Institute Affiliations


  • Member, Maternal & Child Health Research Institute (MCHRI)

Stanford Advisors


All Publications


  • Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma SCIENCE TRANSLATIONAL MEDICINE Wang, D., Starr, R., Chang, W., Aguilar, B., Alizadeh, D., Wright, S. L., Yang, X., Brito, A., Sarkissian, A., Ostberg, J. R., Li, L., Shi, Y., Gutova, M., Aboody, K., Badie, B., Forman, S. J., Barish, M. E., Brown, C. E. 2020; 12 (533)

    Abstract

    Although chimeric antigen receptor (CAR) T cells have demonstrated signs of antitumor activity against glioblastoma (GBM), tumor heterogeneity remains a critical challenge. To achieve broader and more effective GBM targeting, we developed a peptide-bearing CAR exploiting the GBM-binding potential of chlorotoxin (CLTX). We find that CLTX peptide binds a great proportion of tumors and constituent tumor cells. CAR T cells using CLTX as the targeting domain (CLTX-CAR T cells) mediate potent anti-GBM activity and efficiently target tumors lacking expression of other GBM-associated antigens. Treatment with CLTX-CAR T cells resulted in tumor regression in orthotopic xenograft GBM tumor models. CLTX-CAR T cells do not exhibit observable off-target effector activity against normal cells or after adoptive transfer into mice. Effective targeting by CLTX-CAR T cells requires cell surface expression of matrix metalloproteinase-2. Our results pioneer a peptide toxin in CAR design, expanding the repertoire of tumor-selective CAR T cells with the potential to reduce antigen escape.

    View details for DOI 10.1126/scitranslmed.aaw2672

    View details for Web of Science ID 000518934500002

    View details for PubMedID 32132216

  • GFAP Mutations in Astrocytes Impair Oligodendrocyte Progenitor Proliferation and Myelination in an hiPSC Model of Alexander Disease CELL STEM CELL Li, L., Tian, E., Chen, X., Chao, J., Klein, J., Qu, Q., Sun, G., Sun, G., Huang, Y., Warden, C. D., Ye, P., Feng, L., Li, X., Cui, Q., Sultan, A., Douvaras, P., Fossati, V., Sanjana, N. E., Riggs, A. D., Shi, Y. 2018; 23 (2): 239-+

    Abstract

    Alexander disease (AxD) is a leukodystrophy that primarily affects astrocytes and is caused by mutations in the astrocytic filament gene GFAP. While astrocytes are thought to have important roles in controlling myelination, AxD animal models do not recapitulate critical myelination phenotypes and it is therefore not clear how AxD astrocytes contribute to leukodystrophy. Here, we show that AxD patient iPSC-derived astrocytes recapitulate key features of AxD pathology such as GFAP aggregation. Moreover, AxD astrocytes inhibit proliferation of human iPSC-derived oligodendrocyte progenitor cells (OPCs) in co-culture and reduce their myelination potential. CRISPR/Cas9-based correction of GFAP mutations reversed these phenotypes. Transcriptomic analyses of AxD astrocytes and postmortem brains identified CHI3L1 as a key mediator of AxD astrocyte-induced inhibition of OPC activity. Thus, this iPSC-based model of AxD not only recapitulates patient phenotypes not observed in animal models, but also reveals mechanisms underlying disease pathology and provides a platform for assessing therapeutic interventions.

    View details for DOI 10.1016/j.stem.2018.07.009

    View details for Web of Science ID 000440583900014

    View details for PubMedID 30075130

    View details for PubMedCentralID PMC6230521

  • Modeling neurological diseases using iPSC-derived neural cells iPSC modeling of neurological diseases CELL AND TISSUE RESEARCH Li, L., Chao, J., Shi, Y. 2018; 371 (1): 143–51

    Abstract

    Developing efficient models for neurological diseases enables us to uncover disease mechanisms and develop therapeutic strategies to treat them. Discovery of reprogramming somatic cells to induced pluripotent stem cells (iPSCs) has revolutionized the way of modeling human diseases, especially neurological diseases. Currently almost all types of neural cells, including but not limited to neural stem cells, neurons, astrocytes, oligodendrocytes and microglia, can be derived from iPSCs following developmental principles. These iPSC-derived neural cells provide valuable tools for studying neurological disease mechanisms, developing potential therapies, and deepening our understanding of the nervous system.

    View details for DOI 10.1007/s00441-017-2713-x

    View details for Web of Science ID 000419146100012

    View details for PubMedID 29079884

    View details for PubMedCentralID PMC6029980

  • m(6)A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells CELL REPORTS Cui, Q., Shi, H., Ye, P., Li, L., Qu, Q., Sun, G., Sun, G., Lu, Z., Huang, Y., Yang, C., Riggs, A. D., He, C., Shi, Y. 2017; 18 (11): 2622–34

    Abstract

    RNA modifications play critical roles in important biological processes. However, the functions of N6-methyladenosine (m6A) mRNA modification in cancer biology and cancer stem cells remain largely unknown. Here, we show that m6A mRNA modification is critical for glioblastoma stem cell (GSC) self-renewal and tumorigenesis. Knockdown of METTL3 or METTL14, key components of the RNA methyltransferase complex, dramatically promotes human GSC growth, self-renewal, and tumorigenesis. In contrast, overexpression of METTL3 or inhibition of the RNA demethylase FTO suppresses GSC growth and self-renewal. Moreover, inhibition of FTO suppresses tumor progression and prolongs lifespan of GSC-grafted mice substantially. m6A sequencing reveals that knockdown of METTL3 or METTL14 induced changes in mRNA m6A enrichment and altered mRNA expression of genes (e.g., ADAM19) with critical biological functions in GSCs. In summary, this study identifies the m6A mRNA methylation machinery as promising therapeutic targets for glioblastoma.

    View details for DOI 10.1016/j.celrep.2017.02.059

    View details for Web of Science ID 000397330000009

    View details for PubMedID 28297667

    View details for PubMedCentralID PMC5479356