Professional Education


  • Doctor of Philosophy, University of California Los Angeles (2017)
  • Bachelor of Science, Zhongshan University (2010)

All Publications


  • Targeting colorectal cancer with small-molecule inhibitors of ALDH1B1 Nature Chemical Biology Feng, Z., Hom, M. E., Bearrood, T. E., Rosenthal, Z. C., Fernández, D., Ondrus, A. E., Gu, Y., McCormick, A. K., Tomaske, M. G., Marshall, C. R., Chen, C., Mochly-Rosen, D., Kuo, C. J., Chen, J. K. 2022
  • Oncogene Amplification in Growth Factor Signaling Pathways Renders Cancers Dependent on Membrane Lipid Remodeling. Cell metabolism Bi, J., Ichu, T., Zanca, C., Yang, H., Zhang, W., Gu, Y., Chowdhry, S., Reed, A., Ikegami, S., Turner, K. M., Zhang, W., Villa, G. R., Wu, S., Quehenberger, O., Yong, W. H., Kornblum, H. I., Rich, J. N., Cloughesy, T. F., Cavenee, W. K., Furnari, F. B., Cravatt, B. F., Mischel, P. S. 2019

    Abstract

    Advances in DNA sequencing technologies have reshaped our understanding of the molecular basis of cancer, providing a precise genomic view of tumors. Complementary biochemical and biophysical perspectives of cancer point toward profound shifts in nutrient uptake and utilization that propel tumor growth and major changes in the structure of the plasma membrane of tumor cells. The molecular mechanisms that bridge these fundamental aspects of tumor biology remain poorly understood. Here, we show that the lysophosphatidylcholine acyltransferase LPCAT1 functionally links specific genetic alterations in cancer with aberrant metabolism and plasma membrane remodeling to drive tumor growth. Growth factor receptor-driven cancers are found to depend on LPCAT1 to shape plasma membrane composition through enhanced saturated phosphatidylcholine content that is, in turn, required for the transduction of oncogenic signals. These results point to a genotype-informed strategy that prioritizes lipid remodeling pathways as therapeutic targets for diverse cancers.

    View details for DOI 10.1016/j.cmet.2019.06.014

    View details for PubMedID 31303424

  • mTORC2 Regulates Amino Acid Metabolism in Cancer by Phosphorylation of the Cystine-Glutamate Antiporter xCT. Molecular cell Gu, Y., Albuquerque, C. P., Braas, D., Zhang, W., Villa, G. R., Bi, J., Ikegami, S., Masui, K., Gini, B., Yang, H., Gahman, T. C., Shiau, A. K., Cloughesy, T. F., Christofk, H. R., Zhou, H., Guan, K. L., Mischel, P. S. 2017; 67 (1): 128-138.e7

    Abstract

    Mutations in cancer reprogram amino acid metabolism to drive tumor growth, but the molecular mechanisms are not well understood. Using an unbiased proteomic screen, we identified mTORC2 as a critical regulator of amino acid metabolism in cancer via phosphorylation of the cystine-glutamate antiporter xCT. mTORC2 phosphorylates serine 26 at the cytosolic N terminus of xCT, inhibiting its activity. Genetic inhibition of mTORC2, or pharmacologic inhibition of the mammalian target of rapamycin (mTOR) kinase, promotes glutamate secretion, cystine uptake, and incorporation into glutathione, linking growth factor receptor signaling with amino acid uptake and utilization. These results identify an unanticipated mechanism regulating amino acid metabolism in cancer, enabling tumor cells to adapt to changing environmental conditions.

    View details for DOI 10.1016/j.molcel.2017.05.030

    View details for PubMedID 28648777

    View details for PubMedCentralID PMC5521991

  • An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers CANCER CELL Villa, G. R., Hulce, J. J., Zanca, C., Bi, J., Ikegami, S., Cahill, G. L., Gu, Y., Lum, K. M., Masui, K., Yang, H., Rong, X., Hong, C., Turner, K. M., Liu, F., Hon, G. C., Jenkins, D., Martini, M., Armando, A. M., Quehenberger, O., Cloughesy, T. F., Furnari, F. B., Cavenee, W. K., Tontonoz, P., Gahman, T. C., Shiau, A. K., Cravatt, B. F., Mischel, P. S. 2016; 30 (5): 683-693

    Abstract

    Small-molecule inhibitors targeting growth factor receptors have failed to show efficacy for brain cancers, potentially due to their inability to achieve sufficient drug levels in the CNS. Targeting non-oncogene tumor co-dependencies provides an alternative approach, particularly if drugs with high brain penetration can be identified. Here we demonstrate that the highly lethal brain cancer glioblastoma (GBM) is remarkably dependent on cholesterol for survival, rendering these tumors sensitive to Liver X receptor (LXR) agonist-dependent cell death. We show that LXR-623, a clinically viable, highly brain-penetrant LXRα-partial/LXRβ-full agonist selectively kills GBM cells in an LXRβ- and cholesterol-dependent fashion, causing tumor regression and prolonged survival in mouse models. Thus, a metabolic co-dependency provides a pharmacological means to kill growth factor-activated cancers in the CNS.

    View details for DOI 10.1016/j.ccell.2016.09.008

    View details for PubMedID 27746144

  • Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma CANCER CELL Wei, W., Shin, Y. S., Xue, M., Matsutani, T., Masui, K., Yang, H., Ikegami, S., Gu, Y., Herrmann, K., Johnson, D., Ding, X., Hwang, K., Kim, J., Zhou, J., Su, Y., Li, X., Bonetti, B., Chopra, R., James, C. D., Cavenee, W. K., Cloughesy, T. F., Mischel, P. S., Heath, J. R., Gini, B. 2016; 29 (4): 563-573

    Abstract

    Intratumoral heterogeneity of signaling networks may contribute to targeted cancer therapy resistance, including in the highly lethal brain cancer glioblastoma (GBM). We performed single-cell phosphoproteomics on a patient-derived in vivo GBM model of mTOR kinase inhibitor resistance and coupled it to an analytical approach for detecting changes in signaling coordination. Alterations in the protein signaling coordination were resolved as early as 2.5 days after treatment, anticipating drug resistance long before it was clinically manifest. Combination therapies were identified that resulted in complete and sustained tumor suppression in vivo. This approach may identify actionable alterations in signal coordination that underlie adaptive resistance, which can be suppressed through combination drug therapy, including non-obvious drug combinations.

    View details for DOI 10.1016/j.ccell.2016.03.012

    View details for Web of Science ID 000373854600018

    View details for PubMedID 27070703

  • mTOR Complex 2 Controls Glycolytic Metabolism in Glioblastoma through FoxO Acetylation and Upregulation of c-Myc CELL METABOLISM Masui, K., Tanaka, K., Akhavan, D., Babic, I., Gini, B., Matsutani, T., Iwanami, A., Liu, F., Villa, G. R., Gu, Y., Campos, C., Zhu, S., Yang, H., Yong, W. H., Cloughesy, T. F., Mellinghoff, I. K., Cavenee, W. K., Shaw, R. J., Mischel, P. S. 2013; 18 (5): 726-739

    Abstract

    Aerobic glycolysis (the Warburg effect) is a core hallmark of cancer, but the molecular mechanisms underlying it remain unclear. Here, we identify an unexpected central role for mTORC2 in cancer metabolic reprogramming where it controls glycolytic metabolism by ultimately regulating the cellular level of c-Myc. We show that mTORC2 promotes inactivating phosphorylation of class IIa histone deacetylases, which leads to the acetylation of FoxO1 and FoxO3, and this in turn releases c-Myc from a suppressive miR-34c-dependent network. These central features of activated mTORC2 signaling, acetylated FoxO, and c-Myc levels are highly intercorrelated in clinical samples and with shorter survival of GBM patients. These results identify a specific, Akt-independent role for mTORC2 in regulating glycolytic metabolism in cancer.

    View details for DOI 10.1016/j.cmet.2013.09.013

    View details for Web of Science ID 000327253300013

    View details for PubMedID 24140020

  • EGFR mutation-induced alternative splicing of Max contributes to growth of glycolytic tumors in brain cancer. Cell metabolism Babic, I., Anderson, E. S., Tanaka, K., Guo, D., Masui, K., Li, B., Zhu, S., Gu, Y., Villa, G. R., Akhavan, D., Nathanson, D., Gini, B., Mareninov, S., Li, R., Camacho, C. E., Kurdistani, S. K., Eskin, A., Nelson, S. F., Yong, W. H., Cavenee, W. K., Cloughesy, T. F., Christofk, H. R., Black, D. L., Mischel, P. S. 2013; 17 (6): 1000-1008

    Abstract

    Alternative splicing contributes to diverse aspects of cancer pathogenesis including altered cellular metabolism, but the specificity of the process or its consequences are not well understood. We characterized genome-wide alternative splicing induced by the activating EGFRvIII mutation in glioblastoma (GBM). EGFRvIII upregulates the heterogeneous nuclear ribonucleoprotein (hnRNP) A1 splicing factor, promoting glycolytic gene expression and conferring significantly shorter survival in patients. HnRNPA1 promotes splicing of a transcript encoding the Myc-interacting partner Max, generating Delta Max, an enhancer of Myc-dependent transformation. Delta Max, but not full-length Max, rescues Myc-dependent glycolytic gene expression upon induced EGFRvIII loss, and correlates with hnRNPA1 expression and downstream Myc-dependent gene transcription in patients. Finally, Delta Max is shown to promote glioma cell proliferation in vitro and augment EGFRvIII expressing GBM growth in vivo. These results demonstrate an important role for alternative splicing in GBM and identify Delta Max as a mediator of Myc-dependent tumor cell metabolism.

    View details for DOI 10.1016/j.cmet.2013.04.013

    View details for PubMedID 23707073

    View details for PubMedCentralID PMC3679227