Browsing by Author "He, Yiping"
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Item Open Access Chromatin accessibility mapping identifies mediators of basal transcription and retinoid-induced repression of OTX2 in medulloblastoma.(PLoS One, 2014) Wortham, Matthew; Guo, Changcun; Zhang, Monica; Song, Lingyun; Lee, Bum-Kyu; Iyer, Vishwanath R; Furey, Terrence S; Crawford, Gregory E; Yan, Hai; He, YipingDespite an emerging understanding of the genetic alterations giving rise to various tumors, the mechanisms whereby most oncogenes are overexpressed remain unclear. Here we have utilized an integrated approach of genomewide regulatory element mapping via DNase-seq followed by conventional reporter assays and transcription factor binding site discovery to characterize the transcriptional regulation of the medulloblastoma oncogene Orthodenticle Homeobox 2 (OTX2). Through these studies we have revealed that OTX2 is differentially regulated in medulloblastoma at the level of chromatin accessibility, which is in part mediated by DNA methylation. In cell lines exhibiting chromatin accessibility of OTX2 regulatory regions, we found that autoregulation maintains OTX2 expression. Comparison of medulloblastoma regulatory elements with those of the developing brain reveals that these tumors engage a developmental regulatory program to drive OTX2 transcription. Finally, we have identified a transcriptional regulatory element mediating retinoid-induced OTX2 repression in these tumors. This work characterizes for the first time the mechanisms of OTX2 overexpression in medulloblastoma. Furthermore, this study establishes proof of principle for applying ENCODE datasets towards the characterization of upstream trans-acting factors mediating expression of individual genes.Item Open Access Developing Strategies to Target Glioblastoma Stemness and Immunosuppression(2023) Sun, Michael ABrain tumor-initiating cells (BTICs) drive tumor progression, immunosuppression, and resistance to treatments, posing formidable challenges to advancing effective treatments against glioblastoma (GBM). In this dissertation, we demonstrate that clemastine, an over-the-counter drug for treating hay fever and allergy symptoms, effectively attenuated the stemness and suppressed the propagation of primary BTIC cultures bearing PDGFRA amplification. These effects on BTICs were accompanied by altered gene expression profiling indicative of their more differentiated states, resonating with the activity of clemastine in promoting the differentiation of normal oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes. Functional assays for pharmacological targets of clemastine revealed that the Emopamil Binding Protein (EBP), an enzyme in the cholesterol biosynthesis pathway, is a target that mediates the suppressive effects of clemastine. Consistently, we showed that a neural stem cell-derived mouse glioma model displaying predominantly proneural features was similarly susceptible to clemastine treatment in vitro and in vivo. Surprisingly, we discovered that EBP protein is essential for BTIC propagation and stemness properties, and revealed a potential lipid-independent function of EBP in regulating epigenetic programming. Collectively, this original work identifies pathways indispensible for maintaining the stemness and progenitor features of GBMs, uncovers BTIC dependency on EBP, and suggests that non-oncology, low-toxicity drugs with OPC differentiation-promoting activity can be repurposed to target GBM stemness and aid in their treatment.Another key strategy extensively pursued for treating GBMs focuses on targeting endolysosomes, mainly on the basis that the intact function of these subcellular organelles is crucial for tumor cell autophagy and survival. Through gene expression analyses and cell type abundance estimation in GBMs, we showed that genes associated with the endolysosomal machinery are more prominently featured in non-tumor cells in GBMs than in the tumor cells themselves, and that tumor-associated macrophages represent the primary immune cell type that contributes to this phenomenon. Further analyses uncovered an enrichment of endolysosomal pathway genes in immunosuppressive and pro-tumorigenic macrophages, such as M2-like macrophages or those associated with worse prognosis in glioma patients, but not in those linked to inflammation and anti-tumorigenic properties. Specifically, genes critical to the hydrolysis function of endolysosomes, including progranulin and cathepsins, were among the most positively correlated with immunosuppressive macrophages, and elevated expression of these genes is associated with worse patient survival in GBMs. Together, these results implicate the hydrolysis function of endolysosomes in shaping the immunosuppressive microenvironment of GBM. We propose that targeting endolysosomes, in addition to its detrimental effects on tumor cells, can be leveraged for modulating immunosuppression to render GBMs more amendable to immunotherapies.
Item Open Access Disruption of wild-type IDH1 suppresses D-2-hydroxyglutarate production in IDH1-mutated gliomas.(Cancer research, 2013-01) Jin, Genglin; Reitman, Zachary J; Duncan, Christopher G; Spasojevic, Ivan; Gooden, David M; Rasheed, B Ahmed; Yang, Rui; Lopez, Giselle Y; He, Yiping; McLendon, Roger E; Bigner, Darell D; Yan, HaiPoint mutations at Arg132 of the cytoplasmic NADP(+)-dependent isocitrate dehydrogenase 1 (IDH1) occur frequently in gliomas and result in a gain of function to produce the "oncometabolite" D-2-hydroxyglutarate (D-2HG). The mutated IDH1 allele is usually associated with a wild-type IDH1 allele (heterozygous) in cancer. Here, we identify 2 gliomas that underwent loss of the wild-type IDH1 allele but retained the mutant IDH1 allele following tumor progression from World Health Organization (WHO) grade III anaplastic astrocytomas to WHO grade IV glioblastomas. Intratumoral D-2HG was 14-fold lower in the glioblastomas lacking wild-type IDH1 than in glioblastomas with heterozygous IDH1 mutations. To characterize the contribution of wild-type IDH1 to cancer cell D-2HG production, we established an IDH1-mutated astrocytoma (IMA) cell line from a WHO grade III anaplastic astrocytoma. Disruption of the wild-type IDH1 allele in IMA cells by gene targeting resulted in an 87-fold decrease in cellular D-2HG levels, showing that both wild-type and mutant IDH1 alleles are required for D-2HG production in glioma cells. Expression of wild-type IDH1 was also critical for mutant IDH1-associated D-2HG production in the colorectal cancer cell line HCT116. These insights may aid in the development of therapeutic strategies to target IDH1-mutated cancers.Item Open Access Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas.(Oncotarget, 2012-07) Jiao, Yuchen; Killela, Patrick J; Reitman, Zachary J; Rasheed, Ahmed B; Heaphy, Christopher M; de Wilde, Roeland F; Rodriguez, Fausto J; Rosemberg, Sergio; Oba-Shinjo, Sueli Mieko; Nagahashi Marie, Suely Kazue; Bettegowda, Chetan; Agrawal, Nishant; Lipp, Eric; Pirozzi, Christopher; Lopez, Giselle; He, Yiping; Friedman, Henry; Friedman, Allan H; Riggins, Gregory J; Holdhoff, Matthias; Burger, Peter; McLendon, Roger; Bigner, Darell D; Vogelstein, Bert; Meeker, Alan K; Kinzler, Kenneth W; Papadopoulos, Nickolas; Diaz, Luis A; Yan, HaiMutations in the critical chromatin modifier ATRX and mutations in CIC and FUBP1, which are potent regulators of cell growth, have been discovered in specific subtypes of gliomas, the most common type of primary malignant brain tumors. However, the frequency of these mutations in many subtypes of gliomas, and their association with clinical features of the patients, is poorly understood. Here we analyzed these loci in 363 brain tumors. ATRX is frequently mutated in grade II-III astrocytomas (71%), oligoastrocytomas (68%), and secondary glioblastomas (57%), and ATRX mutations are associated with IDH1 mutations and with an alternative lengthening of telomeres phenotype. CIC and FUBP1 mutations occurred frequently in oligodendrogliomas (46% and 24%, respectively) but rarely in astrocytomas or oligoastrocytomas ( more than 10%). This analysis allowed us to define two highly recurrent genetic signatures in gliomas: IDH1/ATRX (I-A) and IDH1/CIC/FUBP1 (I-CF). Patients with I-CF gliomas had a significantly longer median overall survival (96 months) than patients with I-A gliomas (51 months) and patients with gliomas that did not harbor either signature (13 months). The genetic signatures distinguished clinically distinct groups of oligoastrocytoma patients, which usually present a diagnostic challenge, and were associated with differences in clinical outcome even among individual tumor types. In addition to providing new clues about the genetic alterations underlying gliomas, the results have immediate clinical implications, providing a tripartite genetic signature that can serve as a useful adjunct to conventional glioma classification that may aid in prognosis, treatment selection, and therapeutic trial design.Item Open Access Heat shock factor 1 directly regulates transsulfuration pathway to promote prostate cancer proliferation and survival(Communications Biology) Hauck, J Spencer; Moon, David; Jiang, Xue; Wang, Mu-En; Zhao, Yue; Xu, Lingfan; Quang, Holly; Butler, William; Chen, Ming; Macias, Everardo; Gao, Xia; He, Yiping; Huang, JiaotiAbstractThere are limited therapeutic options for patients with advanced prostate cancer (PCa). We previously found that heat shock factor 1 (HSF1) expression is increased in PCa and is an actionable target. In this manuscript, we identify that HSF1 regulates the conversion of homocysteine to cystathionine in the transsulfuration pathway by altering levels of cystathionine-β-synthase (CBS). We find that HSF1 directly binds the CBS gene and upregulates CBS mRNA levels. Targeting CBS decreases PCa growth and induces tumor cell death while benign prostate cells are largely unaffected. Combined inhibition of HSF1 and CBS results in more pronounced inhibition of PCa cell proliferation and reduction of transsulfuration pathway metabolites. Combination of HSF1 and CBS knockout decreases tumor size for a small cell PCa xenograft mouse model. Our study thus provides new insights into the molecular mechanism of HSF1 function and an effective therapeutic strategy against advanced PCa.Item Open Access Molecular Signature to Risk-Stratify Prostate Cancer of Intermediate Risk.(Clin Cancer Res, 2017-01-01) Yin, Yu; Zhang, Qingfu; Zhang, Hong; He, Yiping; Huang, JiaotiA new 30-gene signature has been described that separates prostate cancers of Gleason score ≤6 from those of Gleason score ≥8. It provides independent prognostic information for prostate cancers of intermediate risk (Gleason score of 7), which has the potential to stratify these patients into different risk groups. Clin Cancer Res; 23(1); 6-8. ©2016 AACRSee related article by Sinnott et al., p. 81.Item Open Access Mutant IDH1 is required for IDH1 mutated tumor cell growth.(Oncotarget, 2012-08) Jin, Genglin; Pirozzi, Christopher J; Chen, Lee H; Lopez, Giselle Y; Duncan, Christopher G; Feng, Jie; Spasojevic, Ivan; Bigner, Darell D; He, Yiping; Yan, HaiFrequent somatic hotspot mutations in isocitrate dehydrogenase 1 (IDH1) have been identified in gliomas, acute myeloid leukemias, chondrosarcomas, and other cancers, providing a likely avenue for targeted cancer therapy. However, whether mutant IDH1 protein is required for maintaining IDH1 mutated tumor cell growth remains unknown. Here, using a genetically engineered inducible system, we report that selective suppression of endogenous mutant IDH1 expression in HT1080, a fibrosarcoma cell line with a native IDH1(R132C) heterozygous mutation, significantly inhibits cell proliferation and decreases clonogenic potential. Our findings offer insights into changes that may contribute to the inhibition of cell proliferation and offer a strong preclinical rationale for utilizing mutant IDH1 as a valid therapeutic target.Item Open Access Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas.(Oncotarget, 2014-03-30) Killela, Patrick J; Pirozzi, Christopher J; Healy, Patrick; Reitman, Zachary J; Lipp, Eric; Rasheed, B Ahmed; Yang, Rui; Diplas, Bill H; Wang, Zhaohui; Greer, Paula K; Zhu, Huishan; Wang, Catherine Y; Carpenter, Austin B; Friedman, Henry; Friedman, Allan H; Keir, Stephen T; He, Jie; He, Yiping; McLendon, Roger E; Herndon, James E; Yan, Hai; Bigner, Darell DFrequent mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) and the promoter of telomerase reverse transcriptase (TERT) represent two significant discoveries in glioma genomics. Understanding the degree to which these two mutations co-occur or occur exclusively of one another in glioma subtypes presents a unique opportunity to guide glioma classification and prognosis. We analyzed the relationship between overall survival (OS) and the presence of IDH1/2 and TERT promoter mutations in a panel of 473 adult gliomas. We hypothesized and show that genetic signatures capable of distinguishing among several types of gliomas could be established providing clinically relevant information that can serve as an adjunct to histopathological diagnosis. We found that mutations in the TERT promoter occurred in 74.2% of glioblastomas (GBM), but occurred in a minority of Grade II-III astrocytomas (18.2%). In contrast, IDH1/2 mutations were observed in 78.4% of Grade II-III astrocytomas, but were uncommon in primary GBM. In oligodendrogliomas, TERT promoter and IDH1/2 mutations co-occurred in 79% of cases. Patients whose Grade III-IV gliomas exhibit TERT promoter mutations alone predominately have primary GBMs associated with poor median OS (11.5 months). Patients whose Grade III-IV gliomas exhibit IDH1/2 mutations alone predominately have astrocytic morphologies and exhibit a median OS of 57 months while patients whose tumors exhibit both TERT promoter and IDH1/2 mutations predominately exhibit oligodendroglial morphologies and exhibit median OS of 125 months. Analyzing gliomas based on their genetic signatures allows for the stratification of these patients into distinct cohorts, with unique prognosis and survival.Item Open Access Telomere, Replication Stress and Cancer stem cell(2022) Liu, HengSMARCAL1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A-Like 1) is an ATP-dependent DNA-annealing helicase that reverses stalled replication forks. Its loss of function genetic alterations occurs in a subset of glioblastomas (GBMs) and has been found to be associated with alterative lengthening of telomeres (ALT+) in tumor cells. ALT tumors exploit homologous recombination to maintain telomere length and share common characteristics, including compromised telomere shelterin protein and increased replication stress in the telomere region.We established a SMARCAL1-null, ALT+ primary GBM culture. We show that the primary GBM culture displays stable ALT features and maintains mostly consistent karyotypes after their growth in mice. Transcriptomic profiling of the ALT+ primary GBM cells that have been propagated in vitro and those that have undergone propagation in vivo revealed the effects of microenvironments on the gene expression of these tumor cells. By using a doxycycline-inducible expression system, we show that the ALT+ features in the GBM primary culture can be turned off and on by the restoration or withdraw of exogenous wild-type SMARCAL1, but not its enzymatic dead mutant counterpart. Telomere pull down assays demonstrated the expression of SMARCAL1 effectively attenuates the process of ALT in tumor cells. In supporting the critical roles of ALT for tumor progression, induced restoration of wild-type SMARCAL1, but not its enzymatic dead mutant, effectively suppresses tumor progression in vivo. By taking advantage of our well characterized ALT model system, we are investigating the role of intrinsic DNA damage in tumorigenesis. Intrinsic DNA replicative stress occurs constantly in tumor cells. However, the pathogenic ramifications of replicative stress and the strategies cancer cells undertake to adapt remain to be fully defined. Here, we attempt to address these questions, using isogenic sarcoma and glioma cell line models differing in their intrinsic telomeric replicative stress levels, we show that intrinsic replicative stress promotes cancer stemness in human sarcoma and glioma cells. Further, molecular profiling analysis of human gliomas supports that human gliomas with higher levels of intrinsic replicative stress levels have increased stemness. We show this intrinsic replicative stress-stimulated stemness is accompanied by nonrandom segregation of chromosomes in mitotic cells. More notably, this nonrandom chromosome segregation is associated with asymmetric partition of CD133, a canonical marker for cancer cell stemness, in that the newly synthesized set of chromosomes are placed in one progeny cell while the set serving as templates for DNA replication turns to co-segregate with CD133 in another. We further reveal that this asymmetric co-segregation of chromosomes and CD133 depends on the Wnt/β-catenin signaling pathway. Collectively, these findings identify intrinsic DNA replicative stress as a driver of cancer cell stemness, and suggest a coordinated, Wnt/β-catenin signal-driven process of asymmetrically partitioning DNA and proteins in these cells, potentially as a way of maintaining cellular heterogeneity and population fitness in response to DNA damage. They also highlight and provide new insights into the roles of the Wnt/β-catenin pathway in maintaining tumor cells stemness, and suggest strategies for therapeutically targeting DNA damage-driven stemness in gliomas.
Item Open Access Treating MTAP-Deficient Brain Tumors with Purine Synthesis Inhibition(2022) Singh, SimranjitGlioblastoma (GBM) is a lethal brain cancer exhibiting high levels of drug resistance, a feature partially imparted by tumor cell stemness. Recent work shows that homozygous MTAP deletion, a genetic alteration occurring in about half of all GBMs, promotes stemness in GBM cells. Exploiting MTAP loss-conferred deficiency in purine salvage, we demonstrate that purine blockade via treatment with L-Alanosine (ALA), an inhibitor of de novo purine synthesis, attenuates stemness of MTAP-deficient GBM cells. This ALA-induced reduction in stemness is mediated in part by compromised mitochondrial function, highlighted by ALA-induced elimination of mitochondrial spare respiratory capacity. Notably, these effects of ALA are apparent even when the treatment was transient and with a low dose. Finally, in agreement with diminished stemness and compromised mitochondrial function, we show that ALA sensitizes GBM cells to temozolomide (TMZ) in vitro and in an orthotopic GBM model. Collectively, these results identify purine supply as an essential component in maintaining mitochondrial function in GBM cells and highlight a critical role of mitochondrial function in sustaining GBM stemness. We propose that purine synthesis inhibition can be beneficial in combination with the standard of care for MTAP-deficient GBMs, and that it may be feasible to achieve this benefit without inflicting major toxicity.
Item Open Access Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy.(Nature communications, 2021-01-13) Gromeier, Matthias; Brown, Michael C; Zhang, Gao; Lin, Xiang; Chen, Yeqing; Wei, Zhi; Beaubier, Nike; Yan, Hai; He, Yiping; Desjardins, Annick; Herndon, James E; Varn, Frederick S; Verhaak, Roel G; Zhao, Junfei; Bolognesi, Dani P; Friedman, Allan H; Friedman, Henry S; McSherry, Frances; Muscat, Andrea M; Lipp, Eric S; Nair, Smita K; Khasraw, Mustafa; Peters, Katherine B; Randazzo, Dina; Sampson, John H; McLendon, Roger E; Bigner, Darell D; Ashley, David MSeveral immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10-20% of patients. Here we perform genomic analysis of tumor tissue from recurrent WHO grade IV glioblastoma patients acquired prior to immunotherapy intervention. We report that very low tumor mutation burden is associated with longer survival after recombinant polio virotherapy or after immune checkpoint blockade in recurrent glioblastoma patients. A relationship between tumor mutation burden and survival is not observed in cohorts of immunotherapy naïve newly diagnosed or recurrent glioblastoma patients. Transcriptomic analyses reveal an inverse relationship between tumor mutation burden and enrichment of inflammatory gene signatures in cohorts of recurrent, but not newly diagnosed glioblastoma tumors, implying that a relationship between tumor mutation burden and tumor-intrinsic inflammation evolves upon recurrence.