- Postdoctoral Fellow
- University of Texas McGovern Medical School
- Texas A&M University College of Medicine
Areas of Interest
My long-term research goal is to unravel the detailed mechanisms that underline human cancers. We are particularly interested in KRAS, a small GTPase that operates as a binary switch to control fundamental cellular processes including proliferation, differentiation and survival. Point mutations that lock KRAS into the GTP-bound active state, represent one of the most consequential genetic events in pancreatic, colon and non-small cell lung cancers. To function, KRAS must localize to the plasma membrane (PM) and form nanoclusters. Disruptions of these nanoclusters result in the mislocalization of KRAS from the cell surface and abrogation of signaling outputs that are linked to RAF-MEK-ERK cascades. Therefore, targeting KRAS PM-localization represents a novel approach to address urgent clinical needs to target KRAS mutant cancers.
Surface glycolipids regulate KRAS signaling complex.
Our recent findings revealed that the glycosphingolipid biosynthetic pathway is critical to KRAS plasma membrane localization and nanoclustering, and hence KRAS-induced oncogenesis. Glycosphingolipids are a group of lipids that contain a ceramide backbone and sugar groups. A subset of outer leaflet glycosphingolipids, GM3 and SM4, mediate KRAS PM interactions through cross-bilayer acyl chain interactions with inner leaflet phosphatidylserine. Reciprocally, enhanced KRAS signaling diverted glucose influx into the glycosphingolipid biosynthetic pathway and selectively increased levels of GM3 and SM4 to maintain or strengthen KRAS PM signaling complexes.
Multiple approaches to study KRAS oncogenesis.
We combine high resolution imaging and pharmacogenetic approaches coupled with mouse cancer models to study KRAS oncogenesis. Oncogenic KRAS mutations occur at a high rate in pancreatic and lung cancers; therefore, we employ multiple mouse cancer models to simulate these diseases. In mouse orthotropic PDAC and lung cancer models, KPC (KRAS-LSL.G12D/+, p53R172H/+;Cre+) cells stably expressing luciferase were implanted into the pancreas or lungs of syngeneic mice and monitored by in vivo luminescent imaging. In xenograft models, multiple human lung and pancreatic cancer cell lines carrying varying KRAS mutations were injected subcutaneously into nude mice to evaluate tumor response to different conditions. At the molecular level, we specialize in using transmission electron microscopy (EM) to image KRAS molecules in the plasma membrane using gold-conjugated antibodies. Coupled with spatial statistics, this powerful tool allows us to measure the abundance and extent of nanoclustering of KRAS molecules on the PM. Taken together, these techniques enable us to resolve KRAS biology at molecular, cellular, and whole animal levels.
- Liu, J., Arora, N. & Zhou, Y. (2023). RAS GTPases and Interleaflet Coupling in the Plasma Membrane. In Press at Cold Spring Harb Perspect Biol.
- Liu, J., van der Hoeven, R., Kattan, W.E., Chang, J.T., Montufar-Solis, D., Chen, W., Wong, M., Zhou, Y., Lebrilla, C.B., and Hancock, J.F. (2023). Glycolysis regulates KRAS plasma membrane localization and function through defined glycosphingolipids. Nat Commun 14, 465. 10.1038/s41467-023-36128-5.
- Kattan, W.E., Liu, J., Montufar-Solis, D., Liang, H., Brahmendra Barathi, B., van der Hoeven, R., Zhou, Y., and Hancock, J.F. (2021). Components of the phosphatidylserine endoplasmic reticulum to plasma membrane transport mechanism as targets for KRAS inhibition in pancreatic cancer. Proc Natl Acad Sci U S A 118.
- Glorieux, C., Xia, X., He, Y.Q., Hu, Y., Cremer, K., Robert, A., Liu, J., Wang, F., Ling, J., Chiao, P.J., et al. (2021). Regulation of PD-L1 expression in K-ras-driven cancers through ROS-mediated FGFR1 signaling. Redox Biol 38, 101780.
- Dent, P., Booth, L., Roberts, J.L., Liu, J., Poklepovic, A., Lalani, A.S., Tuveson, D., Martinez, J., and Hancock, J.F. (2019). Neratinib inhibits Hippo/YAP signaling, reduces mutant K-RAS expression, and kills pancreatic and blood cancer cells. Oncogene 38, 5890-5904.
- Wang, C., Ke, Y., Liu, S., Pan, S., Liu, Z., Zhang, H., Fan, Z., Zhou, C., Liu, J., and Wang, F. (2018). Ectopic fibroblast growth factor receptor 1 promotes inflammation by promoting nuclear factor-kappaB signaling in prostate cancer cells. J Biol Chem 293, 14839-14849. 10.1074/jbc.RA118.002907.
- Li, Q., Alsaidan, O.A., Ma, Y., Kim, S., Liu, J., Albers, T., Liu, K., Beharry, Z., Zhao, S., Wang, F., et al. (2018). Pharmacologically targeting the myristoylation of the scaffold protein FRS2alpha inhibits FGF/FGFR-mediated oncogenic signaling and tumor progression. J Biol Chem 293, 6434-6448. 10.1074/jbc.RA117.000940.
- Liu, J., Chen G, Liu Z, Liu S, Cai Z, You P, Ke Y, Lai L, Huang Y, Gao H, et al. (2017). Aberrant FGFR Tyrosine Kinase Signaling Enhances the Warburg Effect by Reprogramming LDH Isoform Expression and Activity in Prostate Cancer. Cancer Res.
- Fu, X., Chen, G., Cai, Z. D., Wang, C., Liu, Z. Z., Lin, Z. Y., Wu, Y. D., Liang, Y. X., Han, Z. D., Liu, J. C., and Zhong, W. D. (2016). Overexpression of BUB1B contributes to progression of prostate cancer and predicts poor outcome in patients with prostate cancer. Onco Targets Ther 9, 2211-2220.
- Liu, J., You, P., Chen, G., Fu, X., Zeng, X., Wang, C., Huang, Y., An, L., Wan, X., Navone, N., Wu, C. L., McKeehan, W. L., Zhang, Z., Zhong, W., and Wang, F. (2015). Hyperactivated FRS2alpha-mediated signaling in prostate cancer cells promotes tumor angiogenesis and predicts poor clinical outcome of patients. Oncogene.