Yiping He

Positions:

Associate Professor in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2002

University of Pennsylvania

Post-doctoral Fellow, Pathology

Johns Hopkins University

Howard Hughes Researcher, Pathology

Johns Hopkins University

Research Associate, Pathology

Johns Hopkins University

Grants:

Exploiting MTAP deletion for GBM therapeutics

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Exploiting MTAP for more effective treatment of glioblastoma with temozolomide

Administered By
Pathology
Awarded By
Southeastern Brain Tumor Foundation
Role
Principal Investigator
Start Date
End Date

Developing novel mouse models for medulloblastoma

Administered By
Pathology
Awarded By
Circle of Service Foundation
Role
Principal Investigator
Start Date
End Date

Repurposing Remyelination Drugs for Oligodendroglioma Therapeutics

Administered By
Pathology
Awarded By
American Brain Tumor Association
Role
Principal Investigator
Start Date
End Date

Publications:

The integrated genomic and epigenomic landscape of brainstem glioma.

Brainstem gliomas are a heterogeneous group of tumors that encompass both benign tumors cured with surgical resection and highly lethal cancers with no efficacious therapies. We perform a comprehensive study incorporating epigenetic and genomic analyses on a large cohort of brainstem gliomas, including Diffuse Intrinsic Pontine Gliomas. Here we report, from DNA methylation data, distinct clusters termed H3-Pons, H3-Medulla, IDH, and PA-like, each associated with unique genomic and clinical profiles. The majority of tumors within H3-Pons and-H3-Medulla harbors H3F3A mutations but shows distinct methylation patterns that correlate with anatomical localization within the pons or medulla, respectively. Clinical data show significantly different overall survival between these clusters, and pathway analysis demonstrates different oncogenic mechanisms in these samples. Our findings indicate that the integration of genetic and epigenetic data can facilitate better understanding of brainstem gliomagenesis and classification, and guide future studies for the development of novel treatments for this disease.
Authors
Chen, LH; Pan, C; Diplas, BH; Xu, C; Hansen, LJ; Wu, Y; Chen, X; Geng, Y; Sun, T; Sun, Y; Zhang, P; Wu, Z; Zhang, J; Li, D; Zhang, Y; Wu, W; Wang, Y; Li, G; Yang, J; Wang, X; Xu, C; Wang, S; Waitkus, MS; He, Y; McLendon, RE; Ashley, DM; Yan, H; Zhang, L
MLA Citation
Chen, Lee H., et al. “The integrated genomic and epigenomic landscape of brainstem glioma.Nat Commun, vol. 11, no. 1, June 2020, p. 3077. Pubmed, doi:10.1038/s41467-020-16682-y.
URI
https://scholars.duke.edu/individual/pub1447966
PMID
32555164
Source
pubmed
Published In
Nature Communications
Volume
11
Published Date
Start Page
3077
DOI
10.1038/s41467-020-16682-y

Targeting Mutant PPM1D Sensitizes Diffuse Intrinsic Pontine Glioma Cells to the PARP Inhibitor Olaparib.

Diffuse intrinsic pontine glioma (DIPG) is an invariably fatal brain tumor occurring predominantly in children. Up to 90% of pediatric DIPGs harbor a somatic heterozygous mutation resulting in the replacement of lysine 27 with methionine (K27M) in genes encoding histone H3.3 (H3F3A, 65%) or H3.1 (HIST1H3B, 25%). Several studies have also identified recurrent truncating mutations in the gene encoding protein phosphatase 1D, PPM1D, in 9%-23% of DIPGs. Here, we sought to investigate the therapeutic potential of targeting PPM1D, alone or in combination with inhibitors targeting specific components of DNA damage response pathways in patient-derived DIPG cell lines. We found that GSK2830371, an allosteric PPM1D inhibitor, suppressed the proliferation of PPM1D-mutant, but not PPM1D wild-type DIPG cells. We further observed that PPM1D inhibition sensitized PPM1D-mutant DIPG cells to PARP inhibitor (PARPi) treatment. Mechanistically, combined PPM1D and PARP inhibition show synergistic effects on suppressing a p53-dependent RAD51 expression and the formation of RAD51 nuclear foci, possibly leading to impaired homologous recombination (HR)-mediated DNA repair in PPM1D-mutant DIPG cells. Collectively, our findings reveal the potential role of the PPM1D-p53 signaling axis in the regulation of HR-mediated DNA repair and provide preclinical evidence demonstrating that combined inhibition of PPM1D and PARP1/2 may be a promising therapeutic combination for targeting PPM1D-mutant DIPG tumors. IMPLICATIONS: The findings support the use of PARPi in combination with PPM1D inhibition against PPM1D-mutant DIPGs.
Authors
Wang, Z; Xu, C; Diplas, BH; Moure, CJ; Chen, C-PJ; Chen, LH; Du, C; Zhu, H; Greer, PK; Zhang, L; He, Y; Waitkus, MS; Yan, H
MLA Citation
Wang, Zhaohui, et al. “Targeting Mutant PPM1D Sensitizes Diffuse Intrinsic Pontine Glioma Cells to the PARP Inhibitor Olaparib.Mol Cancer Res, vol. 18, no. 7, July 2020, pp. 968–80. Pubmed, doi:10.1158/1541-7786.MCR-19-0507.
URI
https://scholars.duke.edu/individual/pub1436984
PMID
32229503
Source
pubmed
Published In
Mol Cancer Res
Volume
18
Published Date
Start Page
968
End Page
980
DOI
10.1158/1541-7786.MCR-19-0507

Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer.

Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR+ luminal tumor cells and AR- neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR+ luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity.
Authors
Li, Y; He, Y; Butler, W; Xu, L; Chang, Y; Lei, K; Zhang, H; Zhou, Y; Gao, AC; Zhang, Q; Taylor, DG; Cheng, D; Farber-Katz, S; Karam, R; Landrith, T; Li, B; Wu, S; Hsuan, V; Yang, Q; Hu, H; Chen, X; Flowers, M; McCall, SJ; Lee, JK; Smith, BA; Park, JW; Goldstein, AS; Witte, ON; Wang, Q; Rettig, MB; Armstrong, AJ; Cheng, Q; Huang, J
MLA Citation
Li, Yanjing, et al. “Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer.Sci Transl Med, vol. 11, no. 521, Dec. 2019. Pubmed, doi:10.1126/scitranslmed.aax0428.
URI
https://scholars.duke.edu/individual/pub1423084
PMID
31801883
Source
pubmed
Published In
Sci Transl Med
Volume
11
Published Date
DOI
10.1126/scitranslmed.aax0428

A PRMT5-RNF168-SMURF2 Axis Controls H2AX Proteostasis.

H2AX safeguards genomic stability in a dose-dependent manner; however, mechanisms governing its proteostasis are poorly understood. Here, we identify a PRMT5-RNF168-SMURF2 cascade that regulates H2AX proteostasis. We show that PRMT5 sustains the expression of RNF168, an E3 ubiquitin ligase essential for DNA damage response (DDR). Suppression of PRMT5 occurs in methylthioadenosine phosphorylase (MTAP)-deficient glioblastoma cells and attenuates the expression of RNF168, leading to destabilization of H2AX by E3 ubiquitin ligase SMURF2. RNF168 and SMURF2 serve as a stabilizer and destabilizer of H2AX, respectively, via their dynamic interactions with H2AX. In supporting an important role of this signaling cascade in regulating H2AX, MTAP-deficient glioblastoma cells display higher levels of DNA damage spontaneously or in response to genotoxic agents. These findings reveal a regulatory mechanism of H2AX proteostasis and define a signaling cascade that is essential to DDR and that is disrupted by the loss of a metabolic enzyme in tumor cells.
Authors
Du, C; Hansen, LJ; Singh, SX; Wang, F; Sun, R; Moure, CJ; Roso, K; Greer, PK; Yan, H; He, Y
MLA Citation
Du, Changzheng, et al. “A PRMT5-RNF168-SMURF2 Axis Controls H2AX Proteostasis.Cell Rep, vol. 28, no. 12, Sept. 2019, pp. 3199-3211.e5. Pubmed, doi:10.1016/j.celrep.2019.08.031.
URI
https://scholars.duke.edu/individual/pub1410992
PMID
31533041
Source
pubmed
Published In
Cell Reports
Volume
28
Published Date
Start Page
3199
End Page
3211.e5
DOI
10.1016/j.celrep.2019.08.031

CRISPR Editing of Mutant IDH1 R132H Induces a CpG Methylation-Low State in Patient-Derived Glioma Models of G-CIMP.

Mutations in isocitrate dehydrogenases 1 and 2 (IDH) occur in the majority of World Health Organization grade II and III gliomas. IDH1/2 active site mutations confer a neomorphic enzyme activity producing the oncometabolite D-2-hydroxyglutarate (D-2HG), which generates the glioma CpG island methylation phenotype (G-CIMP). While IDH1/2 mutations and G-CIMP are commonly retained during tumor recurrence, recent work has uncovered losses of the IDH1 mutation in a subset of secondary glioblastomas. Cooccurrence of the loss of the mutant allele with extensive methylation changes suggests a possible link between the two phenomena. Here, we utilize patient-derived IDH1R132H/WT glioma cell lines and CRISPR-Cas9-mediated gene knockout to model the genetic loss of IDH1R132H, and characterize the effects of this deletion on DNA methylation. After D-2HG production has been abolished by deletions within the IDH1 alleles, these models show persistent DNA hypermethylation at seven CpG sites previously used to define G-CIMP-positivity in patient tumor samples. Despite these defining G-CIMP sites showing persistent hypermethylation, we observed a genome-wide pattern of DNA demethylation, enriched for CpG sites located within open sea regions of the genome, as well as in CpG-island shores of transcription start sites, after loss of D-2HG production. These results suggest that inhibition of D-2HG from genetic deletion of IDH alleles is not sufficient to reverse hypermethylation of all G-CIMP-defining CpG sites, but does result in more demethylation globally and may contribute to the formation of a G-CIMP-low-like phenotype. IMPLICATIONS: These findings show that loss of the IDH1 mutation in malignant glioma cells leads to a pattern of DNA methylation alterations, and shows plausibility of IDH1 mutation loss being causally related to the gain of a G-CIMP-low-like phenotype.
Authors
Moure, CJ; Diplas, BH; Chen, LH; Yang, R; Pirozzi, CJ; Wang, Z; Spasojevic, I; Waitkus, MS; He, Y; Yan, H
MLA Citation
Moure, Casey J., et al. “CRISPR Editing of Mutant IDH1 R132H Induces a CpG Methylation-Low State in Patient-Derived Glioma Models of G-CIMP.Mol Cancer Res, vol. 17, no. 10, Oct. 2019, pp. 2042–50. Pubmed, doi:10.1158/1541-7786.MCR-19-0309.
URI
https://scholars.duke.edu/individual/pub1397070
PMID
31292202
Source
pubmed
Published In
Mol Cancer Res
Volume
17
Published Date
Start Page
2042
End Page
2050
DOI
10.1158/1541-7786.MCR-19-0309