bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Genomic Status of MET Potentiates Sensitivity to MET and MEK Inhibition in NF1-Related Malignant Peripheral Nerve Sheath Tumors
Authors: Peacock Jacqueline D. , Pridgeon Matthew G. , Tovar Elizabeth A. , Essenburg Curt J. , Bowman Megan , Madaj Zachary , Koeman Julie , Boguslawski Elissa A. , Grit Jamie , Dodd Rebecca D. , Khachaturov Vadim , Cardona Diana M. , Chen Mark , Kirsch David G. , Maina Flavio , Dono Rosanna , Winn Mary E. , Graveel Carrie R. , Steensma Matthew R.
Published: March 2023

Abstract
Malignant peripheral nerve sheath tumors (MPNST) are highly resistant sarcomas that occur in up to 13% of individuals with neurofibromatosis type I (NF1). Genomic analysis of longitudinally collected tumor samples in a case of MPNST disease progression revealed early hemizygous microdeletions in NF1 and TP53, with progressive amplifications of MET, HGF, and EGFR. To examine the role of MET in MPNST progression, we developed mice with enhanced MET expression and Nf1 ablation (Nf1fl/ko;lox-stop-loxMETtg/+;Plp-creERTtg/+; referred to as NF1-MET). NF1-MET mice express a robust MPNST phenotype in the absence of additional mutations. A comparison of NF1-MET MPNSTs with MPNSTs derived from Nf1ko/+;p53R172H;Plp-creERTtg/+ (NF1-P53) and Nf1ko/+;Plp-creERTtg/+ (NF1) mice revealed unique Met, Ras, and PI3K signaling patterns. NF1-MET MPNSTs were uniformly sensitive to the highly selective MET inhibitor, capmatinib, whereas a heterogeneous response to MET inhibition was observed in NF1-P53 and NF1 MPNSTs. Combination therapy of capmatinib and the MEK inhibitor trametinib resulted in reduced response variability, enhanced suppression of tumor growth, and suppressed RAS/ERK and PI3K/AKT signaling. These results highlight the influence of concurrent genomic alterations on RAS effector signaling and therapy response to tyrosine kinase inhibitors. Moreover, these findings expand our current understanding of the role of MET signaling in MPNST progression and identify a potential therapeutic niche for NF1-related MPNSTs.

Significance: Longitudinal genomic analysis reveals a positive selection for MET and HGF copy number gain early in malignant peripheral nerve sheath tumor progression. Cancer Res; 78(13); 3672–87. ©2018 AACR.
Data from Gene Expression Integration into Pathway Modules Reveals a Pan-Cancer Metabolic Landscape
Authors: Cubuk Cankut , Hidalgo Marta R. , Amadoz Alicia , Pujana Miguel A. , Mateo Francesca , Herranz Carmen , Carbonell-Caballero Jose , Dopazo Joaquin
Published: March 2023

Abstract
Metabolic reprogramming plays an important role in cancer development and progression and is a well-established hallmark of cancer. Despite its inherent complexity, cellular metabolism can be decomposed into functional modules that represent fundamental metabolic processes. Here, we performed a pan-cancer study involving 9,428 samples from 25 cancer types to reveal metabolic modules whose individual or coordinated activity predict cancer type and outcome, in turn highlighting novel therapeutic opportunities. Integration of gene expression levels into metabolic modules suggests that the activity of specific modules differs between cancers and the corresponding tissues of origin. Some modules may cooperate, as indicated by the positive correlation of their activity across a range of tumors. The activity of many metabolic modules was significantly associated with prognosis at a stronger magnitude than any of their constituent genes. Thus, modules may be classified as tumor suppressors and oncomodules according to their potential impact on cancer progression. Using this modeling framework, we also propose novel potential therapeutic targets that constitute alternative ways of treating cancer by inhibiting their reprogrammed metabolism. Collectively, this study provides an extensive resource of predicted cancer metabolic profiles and dependencies.

Significance: Combining gene expression with metabolic modules identifies molecular mechanisms of cancer undetected on an individual gene level and allows discovery of new potential therapeutic targets. Cancer Res; 78(21); 6059–72. ©2018 AACR.
Data from Long Noncoding RNA CRYBG3 Blocks Cytokinesis by Directly Binding G-Actin
Authors: Pei Hailong , Hu Wentao , Guo Ziyang , Chen Huaiyuan , Ma Ji , Mao Weidong , Li Bingyan , Wang Aiqing , Wan Jianmei , Zhang Jian , Nie Jing , Zhou Guangming , Hei Tom K.
Published: March 2023

Abstract
The dynamic interchange between monomeric globular actin (G-actin) and polymeric filamentous actin filaments (F-actin) is fundamental and essential to many cellular processes, including cytokinesis and maintenance of genomic stability. Here, we report that the long noncoding RNA LNC CRYBG3 directly binds G-actin to inhibit its polymerization and formation of contractile rings, resulting in M-phase cell arrest. Knockdown of LNC CRYBG3 in tumor cells enhanced their malignant phenotypes. Nucleotide sequence 228-237 of the full-length LNC CRYBG3 and the ser14 domain of β-actin is essential for their interaction, and mutation of either of these sites abrogated binding of LNC CRYBG3 to G-actin. Binding of LNC CRYBG3 to G-actin blocked nuclear localization of MAL, which consequently kept serum response factor (SRF) away from the promoter region of several immediate early genes, including JUNB and Arp3, which are necessary for cellular proliferation, tumor growth, adhesion, movement, and metastasis. These findings reveal a novel lncRNA-actin-MAL-SRF pathway and highlight LNC CRYBG3 as a means to block cytokinesis and to treat cancer by targeting the actin cytoskeleton.

Significance: Identification of the long noncoding RNA LNC CRYBG3 as a mediator of microfilament disorganization marks it as a novel therapeutic antitumor strategy. Cancer Res; 78(16); 4563–72. ©2018 AACR.
Data from GFPT2-Expressing Cancer-Associated Fibroblasts Mediate Metabolic Reprogramming in Human Lung Adenocarcinoma
Authors: Zhang Weiruo , Bouchard Gina , Yu Alice , Shafiq Majid , Jamali Mehran , Shrager Joseph B. , Ayers Kelsey , Bakr Shaimaa , Gentles Andrew J. , Diehn Maximilian , Quon Andrew , West Robert B. , Nair Viswam , van de Rijn Matt , Napel Sandy , Plevritis Sylvia K.
Published: March 2023

Abstract
Metabolic reprogramming of the tumor microenvironment is recognized as a cancer hallmark. To identify new molecular processes associated with tumor metabolism, we analyzed the transcriptome of bulk and flow-sorted human primary non–small cell lung cancer (NSCLC) together with 18FDG-PET scans, which provide a clinical measure of glucose uptake. Tumors with higher glucose uptake were functionally enriched for molecular processes associated with invasion in adenocarcinoma and cell growth in squamous cell carcinoma (SCC). Next, we identified genes correlated to glucose uptake that were predominately overexpressed in a single cell–type comprising the tumor microenvironment. For SCC, most of these genes were expressed by malignant cells, whereas in adenocarcinoma, they were predominately expressed by stromal cells, particularly cancer-associated fibroblasts (CAF). Among these adenocarcinoma genes correlated to glucose uptake, we focused on glutamine-fructose-6-phosphate transaminase 2 (GFPT2), which codes for the glutamine-fructose-6-phosphate aminotransferase 2 (GFAT2), a rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), which is responsible for glycosylation. GFPT2 was predictive of glucose uptake independent of GLUT1, the primary glucose transporter, and was prognostically significant at both gene and protein level. We confirmed that normal fibroblasts transformed to CAF-like cells, following TGFβ treatment, upregulated HBP genes, including GFPT2, with less change in genes driving glycolysis, pentose phosphate pathway, and TCA cycle. Our work provides new evidence of histology-specific tumor stromal properties associated with glucose uptake in NSCLC and identifies GFPT2 as a critical regulator of tumor metabolic reprogramming in adenocarcinoma.

Significance: These findings implicate the hexosamine biosynthesis pathway as a potential new therapeutic target in lung adenocarcinoma. Cancer Res; 78(13); 3445–57. ©2018 AACR.
Data from Gene Regulatory Network Analysis Identifies Sex-Linked Differences in Colon Cancer Drug Metabolism
Authors: Lopes-Ramos Camila M. , Kuijjer Marieke L. , Ogino Shuji , Fuchs Charles S. , DeMeo Dawn L. , Glass Kimberly , Quackenbush John
Published: March 2023

Abstract
Understanding sex differences in colon cancer is essential to advance disease prevention, diagnosis, and treatment. Males have a higher risk of developing colon cancer and a lower survival rate than women. However, the molecular features that drive these sex differences are poorly understood. In this study, we use both transcript-based and gene regulatory network methods to analyze RNA-seq data from The Cancer Genome Atlas for 445 patients with colon cancer. We compared gene expression between tumors in men and women and observed significant sex differences in sex chromosome genes only. We then inferred patient-specific gene regulatory networks and found significant regulatory differences between males and females, with drug and xenobiotics metabolism via cytochrome P450 pathways more strongly targeted in females. This finding was validated in a dataset of 1,193 patients from five independent studies. While targeting, the drug metabolism pathway did not change overall survival for males treated with adjuvant chemotherapy, females with greater targeting showed an increase in 10-year overall survival probability, 89% [95% confidence interval (CI), 78–100] survival compared with 61% (95% CI, 45–82) for women with lower targeting, respectively (P = 0.034). Our network analysis uncovers patterns of transcriptional regulation that differentiate male and female colon cancer and identifies differences in regulatory processes involving the drug metabolism pathway associated with survival in women who receive adjuvant chemotherapy. This approach can be used to investigate the molecular features that drive sex differences in other cancers and complex diseases.

Significance: A network-based approach reveals that sex-specific patterns of gene targeting by transcriptional regulators are associated with survival outcome in colon cancer. This approach can be used to understand how sex influences progression and response to therapies in other cancers. Cancer Res; 78(19); 5538–47. ©2018 AACR.
Data from The Canonical Wnt Pathway Drives Macropinocytosis in Cancer
Authors: Redelman-Sidi Gil , Binyamin Anna , Gaeta Isabella , Palm Wilhelm , Thompson Craig B. , Romesser Paul B. , Lowe Scott W. , Bagul Mukta , Doench John G. , Root David E. , Glickman Michael S.
Published: March 2023

Abstract
Macropinocytosis has emerged as an important pathway of protein acquisition in cancer cells, particularly in tumors with activated Ras such as pancreatic and colon cancer. Macropinocytosis is also the route of entry of Bacillus Calmette-Guerin (BCG) and other microbial therapies of cancer. Despite this important role in tumor biology and therapy, the full mechanisms by which cancer cells can activate macropinocytosis remain incompletely defined. Using BCG uptake to assay macropinocytosis, we executed a genome-wide shRNA screen for macropinocytosis activators and identified Wnt pathway activation as a strong driver of macropinocytosis. Wnt-driven macropinocytosis was downstream of the β-catenin–dependent canonical Wnt pathway, was PAK1 dependent, and supported albumin-dependent growth in Ras-WT cells. In cells with activated Ras-dependent macropinocytosis, pharmacologic or genetic inhibition of Wnt signaling suppressed macropinocytosis. In a mouse model of Wnt-driven colonic hyperplasia via APC silencing, Wnt-activated macropinocytosis stimulated uptake of luminal microbiota, a process reversed by topical pharmacologic inhibition of macropinocytosis. Our findings indicate that Wnt pathway activation drives macropinocytosis in cancer, and its inhibition could provide a therapeutic vulnerability in Wnt-driven intestinal polyposis and cancers with Wnt activation.

Significance: The Wnt pathway drives macropinocytosis in cancer cells, thereby contributing to cancer growth in nutrient-deficient conditions and, in the context of colon cancer, to the early phases of oncogenesis. Cancer Res; 78(16); 4658–70. ©2018 AACR.
Data from Extracellular Citrate Affects Critical Elements of Cancer Cell Metabolism and Supports Cancer Development In Vivo
Authors: Mycielska Maria E. , Dettmer Katja , Rümmele Petra , Schmidt Katharina , Prehn Cornelia , Milenkovic Vladimir M. , Jagla Wolfgang , Madej Gregor M. , Lantow Margareta , Schladt Moritz , Cecil Alexander , Koehl Gudrun E. , Eggenhofer Elke , Wachsmuth Christian J. , Ganapathy Vadivel , Schlitt Hans J. , Kunzelmann Karl , Ziegler Christine , Wetzel Christian H. , Gaumann Andreas , Lang Sven A. , Adamski Jerzy , Oefner Peter J. , Geissler Edward K.
Published: March 2023

Abstract
Glycolysis and fatty acid synthesis are highly active in cancer cells through cytosolic citrate metabolism, with intracellular citrate primarily derived from either glucose or glutamine via the tricarboxylic acid cycle. We show here that extracellular citrate is supplied to cancer cells through a plasma membrane-specific variant of the mitochondrial citrate transporter (pmCiC). Metabolomic analysis revealed that citrate uptake broadly affected cancer cell metabolism through citrate-dependent metabolic pathways. Treatment with gluconate specifically blocked pmCiC and decreased tumor growth in murine xenografts of human pancreatic cancer. This treatment altered metabolism within tumors, including fatty acid metabolism. High expression of pmCiC was associated with invasion and advanced tumor stage across many human cancers. These findings support the exploration of extracellular citrate transport as a novel potential target for cancer therapy.

Significance: Uptake of extracellular citrate through pmCiC can be blocked with gluconate to reduce tumor growth and to alter metabolic characteristics of tumor tissue. Cancer Res; 78(10); 2513–23. ©2018 AACR.
Data from An Oncolytic Virus Expressing a T-cell Engager Simultaneously Targets Cancer and Immunosuppressive Stromal Cells
Authors: Freedman Joshua D. , Duffy Margaret R. , Lei-Rossmann Janet , Muntzer Alice , Scott Eleanor M. , Hagel Joachim , Campo Leticia , Bryant Richard J. , Verrill Clare , Lambert Adam , Miller Paul , Champion Brian R. , Seymour Leonard W. , Fisher Kerry D.
Published: March 2023

Abstract
Effective immunotherapy of stromal-rich tumors requires simultaneous targeting of cancer cells and immunosuppressive elements of the microenvironment. Here, we modified the oncolytic group B adenovirus enadenotucirev to express a stroma-targeted bispecific T-cell engager (BiTE). This BiTE bound fibroblast activation protein on cancer-associated fibroblasts (CAF) and CD3ϵ on T cells, leading to potent T-cell activation and fibroblast death. Treatment of fresh clinical biopsies, including malignant ascites and solid prostate cancer tissue, with FAP-BiTE–encoding virus induced activation of tumor-infiltrating PD1+ T cells to kill CAFs. In ascites, this led to depletion of CAF-associated immunosuppressive factors, upregulation of proinflammatory cytokines, and increased gene expression of markers of antigen presentation, T-cell function, and trafficking. M2-like ascites macrophages exhibited a proinflammatory repolarization, indicating spectrum-wide alteration of the tumor microenvironment. With this approach, we have actively killed both cancer cells and tumor fibroblasts, reversing CAF-mediated immunosuppression and yielding a potent single-agent therapeutic that is ready for clinical assessment.
Significance:
An engineered oncolytic adenovirus that encodes a bispecific antibody combines direct virolysis with endogenous T-cell activation to attack stromal fibroblasts, providing a multimodal treatment strategy within a single therapeutic agent.
Data from A Mutant p53-Dependent Embryonic Stem Cell Gene Signature Is Associated with Augmented Tumorigenesis of Stem Cells
Authors: Koifman Gabriela , Shetzer Yoav , Eizenberger Shay , Solomon Hilla , Rotkopf Ron , Molchadsky Alina , Lonetto Giuseppe , Goldfinger Naomi , Rotter Varda
Published: March 2023

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

Significance: Mesenchymal cancer stem cell-like cell lines express a mutant p53-dependent embryonic stem cell gene signature, which can serve as a potential prognostic biomarker and therapeutic target in cancer. Cancer Res; 78(20); 5833–47. ©2018 AACR.
Data from TRIM59 Promotes Gliomagenesis by Inhibiting TC45 Dephosphorylation of STAT3
Authors: Sang Youzhou , Li Yanxin , Song Lina , Alvarez Angel A. , Zhang Weiwei , Lv Deguan , Tang Jianming , Liu Feng , Chang Zhijie , Hatakeyama Shigetsugu , Hu Bo , Cheng Shi-Yuan , Feng Haizhong
Published: March 2023

Abstract
Aberrant EGFR signaling is a common driver of glioblastoma (GBM) pathogenesis; however, the downstream effectors that sustain this oncogenic pathway remain unclarified. Here we demonstrate that tripartite motif-containing protein 59 (TRIM59) acts as a new downstream effector of EGFR signaling by regulating STAT3 activation in GBM. EGFR signaling led to TRIM59 upregulation through SOX9 and enhanced the interaction between TRIM59 and nuclear STAT3, which prevents STAT3 dephosphorylation by the nuclear form of T-cell protein tyrosine phosphatase (TC45), thereby maintaining transcriptional activation and promoting tumorigenesis. Silencing TRIM59 suppresses cell proliferation, migration, and orthotopic xenograft brain tumor formation of GBM cells and glioma stem cells. Evaluation of GBM patient samples revealed an association between EGFR activation, TRIM59 expression, STAT3 phosphorylation, and poor prognoses. Our study identifies TRIM59 as a new regulator of oncogenic EGFR/STAT3 signaling and as a potential therapeutic target for GBM patients with EGFR activation.

Significance: These findings identify a novel component of the EGFR/STAT3 signaling axis in the regulation of glioma tumorigenesis. Cancer Res; 78(7); 1792–804. ©2018 AACR.
Data from LRRC15 Is a Novel Mesenchymal Protein and Stromal Target for Antibody–Drug Conjugates
Authors: Purcell James W. , Tanlimco Sonia G. , Hickson Jonathan , Fox Melvin , Sho Mien , Durkin Lisa , Uziel Tamar , Powers Rick , Foster Kelly , McGonigal Thomas , Kumar Subashri , Samayoa Josue , Zhang Dong , Palma Joann P. , Mishra Sasmita , Hollenbaugh Diane , Gish Kurt , Morgan-Lappe Susan E. , Hsi Eric D. , Chao Debra T.
Published: March 2023

Abstract
Progress in understanding tumor stromal biology has been constrained in part because cancer-associated fibroblasts (CAF) are a heterogeneous population with limited cell-type–specific protein markers. Using RNA expression profiling, we identified the membrane protein leucine-rich repeat containing 15 (LRRC15) as highly expressed in multiple solid tumor indications with limited normal tissue expression. LRRC15 was expressed on stromal fibroblasts in many solid tumors (e.g., breast, head and neck, lung, pancreatic) as well as directly on a subset of cancer cells of mesenchymal origin (e.g., sarcoma, melanoma, glioblastoma). LRRC15 expression was induced by TGFβ on activated fibroblasts (αSMA+) and on mesenchymal stem cells. These collective findings suggested LRRC15 as a novel CAF and mesenchymal marker with utility as a therapeutic target for the treatment of cancers with LRRC15-positive stromal desmoplasia or cancers of mesenchymal origin. ABBV-085 is a monomethyl auristatin E (MMAE)-containing antibody–drug conjugate (ADC) directed against LRRC15, and it demonstrated robust preclinical efficacy against LRRC15 stromal-positive/cancer-negative, and LRRC15 cancer-positive models as a monotherapy, or in combination with standard-of-care therapies. ABBV-085′s unique mechanism of action relied upon the cell-permeable properties of MMAE to preferentially kill cancer cells over LRRC15-positive CAF while also increasing immune infiltrate (e.g., F4/80+ macrophages) in the tumor microenvironment. In summary, these findings validate LRRC15 as a novel therapeutic target in multiple solid tumor indications and support the ongoing clinical development of the LRRC15-targeted ADC ABBV-085.

Significance: These findings identify LRRC15 as a new marker of cancer-associated fibroblasts and cancers of mesenchymal origin and provide preclinical evidence for the efficacy of an antibody-drug conjugate targeting the tumor stroma. Cancer Res; 78(14); 4059–72. ©2018 AACR.
Data from CSTF2-Induced Shortening of the RAC1 3′UTR Promotes the Pathogenesis of Urothelial Carcinoma of the Bladder
Authors: Chen Xin , Zhang Jia-Xing , Luo Jun-Hang , Wu Song , Yuan Gang-Jun , Ma Ning-Fang , Feng Yong , Cai Mu-Yan , Chen Ri-Xin , Lu Jun , Jiang Li-Juan , Chen Jie-Wei , Jin Xiao-Han , Liu Hai-Liang , Chen Wei , Guan Xin-Yuan , Kang Tie-Bang , Zhou Fang-Jian , Xie Dan
Published: March 2023

Abstract
Shortening of the 3′ untranslated regions (3′UTR) of mRNA is an important mechanism for oncogene activation. However, 3′UTR alteration events, their pathologic functions, and underlying mechanisms in human urothelial carcinoma of the bladder (UCB) are not clear. Here, we combine RNA sequencing, bioinformatics, and clinical studies in two independent cohorts of patients with UCB to identify a novel RAC1 shorter 3′UTR isoform that is frequently expressed in UCB and is critical in the tumorigenesis and acquisition of a poor prognostic phenotype in patients. Short 3′UTR isoform of RAC1 substantially upregulated RAC1 expression by escaping from miRNA-targeted repression and played an essential oncogenic role in UCB pathogenesis. An important cleavage/polyadenylation factor, cleavage stimulation factor 2 (CSTF2), induced 3′UTR shortening of RAC1 in UCB by mediating slow transcriptional elongation at RAC1. Cotranscriptional recruitment of CSTF2 on the GUAAU motif at proximal polyadenylation site of RAC1 attenuated the recruitment of two transcription factors AFF1 and AFF4, causing the defects in elongation. CSTF2 regulated the tumorigenic functions of the shorter RAC1 isoform in UCB cells, enhancing cell proliferation, migration, and invasion. The combination of high expression of CSTF2 and high usage of RAC1 short-3′UTR isoform may be used as a powerful biomarker to predict poor prognosis in UCB. Our findings also suggest a CSTF2-regulated RAC1-3′UTR shortening program as an exploitable therapeutic strategy for patients with UCB.

Significance: These findings demonstrate that the short isoform of RAC1 is critical in UCB tumorigenesis and may have implications for developing new therapeutic strategies to treat this disease. Cancer Res; 78(20); 5848–62. ©2018 AACR.
Data from Hypoxic Tumor-Derived Exosomal miR-301a Mediates M2 Macrophage Polarization via PTEN/PI3Kγ to Promote Pancreatic Cancer Metastasis
Authors: Wang Xiaofeng , Luo Guangtao , Zhang Kundong , Cao Jun , Huang Chen , Jiang Tao , Liu Bingya , Su Liping , Qiu Zhengjun
Published: March 2023

Abstract
Exosomes are emerging as important mediators of the cross-talk between tumor cells and the microenvironment. However, the mechanisms by which exosomes modulate tumor development under hypoxia in pancreatic cancer remain largely unknown. Here, we found that hypoxic exosomes derived from pancreatic cancer cells activate macrophages to the M2 phenotype in a HIF1a or HIF2a–dependent manner, which then facilitates the migration, invasion, and epithelial–mesenchymal transition of pancreatic cancer cells. Given that exosomes have been shown to transport miRNAs to alter cellular functions, we discovered that miR-301a-3p was highly expressed in hypoxic pancreatic cancer cells and enriched in hypoxic pancreatic cancer cell–derived exosomes. Circulating exosomal miR-301a-3p levels positively associated with depth of invasion, lymph node metastasis, late TNM stage, and poor prognosis of pancreatic cancer. Hypoxic exosomal miR-301a-3p induced the M2 polarization of macrophages via activation of the PTEN/PI3Kγ signaling pathway. Coculturing of pancreatic cancer cells with macrophages in which miR-301a-3p was upregulated or treated with hypoxic exosomes enhanced their metastatic capacity. Collectively, these data indicate that pancreatic cancer cells generate miR-301a-3p–rich exosomes in a hypoxic microenvironment, which then polarize macrophages to promote malignant behaviors of pancreatic cancer cells. Targeting exosomal miR-301a-3p may provide a potential diagnosis and treatment strategy for pancreatic cancer.

Significance: These findings identify an exosomal miRNA critical for microenvironmental cross-talk that may prove to be a potential target for diagnosis and treatment of pancreatic cancer.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4586/F1.large.jpg. Cancer Res; 78(16); 4586–98. ©2018 AACR.
Data from Transketolase Regulates the Metabolic Switch to Control Breast Cancer Cell Metastasis via the α-Ketoglutarate Signaling Pathway
Authors: Tseng Chien-Wei , Kuo Wen-Hung , Chan Shih-Hsuan , Chan Hong-Lin , Chang King-Jen , Wang Lu-Hai
Published: March 2023

Abstract
Although metabolic reprogramming is recognized as a hallmark of tumorigenesis and progression, little is known about metabolic enzymes and oncometabolites that regulate breast cancer metastasis, and very few metabolic molecules have been identified as potential therapeutic targets. In this study, the transketolase (TKT) expression correlated with tumor size in the 4T1/BALB/c syngeneic model. In addition, TKT expression was higher in lymph node metastases compared with primary tumor or normal tissues of patients, and high TKT levels were associated with poor survival. Depletion of TKT or addition of alpha-ketoglutarate (αKG) enhanced the levels of tumor suppressors succinate dehydrogenase and fumarate hydratase (FH), decreasing oncometabolites succinate and fumarate, and further stabilizing HIF prolyl hydroxylase 2 (PHD2) and decreasing HIF1α, ultimately suppressing breast cancer metastasis. Reduced TKT or addition of αKG mediated a dynamic switch of glucose metabolism from glycolysis to oxidative phosphorylation. Various combinations of the TKT inhibitor oxythiamine, docetaxel, and doxorubicin enhanced cell death in triple-negative breast cancer (TNBC) cells. Furthermore, oxythiamine treatment led to increased levels of αKG in TNBC cells. Together, our study has identified a novel TKT-mediated αKG signaling pathway that regulates breast cancer oncogenesis and can be exploited as a modality for improving therapy.

Significance: These findings uncover the clinical significance of TKT in breast cancer progression and metastasis and demonstrate effective therapy by inhibiting TKT or by adding αKG. Cancer Res; 78(11); 2799–812. ©2018 AACR.
Data from A RIPK3-PGE2 Circuit Mediates Myeloid-Derived Suppressor Cell–Potentiated Colorectal Carcinogenesis
Authors: Yan Guifang , Zhao Huakan , Zhang Qi , Zhou Yu , Wu Lei , Lei Juan , Wang Xiang , Zhang Jiangang , Zhang Xiao , Zheng Lu , Du Guangsheng , Xiao Weidong , Tang Bo , Miao Hongming , Li Yongsheng
Published: March 2023

Abstract
Receptor-interacting protein kinase 3 (RIPK3) is essential for mucosal repair in inflammatory bowel diseases (IBD) and colorectal cancer. However, its role in tumor immunity is unknown. Here, we report that decreased RIPK3 in colorectal cancer correlates with the accumulation of myeloid-derived suppressor cells (MDSC). Deficiency of RIPK3 boosted tumorigenesis via accumulation and immunosuppressive activity of MDSCs. Reduction of RIPK3 in MDSC and colorectal cancer cells elicited NFκB-transcribed COX-2, which catalyzed the synthesis of prostaglandin E2 (PGE2). PGE2 exacerbated the immunosuppressive activity of MDSCs and accelerated tumor growth. Moreover, PGE2 suppressed RIPK3 expression while enhancing expression of NFκB and COX-2 in MDSCs and colorectal cancer cells. Inhibition of COX-2 or PGE2 receptors reversed the immunosuppressive activity of MDSCs and dampened tumorigenesis. Patient databases also delineated the correlation of RIPK3 and COX-2 expression with colorectal cancer survival. Our findings demonstrate a novel signaling circuit by which RIPK3 and PGE2 regulate tumor immunity, providing potential ideas for immunotherapy against colorectal cancer.

Significance: A novel signaling circuit involving RIPK3 and PGE2 enhances accumulation and immunosuppressive activity of MDSCs, implicating its potential as a therapeutic target in anticancer immunotherapy.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/19/5586/F1.large.jpg. Cancer Res; 78(19); 5586–99. ©2018 AACR.
Data from Genomic Characterization of Six Virus-Associated Cancers Identifies Changes in the Tumor Immune Microenvironment and Altered Genetic Programs
Authors: Varn Frederick S. , Schaafsma Evelien , Wang Yue , Cheng Chao
Published: March 2023

Abstract
Viruses affect approximately 20% of all human cancers and induce expression of immunogenic viral oncoproteins that make these tumors potent targets for immune checkpoint inhibitors. In this study, we apply computational tools to The Cancer Genome Atlas (TCGA) and other genomic datasets to define how virus infection shapes the tumor immune microenvironment and genetic architecture of 6 virus-associated tumor types. Across cancers, the cellular composition of the microenvironment varied by viral status, with virus-positive tumors often exhibiting increased infiltration of cytolytic cell types compared with their virus-negative counterparts. Analyses of the infiltrating T-cell receptor repertoire in these patients revealed that Epstein–Barr virus infection was associated with decreased receptor diversity in multiple cancers, suggesting an antigen-driven clonal T-cell response. Tissue-specific gene-expression signatures capturing virus-associated transcriptomic changes successfully predicted virus status in independent datasets and were associated with both immune- and proliferation-related features that were predictive of patient prognosis. Together, the analyses presented suggest viruses have distinct effects in different tumors, with implications for immunotherapy.

Significance: This study utilizes TCGA and other genomic datasets to further our understanding of how viruses affect the tumor immune response in different cancer types.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/22/6413/F1.large.jpg. Cancer Res; 78(22); 6413–23. ©2018 AACR.
Data from Intrathecal Viral Vector Delivery of Trastuzumab Prevents or Inhibits Tumor Growth of Human HER2-Positive Xenografts in Mice
Authors: Rothwell William T. , Bell Peter , Richman Laura K. , Limberis Maria P. , Tretiakova Anna P. , Li Mingyao , Wilson James M.
Published: March 2023

Abstract
Breast cancer brain metastases are a deadly sequela of primary breast tumors that overexpress human epidermal growth factor receptor 2 (HER2); median survival for patients with these tumors is 10 to 13 months from the time of diagnosis. Current treatments for HER2-positive breast cancer brain metastases are invasive, toxic, and largely ineffective. Here, we have developed an adeno-associated virus serotype 9 (AAV9) vector to express the anti-HER2 monoclonal antibody trastuzumab (Herceptin) in vivo. A single prophylactic intrathecal administration of AAV9.trastuzumab vector in a novel orthotopic Rag1−/− murine xenograft model of HER2-positive breast cancer brain metastases significantly increased median survival, attenuated brain tumor growth, and preserved both the HER2 antigen specificity and the natural killer cell–associated mechanism of action of trastuzumab. When administered as a tumor treatment, AAV9.trastuzumab increased median survival. Dose-escalation studies revealed that higher doses of AAV9.trastuzumab resulted in smaller tumor volumes. Our results indicate that intrathecal AAV9.trastuzumab may provide significant antitumor activity in patients with HER2-positive breast cancer brain metastases.

Significance: Intrathecal delivery of trastuzumab via adeno-associated virus has the potential to become a novel, integral part of adjuvant therapy for patients with HER2-positive breast cancer brain metastases. Cancer Res; 78(21); 6171–82. ©2018 AACR.
Data from Inhibition of Casein Kinase 2 Disrupts Differentiation of Myeloid Cells in Cancer and Enhances the Efficacy of Immunotherapy in Mice
Authors: Hashimoto Ayumi , Gao Chan , Mastio Jerome , Kossenkov Andrew , Abrams Scott I. , Purandare Ashok V. , Desilva Heshani , Wee Susan , Hunt John , Jure-Kunkel Maria , Gabrilovich Dmitry I.
Published: March 2023

Abstract
The role of myeloid cells as regulators of tumor progression that significantly impact the efficacy of cancer immunotherapies makes them an attractive target for inhibition. Here we explore the effect of a novel, potent, and selective inhibitor of serine/threonine protein kinase casein kinase 2 (CK2) on modulating myeloid cells in the tumor microenvironment. Although inhibition of CK2 caused only a modest effect on dendritic cells in tumor-bearing mice, it substantially reduced the amount of polymorphonuclear myeloid-derived suppressor cells and tumor-associated macrophages. This effect was not caused by the induction of apoptosis, but rather by a block of differentiation. Our results implicated downregulation of CCAAT-enhancer binding protein-α in this effect. Although CK2 inhibition did not directly affect tumor cells, it dramatically enhanced the antitumor activity of immune checkpoint receptor blockade using anti-CTLA-4 antibody. These results suggest a potential role of CK2 inhibitors in combination therapies against cancer.

Significance: These findings demonstrate the modulatory effects of casein kinase 2 inhibitors on myeloid cell differentiation in the tumor microenvironment, which subsequently synergize with the antitumor effects of checkpoint inhibitor CTLA4. Cancer Res; 78(19); 5644–55. ©2018 AACR.
Data from Canonical Wnt Signaling Remodels Lipid Metabolism in Zebrafish Hepatocytes following Ras Oncogenic Insult
Authors: Yao Yuxiao , Sun Shaoyang , Wang Jingjing , Fei Fei , Dong Zhaoru , Ke Ai-Wu , He Ruoyu , Wang Lei , Zhang Lili , Ji Min-Biao , Li Qiang , Yu Min , Shi Guo-Ming , Fan Jia , Gong Zhiyuan , Wang Xu
Published: March 2023

Abstract
There is limited understanding of the effects of major oncogenic pathways and their combinatorial actions on lipid composition and transformation during hepatic tumorigenesis. Here, we report a negative correlation of Wnt/Myc activity with steatosis in human hepatocellular carcinoma (HCC) and perform in vivo functional studies using three conditional transgenic zebrafish models. Double-transgenic zebrafish larvae conditionally expressing human CTNNB1mt and zebrafish tcf7l2 or murine Myc together with krasv12 in hepatocytes led to severe hepatomegaly and significantly attenuated accumulation of lipid droplets and cell senescence triggered by krasv12 expression alone. UPLC-MS–based, nontargeted lipidomic profiling and transcriptome analyses revealed that Wnt/Myc activity promotes triacylglycerol to phospholipid transformation and increases unsaturated fatty acyl groups in phospholipids in a Ras-dependent manner. Small-scale screenings suggested that supplementation of certain free fatty acids (FA) or inhibition of FA desaturation significantly represses hepatic hyperplasia of double-transgenic larvae and proliferation of three human HCC cells with and without sorafenib. Together, our studies reveal novel Ras-dependent functions of Wnt signaling in remodeling the lipid metabolism of cancerous hepatocytes in zebrafish and identify the SCD inhibitor MK8245 as a candidate drug for therapeutic intervention.

Significance: These findings identify FA desaturation as a significant downstream therapeutic target for antagonizing the combinatorial effects of Wnt and Ras signaling pathways in hepatocellular carcinoma.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/19/5548/F1.large.jpg. Cancer Res; 78(19); 5548–60. ©2018 AACR.
Data from Combined MR Imaging of Oxygen Consumption and Supply Reveals Tumor Hypoxia and Aggressiveness in Prostate Cancer Patients
Authors: Hompland Tord , Hole Knut Håkon , Ragnum Harald Bull , Aarnes Eva-Katrine , Vlatkovic Ljiljana , Lie A. Kathrine , Patzke Sebastian , Brennhovd Bjørn , Seierstad Therese , Lyng Heidi
Published: March 2023

Abstract
The established role of hypoxia-induced signaling in prostate cancer growth, metastasis, and response to treatment suggests that a method to image hypoxia in tumors could aid treatment decisions. Here, we present consumption and supply-based hypoxia (CSH) imaging, an approach that integrates images related to oxygen consumption and supply into a single image. This integration algorithm was developed in patients with prostate cancer receiving hypoxia marker pimonidazole prior to prostatectomy. We exploited the intravoxel incoherent motion (IVIM) signal in diagnostic diffusion-weighted (DW) magnetic resonance (MR) images to generate separate images of the apparent diffusion coefficient (ADC) and fractional blood volume (fBV). ADC and fBV correlated with cell density (CD) and blood vessel density (BVD) in histology and whole-mount sections from 35 patients, thus linking ADC to oxygen consumption and fBV to oxygen supply. Pixel-wise plots of ADC versus fBV were utilized to predict the hypoxia status of each pixel in a tumor and to visualize the predicted value in a single image. The hypoxic fraction (HFDWI) of CSH images correlated strongly (R2 = 0.66; n = 41) with pimonidazole immunoscore (HSPimo); this relationship was validated in a second pimonidazole cohort (R2 = 0.54; n = 54). We observed good agreement between CSH images and pimonidazole staining in whole-mount sections. HFDWI correlated with tumor stage and lymph node status, consistent with findings for HSPimo. Moreover, CSH imaging could be applied on histologic CD and BVD images, demonstrating transferability to a histopathology assay. Thus, CSH represents a robust approach for hypoxia imaging in prostate cancer that could easily be translated into clinical practice.

Significance: These findings present a novel imaging strategy that indirectly measures tumor hypoxia and has potential application in a wide variety of solid tumors and other imaging modalities.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4774/F1.large.jpg. Cancer Res; 78(16); 4774–85. ©2018 AACR.
Data from IL1 Receptor Antagonist Controls Transcriptional Signature of Inflammation in Patients with Metastatic Breast Cancer
Authors: Wu Te-Chia , Xu Kangling , Martinek Jan , Young Robyn R. , Banchereau Romain , George Joshy , Turner Jacob , Kim Kyung In , Zurawski Sandra , Wang Xuan , Blankenship Derek , Brookes Hannah M. , Marches Florentina , Obermoser Gerlinde , Lavecchio Elizabeth , Levin Maren K. , Bae Sookyoung , Chung Cheng-Han , Smith Jennifer L. , Cepika Alma-Martina , Oxley Kyp L. , Snipes George J. , Banchereau Jacques , Pascual Virginia , O'Shaughnessy Joyce , Palucka A. Karolina
Published: March 2023

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

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

See related commentary by Dinarello, p. 5200
Data from Dose and Schedule Determine Distinct Molecular Mechanisms Underlying the Efficacy of the p53–MDM2 Inhibitor HDM201
Authors: Jeay Sébastien , Ferretti Stéphane , Holzer Philipp , Fuchs Jeanette , Chapeau Emilie A. , Wartmann Markus , Sterker Dario , Romanet Vincent , Murakami Masato , Kerr Grainne , Durand Eric Y. , Gaulis Swann , Cortes-Cros Marta , Ruetz Stephan , Stachyra Therese-Marie , Kallen Joerg , Furet Pascal , Würthner Jens , Guerreiro Nelson , Halilovic Ensar , Jullion Astrid , Kauffmann Audrey , Kuriakose Emil , Wiesmann Marion , Jensen Michael R. , Hofmann Francesco , Sellers William R.
Published: March 2023

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

Significance: Pulsed high doses versus sustained low doses of the p53-MDM2 inhibitor HDM201 elicit a proapoptotic response from wild-type p53 cancer cells, offering guidance to current clinical trials with this and other drugs that exploit the activity of p53. Cancer Res; 78(21); 6257–67. ©2018 AACR.
Data from Loss of MED12 Induces Tumor Dormancy in Human Epithelial Ovarian Cancer via Downregulation of EGFR
Authors: Luo Xiao-Lin , Deng Cheng-Cheng , Su Xiao-Dong , Wang Fang , Chen Zhen , Wu Xing-Ping , Liang Shao-Bo , Liu Ji-Hong , Fu Li-Wu
Published: March 2023

Abstract
A high rate of disease relapse makes epithelial ovarian cancer (EOC) the leading cause of death among all gynecologic malignancies. These relapses are often due to tumor dormancy. Here we identify the RNA polymerase II transcriptional mediator subunit 12 (MED12) as an important molecular regulator of tumor dormancy. MED12 knockout (KO) induced dormancy of EOC cells in vitro and in vivo, and microarray analysis showed that MED12 KO decreased expression of EGFR. Restoration of EGFR expression in MED12 KO cells restored proliferation. Additionally, MED12 bound to the promoter of EGFR, and correlation studies showed that MED12 expression positively correlated with EGFR expression in EOC patient samples. Clinical data demonstrated that chemotherapy-resistant patients expressed lower levels of MED12 compared with responsive patients. Overall, our data show that MED12 plays an important role in regulating dormancy of EOC through regulation of EGFR.

Significance: MED12 is identified as a novel, important regulator of tumor dormancy in human ovarian cancer. Cancer Res; 78(13); 3532–43. ©2018 AACR.
Data from Reduced Expression of PROX1 Transitions Glioblastoma Cells into a Mesenchymal Gene Expression Subtype
Authors: Goudarzi Kaveh M. , Espinoza Jaime A. , Guo Min , Bartek Jiri , Nistér Monica , Lindström Mikael S. , Hägerstrand Daniel
Published: March 2023

Abstract
The homeodomain transcription factor PROX1 has been linked to several cancer types, including gliomas, but its functions remain to be further elucidated. Here we describe a functional role and the prognostic value of PROX1 in glioblastoma. Low expression of PROX1 correlated with poor overall survival and the mesenchymal glioblastoma subtype signature. The latter finding was recapitulated in vitro, where suppression or overexpression of PROX1 in glioma cell cultures transitioned cells to a mesenchymal or to a nonmesenchymal glioblastoma gene expression signature, respectively. PROX1 modulation affected proliferation rates that coincided with changes in protein levels of CCNA1 and CCNE1 as well as the cyclin inhibitors CDKN1A, CDKN1B, and CDKN1C. Overexpression of SOX2 increased PROX1 expression, but treatment with a CDK2 inhibitor subsequently decreased PROX1 expression, which was paralleled by decreased SOX2 levels. The THRAP3 protein was a novel binding partner for PROX1, and suppression of THRAP3 increased both transcript and protein levels of PROX1. Together, these findings highlight the prognostic value of PROX1 and its role as a regulator of glioblastoma gene expression subtypes, intratumoral heterogeneity, proliferation, and cell-cycle control.

Significance: These findings demonstrate the role and prognostic value of PROX1 in glioblastomas; low PROX1 levels correlate with a mesenchymal gene expression subtype and shorter survival in glioblastoma tumors. Cancer Res; 78(20); 5901–16. ©2018 AACR.