bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from A Genetic Mouse Model of Invasive Endometrial Cancer Driven by Concurrent Loss of Pten and Lkb1 Is Highly Responsive to mTOR Inhibition
Authors: Cheng Hailing , Liu Pixu , Zhang Fan , Xu Erbo , Symonds Lynn , Ohlson Carolynn E. , Bronson Roderick T. , Maira Sauveur-Michel , Di Tomaso Emmanuelle , Li Jane , Myers Andrea P. , Cantley Lewis C. , Mills Gordon B. , Zhao Jean J.
Published: March 2024

Abstract
Signals from the tumor suppressors PTEN and LKB1 converge on mTOR to negatively regulate its function in cancer cells. Notably, both of these suppressors are attenuated in a significant fraction of human endometrial tumors. In this study, we generated a genetic mouse model of endometrial cancer driven by concomitant loss of these suppressors to gain pathophysiological insight into this disease. Dual loss of Pten and Lkb1 in the endometrial epithelium led to rapid development of advanced endometrioid endometrial tumors with 100% penetrance and short host survival. The tumors displayed dysregulated phosphatidylinositol 3-kinase (PI3K)/Akt and Lkb1/Ampk signaling with hyperactivation of mTOR signaling. Treatment with a dual PI3K/mTOR inhibitor, BEZ235, extended the time before tumor onset and prolonged overall survival. The PI3K inhibitor GDC-0941 used as a single agent reduced the growth rate of primary tumor implants in Pten/Lkb1-deficient mice, and the mTOR inhibitor RAD001 was unexpectedly as effective as BEZ235 in triggering tumor regression. In parallel, we also found that ectopic expression of LKB1 in PTEN/LKB1-deficient human endometrial cancer cells increased their sensitivity to PI3K inhibition. Together, our results demonstrated that Pten/Lkb1-deficient endometrial tumors rely strongly on deregulated mTOR signaling, and they provided evidence that LKB1 status may modulate the response of PTEN-deficient tumors to PI3K or mTOR inhibitors. Cancer Res; 74(1); 15–23. ©2013 AACR.
Data from Histone Deacetylase Inhibitor AR-42 Differentially Affects Cell-cycle Transit in Meningeal and Meningioma Cells, Potently Inhibiting NF2-Deficient Meningioma Growth
Authors: Burns Sarah S. , Akhmametyeva Elena M. , Oblinger Janet L. , Bush Matthew L. , Huang Jie , Senner Volker , Chen Ching-Shih , Jacob Abraham , Welling D. Bradley , Chang Long-Sheng
Published: March 2024

Abstract
Meningiomas constitute about 34% of primary intracranial tumors and are associated with increased mortality in patients with neurofibromatosis type 2 (NF2). To evaluate potential medical therapies for these tumors, we have established a quantifiable orthotopic model for NF2-deficient meningiomas. We showed that telomerase-immortalized Ben-Men-1 benign meningioma cells harbored a single nucleotide deletion in NF2 exon 7 and did not express the NF2 protein, merlin. We also showed that AR-42, a pan-histone deacetylase inhibitor, inhibited proliferation of both Ben-Men-1 and normal meningeal cells by increasing expression of p16INK4A, p21CIP1/WAF1, and p27KIP1. In addition, AR-42 increased proapoptotic Bim expression and decreased anti-apoptotic BclXL levels. However, AR-42 predominantly arrested Ben-Men-1 cells at G2–M whereas it induced cell-cycle arrest at G1 in meningeal cells. Consistently, AR-42 substantially decreased the levels of cyclin D1, E, and A, and proliferating cell nuclear antigen in meningeal cells while significantly reducing the expression of cyclin B, important for progression through G2, in Ben-Men-1 cells. In addition, AR-42 decreased Aurora A and B expression. To compare the in vivo efficacies of AR-42 and AR-12, a PDK1 inhibitor, we generated and used luciferase-expressing Ben-Men-1-LucB cells to establish intracranial xenografts that grew over time. While AR-12 treatment moderately slowed tumor growth, AR-42 caused regression of Ben-Men-1-LucB tumors. Importantly, AR-42–treated tumors showed minimal regrowth when xenograft-bearing mice were switched to normal diet. Together, these results suggest that AR-42 is a potential therapy for meningiomas. The differential effect of AR-42 on cell-cycle progression of normal meningeal and meningioma cells may have implications for why AR-42 is well-tolerated while it potently inhibits tumor growth. Cancer Res; 73(2); 792–803. ©2012 AACR.
Data from Cell Surface Receptor FPR2 Promotes Antitumor Host Defense by Limiting M2 Polarization of Macrophages
Authors: Liu Ying , Chen Keqiang , Wang Chunyan , Gong Wanghua , Yoshimura Teizo , Liu Mingyong , Wang Ji Ming
Published: March 2024

Abstract
FPR2 (Fpr2 in mouse) is a G-protein–coupled receptor interacting with bacterial and host-derived chemotactic agonists. Fpr2 supports innate and adaptive immune responses as illustrated by the reduction in severity of allergic airway inflammation in Fpr2-KO mice, due to impaired trafficking of antigen-presenting dendritic cells (DC). The aim of this study is to examine the role of Fpr2 in host antitumor responses. We found that Fpr2-KO mice bearing subcutaneously implanted Lewis lung carcinoma (LLC) cells exhibited significantly shortened survival than normal mice due to more rapidly growing tumors. In contrast, in Fpr2-transgenic mice overexpressing Fpr2, subcutaneously implanted LLC tumors grew more slowly than those in wild-type (WT) littermates. Investigation of tumor tissues revealed an increased number of macrophages associated with tumors grown in Fpr2-KO mice. Macrophages derived from Fpr2-KO mice showed a more potent chemotactic response to LLC-derived supernatant (LLC Sup), which could be neutralized by an anti-CCL2 antibody. The increased chemotaxis of Fpr2-KO mouse macrophages in response to LLC Sup was due to their higher level expression of CCR4, a chemokine receptor that also recognizes the ligand CCL2. Furthermore, macrophages from Fpr2-KO mice acquired an M2 phenotype after stimulation with LLC Sup. These results suggest that Fpr2 plays an important role in host defense against implanted LLC by sustaining macrophages in an M1 phenotype with more potent antitumor activities. Cancer Res; 73(2); 550–60. ©2012 AACR.
Data from The Major Reverse Transcriptase–Incompetent Splice Variant of the Human Telomerase Protein Inhibits Telomerase Activity but Protects from Apoptosis
Authors: Listerman Imke , Sun Jie , Gazzaniga Francesca S. , Lukas Jason L. , Blackburn Elizabeth H.
Published: March 2024

Abstract
Human telomerase reverse transcriptase (hTERT; the catalytic protein subunit of telomerase) is subjected to numerous alternative splicing events, but the regulation and function of these splice variants is obscure. Full-length hTERT includes conserved domains that encode reverse transcriptase activity, RNA binding, and other functions. The major splice variant termed α+β− or β-deletion is highly expressed in stem and cancer cells, where it codes for a truncated protein lacking most of the reverse transcriptase domain but retaining the known RNA-binding motifs. In a breast cancer cell panel, we found that β-deletion was the hTERT transcript that was most highly expressed. Splicing of this transcript was controlled by the splice regulators SRSF11, HNRNPH2, and HNRNPL, and the β-deletion transcript variant was associated with polyribosomes in cells. When ectopically overexpressed, β-deletion protein competed for binding to telomerase RNA (hTR/TERC), thereby inhibiting endogenous telomerase activity. Overexpressed β-deletion protein localized to the nucleus and mitochondria and protected breast cancer cells from cisplatin-induced apoptosis. Our results reveal that a major hTERT splice variant can confer a growth advantage to cancer cells independent of telomere maintenance, suggesting that hTERT makes multiple contributions to cancer pathophysiology. Cancer Res; 73(9); 2817–28. ©2013 AACR.
Data from Downregulation of the Novel Tumor Suppressor DIRAS1 Predicts Poor Prognosis in Esophageal Squamous Cell Carcinoma
Authors: Zhu Ying-Hui , Fu Li , Chen Leilei , Qin Yan-Ru , Liu Haibo , Xie Fajun , Zeng Tingting , Dong Sui-Sui , Li Jiangchao , Li Yan , Dai Yongdong , Xie Dan , Guan Xin-Yuan
Published: March 2024

Abstract
Loss of chromosome 19p is one of the most frequent allelic imbalances in esophageal squamous cell carcinoma (ESCC), suggesting the existence of one or more tumor suppressor genes within this region. In this study, we investigated a role in ESCCs for a candidate tumor suppressor gene located at 19p13.3, the Ras-like small GTPase DIRAS1. Downregulation of DIRAS1 occurred in approximately 50% of primary ESCCs where it was associated significantly with advanced clinical stage, lymph node metastasis, and poor overall survival. LOH and promoter methylation analyses suggested that loss of DIRAS1 expression was mediated by epigenetic mechanisms. Functional studies established that ectopic re-expression of DIRAS1 in ESCC cells inhibited cell proliferation, clonogenicity, cell motility, and tumor formation. Mechanistic investigations suggested that DIRAS1 acted through extracellular signal–regulated kinase (ERK1/2; MAPK3/1) and p38 mitogen-activated protein kinase (MAPK; MAPK14) signaling to trigger BAD Ser112 dephosphorylation and matrix metalloproteinase (MMP)2/9 transcriptional inactivation to promote apoptosis and inhibit metastasis, respectively. Taken together, our results revealed that DIRAS1 has a pivotal function in ESCC pathogenesis, with possible use as a biomarker and intervention point for new therapeutic strategies. Cancer Res; 73(7); 2298–309. ©2013 AACR.
Data from Genetic and Pharmacological Strategies to Refunctionalize the von Hippel Lindau R167Q Mutant Protein
Authors: Ding Zhiyong , German Peter , Bai Shanshan , Reddy A. Srinivas , Liu Xian-De , Sun Mianen , Zhou Lijun , Chen Xiaohua , Zhao Xiaobei , Wu Chengbiao , Zhang Shuxing , Mills Gordon B. , Jonasch Eric
Published: March 2024

Abstract
Aberrant von Hippel Lindau (VHL) protein function is the underlying driver of VHL-related diseases, including both sporadic and inherited clear cell renal cell carcinoma (ccRCC). About one third of VHL mutations are missense point mutations, with R167Q being the most common VHL point mutation in hereditary VHL disease. Although it has been studied extensively, the ability of VHL-R167Q to downregulate hypoxia-inducible factor 2α (HIF2α) is still controversial. In addition, the manner in which the mutation contributes to tumorigenesis is not fully understood. No therapeutic approach is available to target VHL-R167Q and similar missense point mutations. We analyzed VHL-R167Q proteostasis and function at normoxia, at hypoxia with different oxygen pressure, and in a xenograft mouse model. We showed that the protein levels of VHL-R167Q dictate its ability to downregulate HIF2α and suppress tumor growth. Strikingly, the proteasome inhibitors bortezomib and carfilzomib, which are currently in clinical use, stabilize VHL-R167Q and increase its ability to downregulate HIF2α. VHL-R167Q binds elongin C and elongin B with considerably less avidity than wild-type VHL does but retains residual capacity to generate a VHL-elongin C-elongin B complex, downregulate HIF2α, and suppress tumorigenesis, which could be rescued by increase of VHL-R167Q levels. Finally, we used in silico approaches and identified other missense VHL mutants in addition to VHL-R167Q that might be rescued by similar strategies. Thus, our studies revealed detailed information describing how VHL-R167Q contributes to tumorigenesis and identified a potential targeted therapy for ccRCC and other VHL-related disease in patients carrying VHL-R167Q or similar missense mutations. Cancer Res; 74(11); 3127–36. ©2014 AACR.
Data from MyoD Is a Tumor Suppressor Gene in Medulloblastoma
Authors: Dey Joyoti , Dubuc Adrian M. , Pedro Kyle D. , Thirstrup Derek , Mecham Brig , Northcott Paul A. , Wu Xiaochong , Shih David , Tapscott Stephen J. , LeBlanc Michael , Taylor Michael D. , Olson James M.
Published: March 2024

Abstract
While medulloblastoma, a pediatric tumor of the cerebellum, is characterized by aberrations in developmental pathways, the majority of genetic determinants remain unknown. An unbiased Sleeping Beauty transposon screen revealed MyoD as a putative medulloblastoma tumor suppressor. This was unexpected, as MyoD is a muscle differentiation factor and not previously known to be expressed in cerebellum or medulloblastoma. In response to deletion of one allele of MyoD, two other Sonic hedgehog-driven mouse medulloblastoma models showed accelerated tumor formation and death, confirming MyoD as a tumor suppressor in these models. In normal cerebellum, MyoD was expressed in the proliferating granule neuron progenitors that are thought to be precursors to medulloblastoma. Similar to some other tumor suppressors that are induced in cancer, MyoD was expressed in proliferating medulloblastoma cells in three mouse models and in human medulloblastoma cases. This suggests that although expression of MyoD in a proliferating tumor is insufficient to prevent tumor progression, its expression in the cerebellum hinders medulloblastoma genesis. Cancer Res; 73(22); 6828–37. ©2013 AACR.
Data from Metastasis Suppressor KISS1 Seems to Reverse the Warburg Effect by Enhancing Mitochondrial Biogenesis
Authors: Liu Wen , Beck Benjamin H. , Vaidya Kedar S. , Nash Kevin T. , Feeley Kyle P. , Ballinger Scott W. , Pounds Keke M. , Denning Warren L. , Diers Anne R. , Landar Aimee , Dhar Animesh , Iwakuma Tomoo , Welch Danny R.
Published: March 2024

Abstract
Cancer cells tend to utilize aerobic glycolysis even under normoxic conditions, commonly called the “Warburg effect.” Aerobic glycolysis often directly correlates with malignancy, but its purpose, if any, in metastasis remains unclear. When wild-type KISS1 metastasis suppressor is expressed, aerobic glycolysis decreases and oxidative phosphorylation predominates. However, when KISS1 is missing the secretion signal peptide (ΔSS), invasion and metastasis are no longer suppressed and cells continue to metabolize using aerobic glycolysis. KISS1-expressing cells have 30% to 50% more mitochondrial mass than ΔSS-expressing cells, which are accompanied by correspondingly increased mitochondrial gene expression and higher expression of PGC1α, a master coactivator that regulates mitochondrial mass and metabolism. PGC1α-mediated downstream pathways (i.e., fatty acid synthesis and β-oxidation) are differentially regulated by KISS1, apparently reliant upon direct KISS1 interaction with NRF1, a major transcription factor involved in mitochondrial biogenesis. Since the downstream effects could be reversed using short hairpin RNA to KISS1 or PGC1α, these data appear to directly connect changes in mitochondria mass, cellular glucose metabolism, and metastasis. Cancer Res; 74(3); 954–63. ©2013 AACR.
Data from Blocking Lactate Export by Inhibiting the Myc Target MCT1 Disables Glycolysis and Glutathione Synthesis
Authors: Doherty Joanne R. , Yang Chunying , Scott Kristen E.N. , Cameron Michael D. , Fallahi Mohammad , Li Weimin , Hall Mark A. , Amelio Antonio L. , Mishra Jitendra K. , Li Fangzheng , Tortosa Mariola , Genau Heide Marika , Rounbehler Robert J. , Lu Yunqi , Dang Chi V. , Kumar K. Ganesh , Butler Andrew A. , Bannister Thomas D. , Hooper Andrea T. , Unsal-Kacmaz Keziban , Roush William R. , Cleveland John L.
Published: March 2024

Abstract
Myc oncoproteins induce genes driving aerobic glycolysis, including lactate dehydrogenase-A that generates lactate. Here, we report that Myc controls transcription of the lactate transporter SLC16A1/MCT1 and that elevated MCT1 levels are manifest in premalignant and neoplastic Eμ-Myc transgenic B cells and in human malignancies with MYC or MYCN involvement. Notably, disrupting MCT1 function leads to an accumulation of intracellular lactate that rapidly disables tumor cell growth and glycolysis, provoking marked alterations in glycolytic intermediates, reductions in glucose transport, and in levels of ATP, NADPH, and ultimately, glutathione (GSH). Reductions in GSH then lead to increases in hydrogen peroxide, mitochondrial damage, and ultimately, cell death. Finally, forcing glycolysis by metformin treatment augments this response and the efficacy of MCT1 inhibitors, suggesting an attractive combination therapy for MYC/MCT1-expressing malignancies. Cancer Res; 74(3); 908–20. ©2013 AACR.
Data from Adiponectin Receptor Signaling on Dendritic Cells Blunts Antitumor Immunity
Authors: Tan Peng H. , Tyrrell Helen E.J. , Gao Liquan , Xu Danmei , Quan Jianchao , Gill Dipender , Rai Lena , Ding Yunchuan , Plant Gareth , Chen Yuan , Xue John Z. , Handa Ashok I. , Greenall Michael J. , Walsh Kenneth , Xue Shao-An
Published: March 2024

Abstract
Immune escape is a fundamental trait of cancer. Dendritic cells (DC) that interact with T cells represent a crucial site for the development of tolerance to tumor antigens, but there remains incomplete knowledge about how DC-tolerizing signals evolve during tumorigenesis. In this study, we show that DCs isolated from patients with metastatic or locally advanced breast cancer express high levels of the adiponectin receptors AdipoR1 and AdipoR2, which are sufficient to blunt antitumor immunity. Mechanistic investigations of ligand–receptor interactions on DCs revealed novel signaling pathways for each receptor. AdipoR1 stimulated IL10 production by activating the AMPK and MAPKp38 pathways, whereas AdipoR2 modified inflammatory processes by activating the COX-2 and PPARγ pathways. Stimulation of these pathways was sufficient to block activation of NF-κB in DC, thereby attenuating their ability to stimulate antigen-specific T-cell responses. Together, our findings reveal novel insights into how DC-tolerizing signals evolve in cancer to promote immune escape. Furthermore, by defining a critical role for adiponectin signaling in this process, our work suggests new and broadly applicable strategies for immunometabolic therapy in patients with cancer. Cancer Res; 74(20); 5711–22. ©2014 AACR.
Data from VISTA Is an Immune Checkpoint Molecule for Human T Cells
Authors: Lines J. Louise , Pantazi Eirini , Mak Justin , Sempere Lorenzo F. , Wang Li , O'Connell Samuel , Ceeraz Sabrina , Suriawinata Arief A. , Yan Shaofeng , Ernstoff Marc S. , Noelle Randolph
Published: March 2024

Abstract
V-domain Ig suppressor of T cell activation (VISTA) is a potent negative regulator of T-cell function that is expressed on hematopoietic cells. VISTA levels are heightened within the tumor microenvironment, in which its blockade can enhance antitumor immune responses in mice. In humans, blockade of the related programmed cell death 1 (PD-1) pathway has shown great potential in clinical immunotherapy trials. Here, we report the structure of human VISTA and examine its function in lymphocyte negative regulation in cancer. VISTA is expressed predominantly within the hematopoietic compartment with highest expression within the myeloid lineage. VISTA-Ig suppressed proliferation of T cells but not B cells and blunted the production of T-cell cytokines and activation markers. Our results establish VISTA as a negative checkpoint regulator that suppresses T-cell activation, induces Foxp3 expression, and is highly expressed within the tumor microenvironment. By analogy to PD-1 and PD-L1 blockade, VISTA blockade may offer an immunotherapeutic strategy for human cancer. Cancer Res; 74(7); 1924–32. ©2013 AACR.
Data from JNK Signaling Mediates EPHA2-Dependent Tumor Cell Proliferation, Motility, and Cancer Stem Cell–like Properties in Non–Small Cell Lung Cancer
Authors: Song Wenqiang , Ma Yufang , Wang Jialiang , Brantley-Sieders Dana , Chen Jin
Published: March 2024

Abstract
Recent genome-wide analyses in human lung cancer revealed that EPHA2 receptor tyrosine kinase is overexpressed in non–small cell lung cancer (NSCLC), and high levels of EPHA2 correlate with poor clinical outcome. However, the mechanistic basis for EPHA2-mediated tumor promotion in lung cancer remains poorly understood. Here, we show that the JNK/c-JUN signaling mediates EPHA2-dependent tumor cell proliferation and motility. A screen of phospho-kinase arrays revealed a decrease in phospho-c-JUN levels in EPHA2 knockdown cells. Knockdown of EPHA2 inhibited p-JNK and p-c-JUN levels in approximately 50% of NSCLC lines tested. Treatment of parental cells with SP600125, a c-JUN-NH2-kinase (JNK) inhibitor, recapitulated defects in EPHA2-deficient tumor cells, whereas constitutively activated JNK mutants were sufficient to rescue phenotypes. Knockdown of EPHA2 also inhibited tumor formation and progression in xenograft animal models in vivo. Furthermore, we investigated the role of EPHA2 in cancer stem–like cells (CSC). RNA interference-mediated depletion of EPHA2 in multiple NSCLC lines decreased the ALDH+ cancer stem–like population and tumor spheroid formation in suspension. Depletion of EPHA2 in sorted ALDH+ populations markedly inhibited tumorigenicity in nude mice. Furthermore, analysis of a human lung cancer tissue microarray revealed a significant, positive association between EPHA2 and ALDH expression, indicating an important role for EPHA2 in human lung CSCs. Collectively, these studies revealed a critical role of JNK signaling in EPHA2-dependent lung cancer cell proliferation and motility and a role for EPHA2 in CSC function, providing evidence for EPHA2 as a potential therapeutic target in NSCLC. Cancer Res; 74(9); 2444–54. ©2014 AACR.
Data from Tumor-Derived GM-CSF Promotes Inflammatory Colon Carcinogenesis via Stimulating Epithelial Release of VEGF
Authors: Wang Yi , Han Gencheng , Wang Ke , Liu Guijun , Wang Renxi , Xiao He , Li Xinying , Hou Chunmei , Shen Beifen , Guo Renfeng , Li Yan , Chen Guojiang
Published: March 2024

Abstract
Chronic inflammation is a major driving force for the development of colitis-associated cancer (CAC). Elevated production of granulocyte macrophage colony-stimulating factor (GM-CSF) has been observed in mucosa of patients with inflammatory bowel disease. Its actions in the progression from colitis to cancer, however, remain poorly understood. Herein, we demonstrated that colonic epithelial cells (CEC) were a major cellular source of GM-CSF and its production was significantly augmented when CAC model was established by administration of azoxymethane and dextran sulfate sodium. Furthermore, we showed that GM-CSF was a driver for VEGF release by CEC in autocrine and/or paracrine manners through the extracellular signal-regulated kinase (ERK)-dependent pathway. Blocking GM-CSF activity in vivo significantly decreased epithelial release of VEGF, thereby abrogating CAC formation. In vitro treatment of transformed CEC with recombinant GM-CSF dramatically augmented its invasive potentials, largely in VEGF-dependent fashion. Furthermore, commensal microbiota-derived lipopolysaccharides were identified as a trigger for GM-CSF expression in CEC, as antibiotics treatment or Toll-like receptor 4 ablation considerably impaired its epithelial expression. Overall, these findings may have important implications for the understanding of mechanisms underlying CAC pathogenesis and the therapeutic potentials of regimens targeting GM-CSF or VEGF in clinic. Cancer Res; 74(3); 716–26. ©2013 AACR.
Data from Foxp3+ T Cells Inhibit Antitumor Immune Memory Modulated by mTOR Inhibition
Authors: Wang Yanping , Sparwasser Tim , Figlin Robert , Kim Hyung L.
Published: March 2024

Abstract
Inhibition of mTOR signaling enhances antitumor memory lymphocytes. However, pharmacologic mTOR inhibition also enhances regulatory T-cell (Treg) activity. To counter this effect, Treg control was added to mTOR inhibition in preclinical models. Tregs were controlled with CD4-depleting antibodies because CD4 depletion has high translational potential and already has a well-established safety profile in patients. The antitumor activity of the combination therapy was CD8 dependent and controlled growth of syngeneic tumors even when an adoptive immunotherapy was not used. Lymphocytes resulting from the combination therapy could be transferred into naïve mice to inhibit aggressive growth of lung metastases. The combination therapy enhanced CD8 memory formation as determined by memory markers and functional studies of immune recall. Removal of FoxP3-expressing T lymphocytes was the mechanism underlying immunologic memory formation following CD4 depletion. This was confirmed using transgenic DEREG (depletion of regulatory T cells) mice to specifically remove Foxp3+ T cells. It was further confirmed with reciprocal studies where stimulation of immunologic memory because of CD4 depletion was completely neutralized by adoptively transferring tumor-specific Foxp3+ T cells. Also contributing to tumor control, Tregs that eventually recovered following CD4 depletion were less immunosuppressive. These results provide a rationale for further study of mTOR inhibition and CD4 depletion in patients. Cancer Res; 74(8); 2217–28. ©2014 AACR.
Data from PCAT-1, a Long Noncoding RNA, Regulates BRCA2 and Controls Homologous Recombination in Cancer
Authors: Prensner John R. , Chen Wei , Iyer Matthew K. , Cao Qi , Ma Teng , Han Sumin , Sahu Anirban , Malik Rohit , Wilder-Romans Kari , Navone Nora , Logothetis Christopher J. , Araujo John C. , Pisters Louis L. , Tewari Ashutosh K. , Canman Christine E. , Knudsen Karen E. , Kitabayashi Naoki , Rubin Mark A. , Demichelis Francesca , Lawrence Theodore S. , Chinnaiyan Arul M. , Feng Felix Y.
Published: March 2024

Abstract
Impairment of double-stranded DNA break (DSB) repair is essential to many cancers. However, although mutations in DSB repair proteins are common in hereditary cancers, mechanisms of impaired DSB repair in sporadic cancers remain incompletely understood. Here, we describe the first role for a long noncoding RNA (lncRNA) in DSB repair in prostate cancer. We identify PCAT-1, a prostate cancer outlier lncRNA, which regulates cell response to genotoxic stress. PCAT-1 expression produces a functional deficiency in homologous recombination through its repression of the BRCA2 tumor suppressor, which, in turn, imparts a high sensitivity to small-molecule inhibitors of PARP1. These effects reflected a posttranscriptional repression of the BRCA2 3′UTR by PCAT-1. Our observations thus offer a novel mechanism of “BRCAness” in sporadic cancers. Cancer Res; 74(6); 1651–60. ©2014 AACR.
Data from CBP Loss Cooperates with PTEN Haploinsufficiency to Drive Prostate Cancer: Implications for Epigenetic Therapy
Authors: Ding Liya , Chen Shuai , Liu Ping , Pan Yunqian , Zhong Jian , Regan Kevin M. , Wang Liguo , Yu Chunrong , Rizzardi Anthony , Cheng Liang , Zhang Jun , Schmechel Stephen C. , Cheville John C. , Van Deursen Jan , Tindall Donald J. , Huang Haojie
Published: March 2024

Abstract
Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbppc−/−;Ptenpc+/− mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp−/−; Pten+/− and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27KIP1, and p21CIP1. Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbppc−/−;Ptenpc+/− mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic-targeted therapy in patients with prostate cancer. Cancer Res; 74(7); 2050–61. ©2014 AACR.
Data from Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53
Authors: Zhang Shengliang , Zhou Lanlan , Hong Bo , van den Heuvel A. Pieter J. , Prabhu Varun V. , Warfel Noel A. , Kline Christina Leah B. , Dicker David T. , Kopelovich Levy , El-Deiry Wafik S.
Published: March 2024

Abstract
The tumor-suppressor p53 prevents cancer development via initiating cell-cycle arrest, cell death, repair, or antiangiogenesis processes. Over 50% of human cancers harbor cancer-causing mutant p53. p53 mutations not only abrogate its tumor-suppressor function, but also endow mutant p53 with a gain of function (GOF), creating a proto-oncogene that contributes to tumorigenesis, tumor progression, and chemo- or radiotherapy resistance. Thus, targeting mutant p53 to restore a wild-type p53 signaling pathway provides an attractive strategy for cancer therapy. We demonstrate that small-molecule NSC59984 not only restores wild-type p53 signaling, but also depletes mutant p53 GOF. NSC59984 induces mutant p53 protein degradation via MDM2 and the ubiquitin–proteasome pathway. NSC59984 restores wild-type p53 signaling via p73 activation, specifically in mutant p53-expressing colorectal cancer cells. At therapeutic doses, NSC59984 induces p73-dependent cell death in cancer cells with minimal genotoxicity and without evident toxicity toward normal cells. NSC59984 synergizes with CPT11 to induce cell death in mutant p53-expressing colorectal cancer cells and inhibits mutant p53-associated colon tumor xenograft growth in a p73-dependent manner in vivo. We hypothesize that specific targeting of mutant p53 may be essential for anticancer strategies that involve the stimulation of p73 in order to efficiently restore tumor suppression. Taken together, our data identify NSC59984 as a promising lead compound for anticancer therapy that acts by targeting GOF-mutant p53 and stimulates p73 to restore the p53 pathway signaling. Cancer Res; 75(18); 3842–52. ©2015 AACR.
Data from SIRT1 Limits the Function and Fate of Myeloid-Derived Suppressor Cells in Tumors by Orchestrating HIF-1α–Dependent Glycolysis
Authors: Liu Guangwei , Bi Yujing , Shen Bo , Yang Hui , Zhang Yan , Wang Xiao , Liu Huanrong , Lu Yun , Liao Jiongbo , Chen Xi , Chu Yiwei
Published: March 2024

Abstract
Myeloid-derived suppressor cells (MDSC) display an immature phenotype that may assume a classically activated (M1) or alternatively activated phenotype (M2) in tumors. In this study, we investigated metabolic mechanisms underlying the differentiation of MDSCs into M1 or M2 myeloid lineage and their effect on cancer pathophysiology. We found that SIRT1 deficiency in MDSCs directs a specific switch to M1 lineage when cells enter the periphery from bone marrow, decreasing the suppressive function in favor of a proinflammatory M1 phenotype associated with tumor cell attack. Glycolytic activation through the mTOR–hypoxia-inducible factor-1α (HIF-1α) pathway was required for differentiation to the M1 phenotype, which conferred protection against tumors. Our results define the essential nature of a SIRT1–mTOR/HIF-1α glycolytic pathway in determining MDSC differentiation, with implications for metabolic reprogramming as a cancer therapeutic approach. Cancer Res; 74(3); 727–37. ©2013 AACR.
Data from VISTA Regulates the Development of Protective Antitumor Immunity
Authors: Le Mercier Isabelle , Chen Wenna , Lines Janet L. , Day Maria , Li Jiannan , Sergent Petra , Noelle Randolph J. , Wang Li
Published: March 2024

Abstract
V-domain Ig suppressor of T-cell activation (VISTA) is a novel negative checkpoint ligand that is homologous to PD-L1 and suppresses T-cell activation. This study demonstrates the multiple mechanisms whereby VISTA relieves negative regulation by hematopoietic cells and enhances protective antitumor immunity. VISTA is highly expressed on myeloid cells and Foxp3+CD4+ regulatory cells, but not on tumor cells within the tumor microenvironment (TME). VISTA monoclonal antibody (mAb) treatment increased the number of tumor-specific T cells in the periphery and enhanced the infiltration, proliferation, and effector function of tumor-reactive T cells within the TME. VISTA blockade altered the suppressive feature of the TME by decreasing the presence of monocytic myeloid-derived suppressor cells and increasing the presence of activated dendritic cells within the tumor microenvironment. In addition, VISTA blockade impaired the suppressive function and reduced the emergence of tumor-specific Foxp3+CD4+ regulatory T cells. Consequently, VISTA mAb administration as a monotherapy significantly suppressed the growth of both transplantable and inducible melanoma. Initial studies explored a combinatorial regimen using VISTA blockade and a peptide-based cancer vaccine with TLR agonists as adjuvants. VISTA blockade synergized with the vaccine to effectively impair the growth of established tumors. Our study therefore establishes a foundation for designing VISTA-targeted approaches either as a monotherapy or in combination with additional immune-targeted strategies for cancer immunotherapy. Cancer Res; 74(7); 1933–44. ©2014 AACR.
Data from FANCJ Localization by Mismatch Repair Is Vital to Maintain Genomic Integrity after UV Irradiation
Authors: Guillemette Shawna , Branagan Amy , Peng Min , Dhruva Aashana , Schärer Orlando D. , Cantor Sharon B.
Published: March 2024

Abstract
Nucleotide excision repair (NER) is critical for the repair of DNA lesions induced by UV radiation, but its contribution in replicating cells is less clear. Here, we show that dual incision by NER endonucleases, including XPF and XPG, promotes the S-phase accumulation of the BRCA1 and Fanconi anemia–associated DNA helicase FANCJ to sites of UV-induced damage. FANCJ promotes replication protein A phosphorylation and the arrest of DNA synthesis following UV irradiation. Interaction defective mutants of FANCJ reveal that BRCA1 binding is not required for FANCJ localization, whereas interaction with the mismatch repair (MMR) protein MLH1 is essential. Correspondingly, we find that FANCJ, its direct interaction with MLH1, and the MMR protein MSH2 function in a common pathway in response to UV irradiation. FANCJ-deficient cells are not sensitive to killing by UV irradiation, yet we find that DNA mutations are significantly enhanced. Thus, we considered that FANCJ deficiency could be associated with skin cancer. Along these lines, in melanoma we found several somatic mutations in FANCJ, some of which were previously identified in hereditary breast cancer and Fanconi anemia. Given that, mutations in XPF can also lead to Fanconi anemia, we propose collaborations between Fanconi anemia, NER, and MMR are necessary to initiate checkpoint activation in replicating human cells to limit genomic instability. Cancer Res; 74(3); 932–44. ©2013 AACR.
Data from GPR56 Inhibits Melanoma Growth by Internalizing and Degrading Its Ligand TG2
Authors: Yang Liquan , Friedland Scott , Corson Nancy , Xu Lei
Published: March 2024

Abstract
Excessive accumulation of extracellular matrix (ECM) is a hallmark of tumor microenvironment and plays active roles during tumor progression. How this process is regulated and whether it is reversible for cancer treatment are outstanding questions. The adhesion G protein–coupled receptor GPR56 inhibits melanoma growth and binds to tissue transglutaminase (TG2), a major crosslinking enzyme in ECM. To understand the function of TG2 in GPR56-mediated melanoma inhibition, we performed xenograft studies in immunodeficient Tg2−/− mice. Our results revealed an antagonistic relationship between GPR56 and TG2 in melanoma, although TG2 and its crosslinking activity promote melanoma growth, GPR56 antagonizes this effect by internalizing and degrading it. The negative regulation of TG2 by GPR56 associates with the decreased deposition of a major ECM protein, fibronectin, and impaired accumulation of focal adhesion kinase, indicating that the GPR56–TG2 interaction regulates ECM deposition and cell–ECM adhesion. Taken together, our findings establish the roles of TG2 in GPR56-mediated melanoma inhibition. The uncovered antagonistic relationship between GPR56 and TG2 proposes a mechanism by which ECM accumulation/crosslinking in tumors may be reversed, and thus could have therapeutic potential for cancer control and treatment. Cancer Res; 74(4); 1022–31. ©2013 AACR.
Data from The Alarmin HMGN1 Contributes to Antitumor Immunity and Is a Potent Immunoadjuvant
Authors: Wei Feng , Yang De , Tewary Poonam , Li Yana , Li Sandra , Chen Xin , Howard O.M. Zack , Bustin Michael , Oppenheim Joost J.
Published: March 2024

Abstract
Alarmins are endogenous mediators that are elicited rapidly in response to danger signals, enhancing innate and adaptive immune responses by promoting the recruitment and maturation of antigen-presenting cells (APC). The nucleosome-binding protein HMGN1 is a potent alarmin that binds TLR4 and induces antigen-specific Th1 immune responses, but its contributions to antitumor immunity have not been explored. We found that ovalbumin (OVA)-expressing EG7 mouse thymoma cells grew much faster in Hmgn1-deficient mice than littermate-matched controls. Tumor-bearing Hmgn1−/− mice generated fewer OVA-specific CD8 cells in the spleen than EG7-bearing Hmgn1+/+ mice, suggesting that HMGN1 supported T cell–mediated antitumor immunity. In addition, EG7 tumors expressing HMGN1 grew more slowly than control EG7 tumors, suggesting greater resistance to HMGN1-expressing tumors. This resistance relied on T cell–mediated immunity because it was abolished by in vivo depletion of CD4+ and CD8+ T cells. Moreover, mice vaccinated with a DNA vector expressing an HMGN1–gp100 fusion protein manifested gp100-specific, Th1-polarized immune responses, acquiring resistance to challenge with mouse B16F1 melanoma. Overall, our findings show that HMGN1 contributes to antitumor immunity and it may offer an effective adjuvant to heighten responses to cancer vaccines. Cancer Res; 74(21); 5989–98. ©2014 AACR.
Data from Genetic Validation of the Protein Arginine Methyltransferase PRMT5 as a Candidate Therapeutic Target in Glioblastoma
Authors: Yan Fengting , Alinari Lapo , Lustberg Mark E. , Katherine Martin Ludmila , Cordero-Nieves Hector M. , Banasavadi-Siddegowda Yeshavanth , Virk Selene , Barnholtz-Sloan Jill , Bell Erica Hlavin , Wojton Jeffrey , Jacob Naduparambil K. , Chakravarti Arnab , Nowicki Michal O. , Wu Xin , Lapalombella Rosa , Datta Jharna , Yu Bo , Gordon Kate , Haseley Amy , Patton John T. , Smith Porsha L. , Ryu John , Zhang Xiaoli , Mo Xiaokui , Marcucci Guido , Nuovo Gerard , Kwon Chang-Hyuk , Byrd John C. , Chiocca E. Antonio , Li Chenglong , Sif Said , Jacob Samson , Lawler Sean , Kaur Balveen , Baiocchi Robert A.
Published: March 2024

Abstract
Glioblastoma is the most common and aggressive histologic subtype of brain cancer with poor outcomes and limited treatment options. Here, we report the selective overexpression of the protein arginine methyltransferase PRMT5 as a novel candidate theranostic target in this disease. PRMT5 silences the transcription of regulatory genes by catalyzing symmetric dimethylation of arginine residues on histone tails. PRMT5 overexpression in patient-derived primary tumors and cell lines correlated with cell line growth rate and inversely with overall patient survival. Genetic attenuation of PRMT5 led to cell-cycle arrest, apoptosis, and loss of cell migratory activity. Cell death was p53-independent but caspase-dependent and enhanced with temozolomide, a chemotherapeutic agent used as a present standard of care. Global gene profiling and chromatin immunoprecipitation identified the tumor suppressor ST7 as a key gene silenced by PRMT5. Diminished ST7 expression was associated with reduced patient survival. PRMT5 attenuation limited PRMT5 recruitment to the ST7 promoter, led to restored expression of ST7 and cell growth inhibition. Finally, PRMT5 attenuation enhanced glioblastoma cell survival in a mouse xenograft model of aggressive glioblastoma. Together, our findings defined PRMT5 as a candidate prognostic factor and therapeutic target in glioblastoma, offering a preclinical justification for targeting PRMT5-driven oncogenic pathways in this deadly disease. Cancer Res; 74(6); 1752–65. ©2014 AACR.
Data from HMGB1 Enhances Immune Suppression by Facilitating the Differentiation and Suppressive Activity of Myeloid-Derived Suppressor Cells
Authors: Parker Katherine H. , Sinha Pratima , Horn Lucas A. , Clements Virginia K. , Yang Huan , Li Jianhua , Tracey Kevin J. , Ostrand-Rosenberg Suzanne
Published: March 2024

Abstract
Chronic inflammation often precedes malignant transformation and later drives tumor progression. Likewise, subversion of the immune system plays a role in tumor progression, with tumoral immune escape now well recognized as a crucial hallmark of cancer. Myeloid-derived suppressor cells (MDSC) are elevated in most individuals with cancer, where their accumulation and suppressive activity are driven by inflammation. Thus, MDSCs may define an element of the pathogenic inflammatory processes that drives immune escape. The secreted alarmin HMGB1 is a proinflammatory partner, inducer, and chaperone for many proinflammatory molecules that MDSCs develop. Therefore, in this study, we examined HMGB1 as a potential regulator of MDSCs. In murine tumor systems, HMGB1 was ubiquitous in the tumor microenvironment, activating the NF-κB signal transduction pathway in MDSCs and regulating their quantity and quality. We found that HMGB1 promotes the development of MDSCs from bone marrow progenitor cells, contributing to their ability to suppress antigen-driven activation of CD4+ and CD8+ T cells. Furthermore, HMGB1 increased MDSC-mediated production of IL-10, enhanced crosstalk between MDSCs and macrophages, and facilitated the ability of MDSCs to downregulate expression of the T-cell homing receptor L-selectin. Overall, our results revealed a pivotal role for HMGB1 in the development and cancerous contributions of MDSCs. Cancer Res; 74(20); 5723–33. ©2014 AACR.
Data from Activation of the NOTCH Pathway in Head and Neck Cancer
Authors: Sun Wenyue , Gaykalova Daria A. , Ochs Michael F. , Mambo Elizabeth , Arnaoutakis Demetri , Liu Yan , Loyo Myriam , Agrawal Nishant , Howard Jason , Li Ryan , Ahn Sun , Fertig Elana , Sidransky David , Houghton Jeffery , Buddavarapu Kalyan , Sanford Tiffany , Choudhary Ashish , Darden Will , Adai Alex , Latham Gary , Bishop Justin , Sharma Rajni , Westra William H. , Hennessey Patrick , Chung Christine H. , Califano Joseph A.
Published: March 2024

Abstract
NOTCH1 mutations have been reported to occur in 10% to 15% of head and neck squamous cell carcinomas (HNSCC). To determine the significance of these mutations, we embarked upon a comprehensive study of NOTCH signaling in a cohort of 44 HNSCC tumors and 25 normal mucosal samples through a set of expression, copy number, methylation, and mutation analyses. Copy number increases were identified in NOTCH pathway genes, including the NOTCH ligand JAG1. Gene set analysis defined a differential expression of the NOTCH signaling pathway in HNSCC relative to normal tissues. Analysis of individual pathway-related genes revealed overexpression of ligands JAG1 and JAG2 and receptor NOTCH3. In 32% of the HNSCC examined, activation of the downstream NOTCH effectors HES1/HEY1 was documented. Notably, exomic sequencing identified 5 novel inactivating NOTCH1 mutations in 4 of the 37 tumors analyzed, with none of these tumors exhibiting HES1/HEY1 overexpression. Our results revealed a bimodal pattern of NOTCH pathway alterations in HNSCC, with a smaller subset exhibiting inactivating NOTCH1 receptor mutations but a larger subset exhibiting other NOTCH1 pathway alterations, including increases in expression or gene copy number of the receptor or ligands as well as downstream pathway activation. Our results imply that therapies that target the NOTCH pathway may be more widely suitable for HNSCC treatment than appreciated currently. Cancer Res; 74(4); 1091–104. ©2013 AACR.
Data from Contributions to Drug Resistance in Glioblastoma Derived from Malignant Cells in the Sub-Ependymal Zone
Authors: Piccirillo Sara G.M. , Spiteri Inmaculada , Sottoriva Andrea , Touloumis Anestis , Ber Suzan , Price Stephen J. , Heywood Richard , Francis Nicola-Jane , Howarth Karen D. , Collins Vincent P. , Venkitaraman Ashok R. , Curtis Christina , Marioni John C. , Tavaré Simon , Watts Colin
Published: March 2024

Abstract
Glioblastoma, the most common and aggressive adult brain tumor, is characterized by extreme phenotypic diversity and treatment failure. Through fluorescence-guided resection, we identified fluorescent tissue in the sub-ependymal zone (SEZ) of patients with glioblastoma. Histologic analysis and genomic characterization revealed that the SEZ harbors malignant cells with tumor-initiating capacity, analogous to cells isolated from the fluorescent tumor mass (T). We observed resistance to supramaximal chemotherapy doses along with differential patterns of drug response between T and SEZ in the same tumor. Our results reveal novel insights into glioblastoma growth dynamics, with implications for understanding and limiting treatment resistance. Cancer Res; 75(1); 194–202. ©2014 AACR.
Data from Expression of Variant Isoforms of the Tyrosine Kinase SYK Determines the Prognosis of Hepatocellular Carcinoma
Authors: Hong Jian , Yuan Yunfei , Wang Jianping , Liao Yadi , Zou Ruhai , Zhu Chuanlong , Li Binkui , Liang Yi , Huang Pinzhu , Wang Zongwei , Lin Wenyu , Zeng Yixin , Le Dai Jia , Chung Raymond T.
Published: March 2024

Abstract
The spleen tyrosine kinase (SYK) has been reported as a novel biomarker for human hepatocellular carcinoma, but the functional contributions of its two isoforms SYK(L) and SYK(S) are undefined. In this study, we investigated their biologic functions and possible prognostic values in hepatocellular carcinoma. SYK(L) was downregulated in 38% of human specimens of hepatocellular carcinoma examined, whereas SYK(S) was detectable in 40% of these specimens but not in normal liver tissue samples without cirrhosis. SYK(S) expression correlated with pathologic parameters characteristic of tumor metastasis, including multiple tumors (P = 0.003) and vascular invasion (P = 0.001). Further, SYK(S) was specifically associated with epithelial–mesenchymal transition (EMT) in hepatocellular carcinoma specimens. Functional studies showed that SYK(S) promoted tumor growth, suppressed apoptosis, and induced EMT through the extracellular signal–regulated kinase pathway, countering the opposite effects of SYK(L). Patients with SYK(L+/S−) tumors exhibited longer overall survival and time to recurrence than those with SYK(L−/S−) or SYK(L+/S+) tumors (P < 0.001). Taken together, our findings showed that SYK(S) enhances invasion, whereas SYK(L) inhibits metastasis in hepatocellular carcinoma. We suggest that SYK(L) downregulation or SYK(S) elevation are strong predictors of poor survival in patients with hepatocellular carcinoma, indicative of a need for aggressive therapeutic intervention. Cancer Res; 74(6); 1845–56. ©2014 AACR.
Data from Fatty Acid-Binding Protein E-FABP Restricts Tumor Growth by Promoting IFN-β Responses in Tumor-Associated Macrophages
Authors: Zhang Yuwen , Sun Yanwen , Rao Enyu , Yan Fei , Li Qiang , Zhang Ying , Silverstein Kevin A.T. , Liu Shujun , Sauter Edward , Cleary Margot P. , Li Bing
Published: March 2024

Abstract
Fatty acid-binding proteins (FABP) are known central regulators of both metabolic and inflammatory pathways, but their role in tumor development remains largely unexplored. Here, we report that host expression of epidermal FABP (E-FABP) protects against mammary tumor growth. We find that E-FABP is highly expressed in macrophages, particularly in a specific subset, promoting their antitumor activity. In the tumor stroma, E-FABP–expressing tumor-associated macrophages (TAM) produce high levels of IFN-β through upregulation of lipid droplet formation in response to tumors. E-FABP–mediated IFN-β signaling can further enhance recruitment of tumoricidal effector cells, in particular natural killer cells, to the tumor stroma for antitumor activity. These findings identify E-FABP as a new protective factor to strengthen IFN-β responses against tumor growth. Cancer Res; 74(11); 2986–98. ©2014 AACR.