Honors and Awards:
- Fellow, American Society of Cell Biology
- Pew Scholar in Biomedical Sciences
- American Heart Association Established Investigator
- Biology Department Teaching Award (2008)
Molecular mechanisms of exocytic trafficking, tumor invasion, and immune suppression
1. Molecular basis of exocytosis: Exocytosis is a basic cell biological process mediated by transport, docking, and fusion of secretory vesicles carrying proteins and lipids to the plasma membrane. Through exocytosis, hormones and neurotransmitters can be released. Also, through exocytosis, membrane proteins and lipids can be incorporated into specific domains of plasma membrane for cell surface expansion, cell growth, morphogenesis, and cell migration. Our research aims to address three fundamental questions in cell biology: (1) what is the molecular basis for exocytosis; (2) how do the secretory machinery functions in concert with cytoskeleton and small-GTP-binding proteins during cell polarization and cell migration; (3) how the basic cell biological processes mentioned above are implicated in diseases such as cancer and diabetes. One of our research interests is the evolutionarily conserved multi-protein complex, named the exocyst. The exocyst consists of eight components: Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70 and Exo84, and plays essential roles in secretory vesicle targeting and docking at the plasma membrane during exocytosis. The exocyst is specifically localized to sites of active exocytosis and polarized cell growth, and is a downstream effector of many small GTPases including Rab, Rho, and Ral. In addition, the exocyst is a direct target of many kinases in the cell. Under the control of these signaling proteins, the exocyst coordinates with actin cytoskeleton in many pathophysiological processes such as cytokinesis, ciliogenesis, cell migration, and tumor invasion.
2. Exosomes in cancer: We are studying the molecular mechanisms that regulate the biogenesis and secretion of exosomes, which are lipid-encapsulated small vesicles secreted by a wide variety of cells. Furthermore, we aim to understanding how exosomes and other types of extracellular vesicles influence tumor microenvironment to effectively promote tumor growth, metastasis and immune evasion. We recently found that tumor-derived exosomes carry the immune checkpoint protein PD-L1, and systemically suppress the immune system. We are currently investigating how oncogenic signals regulate the biogenesis of PD-L1 exosomes and how manipulating exosome trafficking could improve the response of cancer patients to immune checkpoint-based therapies. Exosomes are considered as "treasure troves" of diagnostic biomarkers. We are developing technologies to identify exosome-based biomarkers in blood that help monitor tumor progression and patient response to immunotherapy.
We take a multidisciplinary approach that combines biochemistry, biophysics, structure biology, molecular biology, genetics, cell biology, and immunology in our research. We also integrate fundamental cell biology and clinical research, as we believe basic science and medicine can inspire and instruct each other.
Key Words:
Membrane traffic, exocytosis, exosomes, cell migration, the exocyst complex, cytoskeleton, small GTPases, cancer, tumor immune evasion, metastasis.
- BIOL 2010 (Cell Biology)
- BIOL 5010 (Advanced Cell Biology)
Liu, D., Tao, K., Wu, B., Yu, Z., Szczepaniak, M., Rames, M., Yang, C., Svitkina, T., Zhu, Y., Nan, X., Guo, W. A phosphoinositide switch mediates exocyst recruitment to multivesicular endosomes for exosome secretion. Nature Communications (2023) 14:6883.
Zhang, W. Yang, J., Wang, B., Lu, Y., Yang, J., Zhong, W., Yu, Z., Qin, Z., Xiao, B., Wang, K., Ma, Y., Amaravadi, R., Herlyn, M., Kim, J., Xu, X. Guo, W. HGS mediates tumor immune evasion by regulating proteostasis-associated interferon pathway activation. Cell Reports (2023) 42:113352.
Zhong, W., Lu, L. Han, X., Yang, J., Qin, Z., Zhang, W., Yu, Z., Wu, B., Liu, L., Xu, W., Zheng, C., Schuchter, L.M., Karakousis, G.C., Mitchell, T.C., Amaravadi, R., Flowers, A.J., Gimotty, P.A., Xiao, M., Mills, G., Herlyn, M., Dong, H., Mitchell, M.J., Kim, J., Xu, X., Guo, W. Upregulation of exosome secretion from tumor-associated macrophages plays a key role in the suppression of anti-tumor immunity. Cell Reports (2023) 42:113224.
Zhong, W., Xiao, Z., Qin, Z., Yang, J., Wen, Y., Yu, Z., Li, Y., Sheppard, N.C. Fuchs, S.Y. Xu, X., Herlyn, M., June, C.H., Puré, E., Guo, W. Tumor-derived immune suppressive extracellular vesicles in CAR T therapy of solid tumors. Cancer Research (2023) doi.org/10.1158/0008-5472.CAN-22-2220 (Featured in issue Commentary)
Wu, B., Liu, D., Guan, L., Myint, P.K., Chin, L-K., Dang, H., Xu, Y., Ren, J., Li, T., Yu, Z., Jabban, S., Mills, G.B., Nukpezah, J., Chen, Y-H., Furth, E.F., Gimotty, P.A., Wells, R.G., Weaver, V.M., Radhakrishnan, R., Wang, X., Guo, W. Stiff matrix induces exosome secretion and promotes tumor growth. Nature Cell Biology (2023) doi: 10.1038/s41556-023-01092-1. (Featured in NCB News & Views, Penn Today and other media)
Zhong, W. and Guo, W. Immune suppressive extracellular vesicles in CLL. Blood Cancer Discovery (2023) 4: 5-7.
Guan, L., Wu, B., Li, T., Beer, L., Sharma, G., Li, M., Lee, C., Liu, S., Yang, C., Huang, L., Frederick, D., Boland, G., Shao, G., Svitkina, T.M., Cai, Q., Chen, F., Dong, M., Mills, G., Schuchter, L., Karakousis, G., Mitchell, T., Flaherty, K., Speicher, D., Chen, Y., Amaravadi, R., Herlyn, M., Kim, J., Xu, X. Guo, W. HRS Phosphorylation Drives Immunosuppressive Exosome Secretion and Restricts CD8+ T Cell Infiltration into Tumors. Nature Communications (2022) 13:4078 | https://doi.org/10.1038/s41467-022-31713-6. (Featured in Faculty Opinions, Penn Today and other media)
Zhang, W., Zhong, W., Wang, B., Yang, J., Yang, J., Yu, Z., Shi, A., Xu, W., Zheng, C., Schuchter, L.M., Karakousis, G.C., Mitchell, T.C., Amaravadi, R., Herlyn, M., Dong, H., Gimotty, P.A., Daaboul, G., Xu, X., Guo, W. ICAM-1-mediated Adhesion is a Prerequisite for Exosome-induced T Cell Suppression. Developmental CELL (2022) 57:329-343.
Wang, B., Zhang, W., Zhang G., Kwong L., Lu H., Tan J., Sadek N., Xiao, M., Zhang, J, Labrie, M., Randell, R., Beroard, O., Sugarman, E, Rebecca, V., Wei, Z., Lu, Y., Mills, G., Field, J., Villanueva, J., Xu, X, Herlyn, M., Guo, W. Targeting mTOR Signaling Overcomes Acquired Resistance to Combined BRAF and MEK Inhibition in BRAF-Mutant Melanoma. Oncogene (2021) 40(37):5590-5599.
Mao, L., Zhan Y., Wu, B., Yu, Q., Xu, L., Hong, X., Zhong L., Mi, P., Mei, K., Xiao, L., Wang, X., Cao, X., Zhang, W, Chen, B., Xiang, J., Radhakrishnan, R., , Guo, W.*, Hu, T.* ULK1 phosphorylates Exo70 to suppress breast cancer metastasis. Nature Communications (*co-corresponding authors) (2020) 11-117
Chen, G., Huang, A., Zhang, W., Zhang, G., Wu, M., Xu, W., Yu, Z., Yang, J. Wang, B., Sun, H., Xia, H., Man, Q., Zhong, W., Antelo, L., Wu, B., Xiong, X., Liu, X., Guan, L., Li, T., Liu, S., Yang, R., Lu, Y., Dong, L., McGettigan, S., Somasundaram, R., Radhakrishnan, R., Mills, G., Lu, Y., Kim., J., Chen, YH., Dong, H., Zhao, Y., Karakousis, G.C., Mitchell, T.C., Schuchter, L.M., Herlyn, M., Wherry, E.J., Xu, X., Guo, W. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. NATURE (2018) 560:382-386. (Highlighted in Philadelphia Inquirer, New York Time, Boston Herald-STAT news, Genetic Engineering and Biotechnology News, Research at Penn, Penn Today, Science Daily, EurekAlert, American Cancer Immunotherapy Research, etc.). *2019 National Clinical Research Forum Top 10 Clinical Research Achievement Award Finalist. ESI top 1% highly citated article.
Mei, K., Li, Y., Wang, S, Shao, G., Wang, J., Ding, Y., Luo, G., Yue, P. Liu, J., Wang, X., Dong, M-Q, Wang, H., Guo, W. Cryo-EM structure of the exocyst complex. NATURE Structural & Molecular Biology (2018) 25:139-146. (cover highlight, Faculty of 1000 highlight)
Mei, K. and Guo, W. The Exocyst Complex. Curr. Biol. (2018) R909-930
Lu, H., Liu, S., Zhang, G., Wu, B., Zhu, Y., Frederick, D., Hu, Y., Zhong, W., Randell, S., Sadek, N., Zhang, W., Chen, G., Cheng, C., Zeng, J., Wu, L., Zhang, J., Liu, X., Xu, W., Clemens Krepler, C., Sproesser, K., Xiao, M., Miao, B., Liu, J., Song, C., Liu, J., Karakousis, G., Schuchter, L., Yiling Lu, Y., Mills, G., Cong, Y., Chernoff, J., Guo, J., Boland, G., Sullivan, R., Wei, Z., Field, J., Amaravadi, R., Flaherty, K., Herlyn, M., Xu, X., Guo, W. PAK signaling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas. NATURE (2017) 550:133-136. (Featured in Nature Research Highlights, AAAS, Cancer Discovery, etc.).
Yue, P., Zhang, Y, Mei, K., Wang, S., Lesigang, J., Zhu, Y., Dong, G. and Guo, W. Sec3 promotes the initial binary t-SNARE complex assembly and membrane fusion. NATURE COMMUNICATIONS (2017) 8:14236. (Faculty of 1000 highlight)
Lu, H., Liu, S., Zhang, G., Kwong L., Zhu, Y., Miller, J.P., Hu, Y., Zhong, W., Zeng, J., Wu, L., Krepler, C., Sproesser, K., Xiao, M., Xu, W., Karakousis, G.C., Schuchter, L., Field, J., Zhang, P.J., Herlyn, M., Xu, X., and Guo, W. Oncogenic BRAF-mediated melanoma cell invasion. CELL REPORTS (2016) 15: 2012-2024.
Wu, B., Guo, W. The Exocyst at a Glance. J. Cell Science (2015) 128(16):2957-64.
Wang, J., Ren, J., Wu, B., Feng, S., Cai, G., Tuluc, F., Peränen, J., and Guo, W. Activation of Rab8 guanine nucleotide exchange factor Rabin8 by ERK1/2 in response to EGF signaling. PNAS (2015) 112(1):148-153.
Das, A., Gajendra, S. Falenta, K., Oudin, O., Peschard, P. Feng, S. Wu, B., Marshall, C.J., Doherty, P.., ·Lalli, G., ·Guo, W. RalA promotes a direct exocyst-Par6 interaction to regulate polarity in neuronal development. (·co-corresponding authors). J. Cell Science (2014) 127: 686-699
Lu, H., Liu, J., Liu, S. Zeng, J., Ding, D., Carstens, R., Cong, Y., Xu, X., Guo, W. Exo70 isoform switching upon epithelial-mesenchymal transition regulates cancer cell invasion. Developmental CELL (2013) 27:560-573
Zhao, Y., Liu, J., Yang, C., Capraro, B., Baumgart, T., Bradley, R.P., Ramakrishnan, N., Xu, X. Radhakrishnan, R., Svitkina, T., Guo, W. Exo70 generates membrane curvature for morphogenesis and cell migration. Developmental CELL (2013) 26, 266-278.
Luo, G., Zhang, J., Luca, F., Guo, W. Mitotic phosphorylation of Exo84 disrupts exocyst assembly and arrests cell growth. J. Cell Biol. (2013) 202 (1): 97-111.
Ren, J. and Guo, W. ERK1/2 regulates post-Golgi exocytosis through phosphorylation of the exocyst component Exo70. Developmental CELL (2012) 22(5):967-978.
Liu, J., Zhao, Y., Sun, Y., Yang, C., He, B., Goldman Y., Svitkina, T., Guo, W. Exo70 stimulates actin branching for lamellipodia formation and cell migration. Current Biology (2012) 22:1510-1515.
Das, A. and Guo, W. Rabs and exocyst in ciliogenesis, lumenogenesis and beyond. Trends in Cell Biol. (2011) 21(7) 383-386.
Orlando, K., Sun, X. Zhang, J. Lu, T., Yokomizo, L., Wang, P. and Guo, W. Exo-endocytic trafficking and the septin-based diffusion barrier are required for the maintenance of Cdc42p polarization during budding yeast asymmetrical growth. Mol. Biol. Cell (2011) 22:624-633.
Knödler, A., Feng, S., Zhang, X., Zhang, J., Das, A., Peränen, J. Guo, W. Coordination of Rab11 and Rab8 in primary ciliogenesis. PNAS (2010) 107 (14) 6346-6351.
Baek, K., Knödler, A., Lee, S., Zhang, X., Orlando, K., Zhang, J., Foskett, T.J., Guo, W*., Dominguez, D*. Structural basis for membrane and GTPase-binding by Sec3. J. Biol. Chem. (2010) 285(14):10424-33. (*co-corresponding authors).
Orlando, K., Zhang, J., Zhang, X., Yue, P., Chiang, T., Bi, E., and Guo, W. Regulation of Gic2 function by PI(4,5)P2 and Cdc42. J. Biol. Chem. (2008). 283:14205-14212.
Zhang, X., Orlando, K., He, B., Xi, F., Zhang, J., Zajac, A., and Guo, W. Membrane association and functional regulation of Sec3 by phospholipids and Cdc42. J. Cell Biol. (2008) 180(1): 145-158.
He, B., Xi, F., Zhang, X., Zhang, J., and Guo, W. Exo70 interacts with phospholipids and mediates the targeting of the exocyst to the plasma membrane. EMBO J. (2007) 26, 4053-4065.
He, B., Xi, F., Zhang, J., TerBush D., Zhang, X., and Guo, W. Exo70 mediates the secretion of specific exocytic vesicles at early stages of cell cycle for polarized cell growth. J. Cell Biol. (2007) 176(6):771-777.
Zuo, X., Zhang, J., Zhang, Y., Hsu, S., Zhou, D., and Guo, W. Exo70 interacts with the Arp2/3 complex and regulates cell migration. NATURE-Cell Biology (2006) 8(12):1383-1388.
Zajac, A., Sun, X., Zhang, J. and Guo, W. (2005) Cyclical Regulation of the Exocyst and Cell Polarity Determinants for Polarized Growth. Mol. Biol. Cell 16(3), 1500-1512.