoma patient specimens, we documented EVI1 overexpression in both estrogen receptor–positive (ER+) and estrogen receptor–negative (ER−) breast carcinomas. Here, we report prognostic relevance of EVI1 overexpression in triple-negative breast carcinoma but not in the HER2-positive breast carcinoma subset. In human breast cancer cells, EVI1 silencing reduced proliferation, apoptosis resistance, and tumorigenicity, effects rescued by estrogen supplementation in ER+ breast carcinoma cells. Estrogen addition restored ERK phosphorylation in EVI1-silenced cells, suggesting that EVI1 and estradiol signaling merge in MAPK activation. Conversely, EVI1 silencing had no effect on constitutive ERK activity in HER2+ breast carcinoma cells. Microarray analyses revealed G-protein–coupled receptor (GPR) signaling as a prominent EVI1 effector mechanism in breast carcinoma. Among others, the GPR54-ligand KISS1 was identified as a direct transcriptional target of EVI1, which together with other EVI1-dependent cell motility factors such as RHOJ regulated breast carcinoma cell migration. Overall, our results establish the oncogenic contributions of EVI1 in ER- and HER2-negative subsets of breast cancer. Cancer Res; 77(8); 2148–60. ©2017 AACR.
Data from Inflammatory Monocytes Promote Perineural Invasion via CCL2-Mediated Recruitment and Cathepsin B Expression
Authors: Bakst Richard L. , Xiong Huizhong , Chen Chun-Hao , Deborde Sylvie , Lyubchik Anna , Zhou Yi , He Shizhi , McNamara William , Lee Sei-Young , Olson Oakley C. , Leiner Ingrid M. , Marcadis Andrea R. , Keith James W. , Al-Ahmadie Hikmat A. , Katabi Nora , Gil Ziv , Vakiani Efsevia , Joyce Johanna A. , Pamer Eric , Wong Richard J.
Published: March 2023

Abstract
Perineural invasion (PNI) is an ominous event strongly linked to poor clinical outcome. Cells residing within peripheral nerves collaborate with cancer cells to enable PNI, but the contributing conditions within the tumor microenvironment are not well understood. Here, we show that CCR2-expressing inflammatory monocytes (IM) are preferentially recruited to sites of PNI, where they differentiate into macrophages and potentiate nerve invasion through a cathepsin B–mediated process. A series of adoptive transfer experiments with genetically engineered donors and recipients demonstrated that IM recruitment to nerves was driven by CCL2 released from Schwann cells at the site of PNI, but not CCL7, an alternate ligand for CCR2. Interruption of either CCL2–CCR2 signaling or cathepsin B function significantly impaired PNI in vivo. Correlative studies in human specimens demonstrated that cathepsin B–producing macrophages were enriched in invaded nerves, which was associated with increased local tumor recurrence. These findings deepen our understanding of PNI pathogenesis and illuminate how PNI is driven in part by corruption of a nerve repair program. Further, they support the exploration of inhibiting IM recruitment and function as a targeted therapy for PNI. Cancer Res; 77(22); 6400–14. ©2017 AACR.
Data from Posttranscriptional Regulation of PARG mRNA by HuR Facilitates DNA Repair and Resistance to PARP Inhibitors
Authors: Chand Saswati N. , Zarei Mahsa , Schiewer Matthew J. , Kamath Akshay R. , Romeo Carmella , Lal Shruti , Cozzitorto Joseph A. , Nevler Avinoam , Scolaro Laura , Londin Eric , Jiang Wei , Meisner-Kober Nicole , Pishvaian Michael J. , Knudsen Karen E. , Yeo Charles J. , Pascal John M. , Winter Jordan M. , Brody Jonathan R.
Published: March 2023

Abstract
The majority of pancreatic ductal adenocarcinomas (PDAC) rely on the mRNA stability factor HuR (ELAV-L1) to drive cancer growth and progression. Here, we show that CRISPR-Cas9–mediated silencing of the HuR locus increases the relative sensitivity of PDAC cells to PARP inhibitors (PARPi). PDAC cells treated with PARPi stimulated translocation of HuR from the nucleus to the cytoplasm, specifically promoting stabilization of a new target, poly (ADP-ribose) glycohydrolase (PARG) mRNA, by binding a unique sequence embedded in its 3′ untranslated region. HuR-dependent upregulation of PARG expression facilitated DNA repair via hydrolysis of polyADP-ribose on related repair proteins. Accordingly, strategies to inhibit HuR directly promoted DNA damage accumulation, inefficient PAR removal, and persistent PARP-1 residency on chromatin (PARP-1 trapping). Immunoprecipitation assays demonstrated that the PARP-1 protein binds and posttranslationally modifies HuR in PARPi-treated PDAC cells. In a mouse xenograft model of human PDAC, PARPi monotherapy combined with targeted silencing of HuR significantly reduced tumor growth compared with PARPi therapy alone. Our results highlight the HuR–PARG axis as an opportunity to enhance PARPi-based therapies. Cancer Res; 77(18); 5011–25. ©2017 AACR.
Data from CD4+ T-cell–Mediated Rejection of MHC Class II–Positive Tumor Cells Is Dependent on Antigen Secretion and Indirect Presentation on Host APCs
Authors: Haabeth Ole Audun W. , Fauskanger Marte , Manzke Melanie , Lundin Katrin U. , Corthay Alexandre , Bogen Bjarne , Tveita Anders A.
Published: March 2023

Abstract
Tumor-specific CD4+ T cells have been shown to mediate efficient antitumor immune responses against cancer. Such responses can occur through direct binding to MHC class II (MHC II)–expressing tumor cells, or indirectly via activation of professional antigen-presenting cells (APC) that take up and present the tumor antigen. We have previously shown that CD4+ T cells reactive against an epitope within the Ig light chain variable region of a murine B-cell lymphoma can reject established tumors. Given the presence of MHC II molecules at the surface of lymphoma cells, we investigated whether MHC II–restricted antigen presentation on tumor cells alone was required for rejection. Variants of the A20 B lymphoma cell line that either secreted or intracellularly retained different versions of the tumor-specific antigen revealed that antigen secretion by the MHC II–expressing tumor cells was essential both for the priming and effector phase of CD4+ T-cell–driven antitumor immune responses. Consistent with this, genetic ablation of MHC II in tumor cells, both in the case of B lymphoma and B16 melanoma, did not preclude rejection of tumors by tumor antigen–specific CD4+ T cells in vivo. These findings demonstrate that MHC class II expression on tumor cells themselves is not required for CD4+ T-cell–mediated rejection and that indirect display on host APC is sufficient for effective tumor elimination. These results support the importance of tumor-infiltrating APC as mediators of tumor cell killing by CD4+ T cells.

Significance: Elimination of tumors by CD4+ T cells recognizing secreted tumor neoantigens can occur in the absence of tumor cell-intrinsic MHC II expression, highlighting the potential clinical relevance of indirect antigen recognition by tumor-infiltrating APC.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4573/F1.large.jpg. Cancer Res; 78(16); 4573–85. ©2018 AACR.
Data from The FACT inhibitor CBL0137 Synergizes with Cisplatin in Small-Cell Lung Cancer by Increasing NOTCH1 Expression and Targeting Tumor-Initiating Cells
Authors: De Sarmishtha , Lindner Daniel J. , Coleman Claire J. , Wildey Gary , Dowlati Afshin , Stark George R.
Published: March 2023

Abstract
Traditional treatments of small-cell lung cancer (SCLC) with cisplatin, a standard-of-care therapy, spare the tumor-initiating cells (TIC) that mediate drug resistance. Here we report a novel therapeutic strategy that preferentially targets TICs in SCLC, in which cisplatin is combined with CBL0137, an inhibitor of the histone chaperone facilitates chromatin transcription (FACT), which is highly expressed in TICs. Combination of cisplatin and CBL0137 killed patient-derived and murine SCLC cell lines synergistically. In response to CBL0137 alone, TICs were more sensitive than non-TICs, in part, because CBL0137 increased expression of the tumor suppressor NOTCH1 by abrogating the binding of negative regulator SP3 to the NOTCH1 promoter, and in part because treatment decreased the high expression of stem cell transcription factors. The combination of cisplatin and CBL0137 greatly reduced the growth of a patient-derived xenograft in mice and also the growth of a syngeneic mouse SCLC tumor. Thus, CBL0137 can be a highly effective drug against SCLC, especially in combination with cisplatin.

Significance: These findings reveal a novel therapeutic regimen for SCLC, combining cisplatin with an inhibitor that preferentially targets tumor-initiating cells. Cancer Res; 78(9); 2396–406. ©2018 AACR.
Data from Oncolytic Adenoviral Delivery of an EGFR-Targeting T-cell Engager Improves Antitumor Efficacy
Authors: Fajardo Carlos Alberto , Guedan Sonia , Rojas Luis Alfonso , Moreno Rafael , Arias-Badia Marcel , de Sostoa Jana , June Carl H. , Alemany Ramon
Published: March 2023

Abstract
Antiviral immune responses present a major hurdle to the efficacious use of oncolytic adenoviruses as cancer treatments. Despite the existence of a highly immunosuppressive tumor environment, adenovirus-infected cells can nonetheless be efficiently cleared by infiltrating cytotoxic T lymphocytes (CTL) without compromising tumor burden. In this study, we tested the hypothesis that tumor-infiltrating T cells could be more effectively activated and redirected by oncolytic adenoviruses that were armed with bispecific T-cell–engager (BiTE) antibodies. The oncolytic adenovirus ICOVIR-15K was engineered to express an EGFR-targeting BiTE (cBiTE) antibody under the control of the major late promoter, leading to generation of ICOVIR-15K-cBiTE, which retained its oncolytic properties in vitro. cBiTE expression and secretion was detected in supernatants from ICOVIR-15K-cBiTE–infected cells, and the secreted BiTEs bound specifically to both CD3+ and EGFR+ cells. In cell coculture assays, ICOVIR-15K-cBiTE–mediated oncolysis resulted in robust T-cell activation, proliferation, and bystander cell-mediated cytotoxicity. Notably, intratumoral injection of this cBiTE-expressing adenovirus increased the persistence and accumulation of tumor-infiltrating T cells in vivo, compared with the parental virus lacking such effects. Moreover, in two distinct tumor xenograft models, combined delivery of ICOVIR-15K-cBiTE with peripheral blood mononuclear cells or T cells enhanced the antitumor efficacy achieved by the parental counterpart. Overall, our results show how arming oncolytic adenoviruses with BiTE can overcome key limitations in oncolytic virotherapy. Cancer Res; 77(8); 2052–63. ©2017 AACR.
Data from A Subpopulation of Stromal Cells Controls Cancer Cell Homing to the Bone Marrow
Authors: Rossnagl Stephanie , Ghura Hiba , Groth Christopher , Altrock Eva , Jakob Franz , Schott Sarah , Wimberger Pauline , Link Theresa , Kuhlmann Jan Dominik , Stenzl Arnulf , Hennenlotter Jörg , Todenhöfer Tilmann , Rojewski Markus , Bieback Karen , Nakchbandi Inaam A.
Published: March 2023

Abstract
Breast and prostate cancer cells home to the bone marrow, where they presumably hijack the hematopoietic stem cell niche. We characterize here the elusive premetastatic niche by examining the role of mesenchymal stromal cells (MSC) in cancer cell homing. Decreasing the number of MSC pharmacologically enhanced cancer cell homing to the bone marrow in mice. In contrast, increasing the number of these MSCs by various interventions including G-CSF administration diminished cancer cell homing. The MSC subpopulation that correlated best with cancer cells expressed stem, endothelial, and pericytic cell markers, suggesting these cells represent an undifferentiated component of the niche with vascular commitment. In humans, a MSC subpopulation carrying markers for endothelial and pericytic cells was lower in the presence of cytokeratin+ cells in bone marrow. Taken together, our data show that a subpopulation of MSC with both endothelial and pericytic cell surface markers suppresses the homing of cancer cells to the bone marrow. Similar to the presence of cytokeratin+ cells in the bone marrow, this MSC subpopulation could prove useful in determining the risk of metastatic disease, and its manipulation might offer a new possibility for diminishing bone metastasis formation.

Significance: These findings establish an inverse relationship between a subpopulation of mesenchymal stromal cells and cancer cells in the bone marrow. Cancer Res; 78(1); 129–42. ©2017 AACR.
Data from LSD1 Stimulates Cancer-Associated Fibroblasts to Drive Notch3-Dependent Self-Renewal of Liver Cancer Stem–like Cells
Authors: Liu Chungang , Liu Limei , Chen Xuejiao , Cheng Jiamin , Zhang Heng , Zhang Chengcheng , Shan Juanjuan , Shen Junjie , Qian Cheng
Published: March 2023

Abstract
Cancer stem-like cells (CSC) in hepatocellular carcinoma (HCC) are thought to mediate therapeutic resistance and poor survival outcomes, but their intrinsic and extrinsic control is not well understood. In this study, we found that the chromatin modification factor LSD1 is highly expressed in HCC CSC where it decreases during differentiation. LSD1 was responsible for maintaining CSC self-renewal and tumorigenicity in HCC, and its overexpression was sufficient to drive self-renewal of non-CSC. Levels of acetylated LSD1 were low in CSC with high LSD1 activity, and these CSC were capable of self-renewal. Notch signaling activated LSD1 through induction of the sirtuin SIRT1, leading to deacetylation and activation of LSD1 and CSC self-renewal. Notably, we found that LSD1 expression was increased in cancer-associated fibroblasts (CAF) as an upstream driver of Notch3-mediated CSC self-renewal. In clinical specimens of HCC, the presence of CAF, LSD1, and Notch3 strongly associated with poor patient survival. Overall, our results reveal that CAF-induced expression of Notch3 is responsible for LSD1 activation in CSC, driving their self-renewal in HCC.

Significance: These seminal findings illuminate a complex pathway in the tissue microenvironment of liver cancer, which is responsible for orchestrating the self-renewal of stem-like cancer cells, with potential implications to improve therapy and limit relapses. Cancer Res; 78(4); 938–49. ©2017 AACR.
Data from Nkx2-2as Suppression Contributes to the Pathogenesis of Sonic Hedgehog Medulloblastoma
Authors: Zhang Yimeng , Wang Ting , Wang Shan , Xiong Yanlu , Zhang Rui , Zhang Xiang , Zhao Jing , Yang An-Gang , Wang Lei , Jia Lintao
Published: March 2023

Abstract
Aberrant Hedgehog signaling and excessive activation of the Gli family of transcriptional activators are key drivers of medulloblastoma (MB), the most common human pediatric brain malignancy. MB originates mainly from cerebellar granule neuron progenitors (CGNP), but the mechanisms underlying CGNP transformation remain largely obscure. In this study, we found that suppression of the noncoding RNA Nkx2-2as promoted Sonic Hedgehog (Shh)-potentiated MB development. Nkx2-2as functioned as a competing endogenous RNA against miR-103 and miR-107, sequestering them and thereby derepressing their tumor suppressive targets BTG2 and LATS1 and impeding cell division and migration. We also found that Nkx2-2as tethered miR-548m and abrogated its LATS2 targeting activity. Shh signaling impaired Nkx2-2as expression by upregulating the transcriptional repressor FoxD1. In clinical specimens of Shh-subgroup MB, we validated coordinated expression of the aforementioned proteins. Notably, exogenous expression of Nkx2-2as suppressed tumorigenesis and prolonged animal survival in MB mouse models. Our findings illuminate the role of noncoding RNAs in Hedgehog signaling and MB occurrence, with implications for identifying candidate therapeutic targets for MB treatment.

Significance: These findings illuminate the role of noncoding RNAs in Hedgehog signaling and an interplay between the Hedgehog and Hippo pathways in medulloblastoma pathogenesis. Cancer Res; 78(4); 962–73. ©2017 AACR.
Data from Integrative Genome-Wide Analysis of Long Noncoding RNAs in Diverse Immune Cell Types of Melanoma Patients
Authors: Wang Lei , Felts Sara J. , Van Keulen Virginia P. , Scheid Adam D. , Block Matthew S. , Markovic Svetomir N. , Pease Larry R. , Zhang Yuji
Published: March 2023

Abstract
Genome-wide identification and characterization of long noncoding RNAs (lncRNA) in individual immune cell lineages helps us better understand the driving mechanisms behind melanoma and advance personalized patient treatment. To elucidate the transcriptional landscape in diverse immune cell types of peripheral blood cells (PBC) in stage IV melanoma, we used whole transcriptome RNA sequencing to profile lncRNAs in CD4+, CD8+, and CD14+ PBC from 132 patient samples. Our integrative computational approach identified 27,625 expressed lncRNAs, 2,744 of which were novel. Both T cells (i.e., CD4+ and CD8+ PBC) and monocytes (i.e., CD14+ PBC) exhibited differential transcriptional expression profiles between patients with melanoma and healthy subjects. Cis- and trans-level coexpression analysis suggested that lncRNAs are potentially involved in many important immune-related pathways and the programmed cell death receptor 1 checkpoint pathways. We also identified nine gene coexpression modules significantly associated with melanoma status, all of which were significantly enriched for three mRNA translation processes. Age and melanoma traits closely correlated with each other, implying that melanoma contains age-associated immune changes. Our computational prediction analysis suggests that many cis- and trans-regulatory lncRNAs could interact with multiple transcriptional and posttranscriptional regulatory elements in CD4+, CD8+, and CD14+ PBC, respectively. These results provide novel insights into the regulatory mechanisms involving lncRNAs in individual immune cell types in melanoma and can help expedite cell type-specific immunotherapy treatments for such diseases.

Significance: These findings elucidate melanoma-associated changes to the noncoding transcriptional landscape of distinct immune cell classes, thus providing cell type-specific guidance to targeted immunotherapy regimens. Cancer Res; 78(15); 4411–23. ©2018 AACR.
Data from SlicerDMRI: Open Source Diffusion MRI Software for Brain Cancer Research
Authors: Norton Isaiah , Essayed Walid Ibn , Zhang Fan , Pujol Sonia , Yarmarkovich Alex , Golby Alexandra J. , Kindlmann Gordon , Wassermann Demian , Estepar Raul San Jose , Rathi Yogesh , Pieper Steve , Kikinis Ron , Johnson Hans J. , Westin Carl-Fredrik , O'Donnell Lauren J.
Published: March 2023

Abstract
Diffusion MRI (dMRI) is the only noninvasive method for mapping white matter connections in the brain. We describe SlicerDMRI, a software suite that enables visualization and analysis of dMRI for neuroscientific studies and patient-specific anatomic assessment. SlicerDMRI has been successfully applied in multiple studies of the human brain in health and disease, and here, we especially focus on its cancer research applications. As an extension module of the 3D Slicer medical image computing platform, the SlicerDMRI suite enables dMRI analysis in a clinically relevant multimodal imaging workflow. Core SlicerDMRI functionality includes diffusion tensor estimation, white matter tractography with single and multi-fiber models, and dMRI quantification. SlicerDMRI supports clinical DICOM and research file formats, is open-source and cross-platform, and can be installed as an extension to 3D Slicer (www.slicer.org). More information, videos, tutorials, and sample data are available at dmri.slicer.org. Cancer Res; 77(21); e101–3. ©2017 AACR.
Data from LesionTracker: Extensible Open-Source Zero-Footprint Web Viewer for Cancer Imaging Research and Clinical Trials
Authors: Urban Trinity , Ziegler Erik , Lewis Rob , Hafey Chris , Sadow Cheryl , Van den Abbeele Annick D. , Harris Gordon J.
Published: March 2023

Abstract
Oncology clinical trials have become increasingly dependent upon image-based surrogate endpoints for determining patient eligibility and treatment efficacy. As therapeutics have evolved and multiplied in number, the tumor metrics criteria used to characterize therapeutic response have become progressively more varied and complex. The growing intricacies of image-based response evaluation, together with rising expectations for rapid and consistent results reporting, make it difficult for site radiologists to adequately address local and multicenter imaging demands. These challenges demonstrate the need for advanced cancer imaging informatics tools that can help ensure protocol-compliant image evaluation while simultaneously promoting reviewer efficiency. LesionTracker is a quantitative imaging package optimized for oncology clinical trial workflows. The goal of the project is to create an open source zero-footprint viewer for image analysis that is designed to be extensible as well as capable of being integrated into third-party systems for advanced imaging tools and clinical trials informatics platforms. Cancer Res; 77(21); e119–22. ©2017 AACR.
Data from Anti-CD137 Suppresses Tumor Growth by Blocking Reverse Signaling by CD137 Ligand
Authors: Kang Sang W. , Lee Sang C. , Park So H. , Kim Juyang , Kim Hyeon H. , Lee Hyeon-Woo , Seo Su K. , Kwon Byoung S. , Cho Hong R. , Kwon Byungsuk
Published: March 2023

Abstract
CD137 (4-1BB) is a T-cell costimulatory molecule, and agonstic CD137 antibodies are currently being evaluated in the clinic as cancer immunotherapy. Recently, it was found that CD137−/− mice or mice injected with agonistic anti-CD137 antibodies exhibit heightened antitumor responses, contrary to expectations based on other knowledge of CD137 function. Here, we report findings related to reverse signaling by CD137 ligand (CD137L) in antigen-presenting dendritic cells (DC) in tumors that address these paradoxical results. Specifically, CD137L suppressed intratumoral differentiation of IL12-producing CD103+ DC and type 1 tumor-associated macrophages (TAM). Differentiation of these cell types is important because they are required to generate IFNγ-producing CD8+ cytotoxic T lymphocytes (Tc1). Notably, CD137L blockade increased levels of IL12 and IFNγ, which promoted intratumoral differentiation of IFNγ-producing Tc1, IL12-producing CD103+ DC, and type 1 TAM within tumors. Our results offer an explanation for the paradoxical effects of CD137 blockade, based on differential immunomodulatory effects of CD137 signaling and reverse signaling in T cells and DC, respectively. Further, they show how CD137L blockade can seed a forward-feedback loop for activation of CD103+ DC/type 1 TAM and Tc1 that can create a self-perpetuating cycle of highly effective immunosurveillance. Cancer Res; 77(21); 5989–6000. ©2017 AACR.