The microenvironment determines cell fate by providing both biochemical and biophysical cues that normal and cancerous cells sense and interpret. In turn, cells also modify their ‘niches’ by secreting soluble signaling molecules (e.g., nutrients, growth factors, and hormones) and exerting mechanical forces. Recent advances in bioengineering technology have enabled us to recognize the physiological significances of physical cues, defined here as passive and active forces applied by tumor/stromal cells and extracellular matrix proteins (Broders-Bondon et al. J Cell Biol 2018 PMID: 29467174). Many difficult-to-treat cancers, such as pancreatic ductal adenocarcinoma and gastric cancer, exhibit desmoplasia, a condition characterized by concurrent uncontrolled fibrogenesis and inflammation.
YAP/TAZ are effectors of the Hippo pathway, a master regulator of tissue homeostasis and organ size whose components are frequently mutated in human cancers (Zanconato et al. Cancer Cell 2016 PMID: 27300434). We recently identified a non-canonical Hippo pathway in which Misshapen MAP4Ks and Happyhour MAP4Ks inhibit YAP/TAZ by directly phosphorylating LATS1/2 (Meng et al. Nat Commun 2015 PMID: 26437443), and further discovered that ECM stiffness can regulate this pathway through modulating RAP2 GTPase activities (Meng et al. Nature 2018 PMID: 30135582). For the future research, We would like to focus on (1) Regulation and biological impact of the non-canonical Hippo pathway by identifying new components and signals that are associated with this pathway; and (2) Identifying novel mechanosensing mechanisms, and characterizing integration of mechanical cues and biochemical signals.
Publications:
2021-
Cai X, Wang KC, Meng Z. Mechanoregulation of YAP and TAZ in Cellular Homeostasis and Disease Progression. Front Cell Dev Biol. 2021 May 24;9:673599. doi: 10.3389/fcell.2021.673599.
2020-
Luo M, Meng Z, Moroishi T, Lin K, Shen G, Mo F, Shao B, Wei X, Zhang P, Wei Y, Guan KL. YAP/TAZ are activated by and contribute to cellular heat shock response. Nat Cell Biol. 2020 Dec;22(12):1447-1459. PMID: 33199845; PubMed Central PMCID: PMC7757600
Wu B, Gan Y, Xu Y, Wu Z, Xu G, Wang P, Wang C, Meng Z, Li M, Zhang J, Zhuang H, Zhang X, Yang L, Li J, Gan X, Yu X, Huang W, Gu Y, Xu R. Identification of the novel Np17 oncogene in human leukemia. Aging (Albany NY). 2020 Nov 21.
Zhu H, Blum RH, Bernareggi D, Ask EH, Wu Z, Hoel HJ, Meng Z, Wu C, Guan KL, Malmberg KJ, Kaufman DS. Metabolic Reprograming via Deletion of CISH in Human iPSC-Derived NK Cells Promotes In Vivo Persistence and Enhances Anti-tumor Activity. Cell Stem Cell. 2020 Aug 6;27(2):224-237.e6. doi:10.1016/j.stem.2020.05.008.
Hong AW, Meng Z, Plouffe SW, Lin Z, Zhang M, Guan KL. Critical roles of phosphoinositides and NF2 in Hippo pathway regulation. Genes Dev. 2020 Feb 27. doi: 10.1101/gad.333435.119.
Koo JH, Plouffe SW, Meng Z, Lee DH, Yang D, Lim DS, Wang CY, Guan KL. Induction of AP-1 by YAP/TAZ contributes to cell proliferation and organ growth. Genes Dev. 2020 Jan 1; 34: 72-86. doi: 10.1101/gad.331546.119.
2019-
Chen R, Xie R, Meng Z, Ma S, Guan KL. STRIPAK integrates upstream signals to initiate the Hippo kinase cascade. Nat Cell Biol. 2019 Dec;21(12):1565-1577. doi: 10.1038/s41556-019-0426-y
Ma S, Meng Z, Chen R, Guan KL. The Hippo Pathway: Biology and Pathophysiology. Annu Rev Biochem. 2019 Jun 20;88:577-604. doi: 10.1146/annurev-biochem-013118-111829.
2018-
Meng Z, Qiu Y, Lin KC, Kumar A, Placone JK, Fang C, Wang K-C, Lu S, Hong AW, Pan W, Moroishi T, Luo M, PlouffeSW, Diao Y, Ye Z, Park HW, Wang X, Yu F-X, Chien S, Wang C-Y, Ren B, Engler AJ, Guan KL. RAP2 Mediates Mechano-responses of Hippo pathway. Nature. 2018 Aug;560(7720):655-660. doi: 10.1038/s41586-018-0444-0.
Lin KC, Moroishi T, Meng Z, Jeong HS, Plouffe SW, Sekido Y, Han J, Park HW, Guan KL. Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation. Nat Cell Biol. 2018 Sep;20(9):1098. doi: 10.1038/ncb3581.
2017-
Diao Y, Fang R, Li B, Meng Z, Yu J, Qiu Y, Lin KC, Huang H, Liu T, Marina RJ, Jung I, Shen Y, Guan KL, Ren B. A tiling-deletion-based genetic screen for cis-regulatory element identification in mammalian cells. Nat Methods. 2017 Apr 17. doi: 10.1038/nmeth.4264.
Ma X, Meng Z, Jin L, Xiao Z, Wang X, Tsark WM, Ding L, Gu Y, Zhang J, Kim B, He M, Gan X, Shively JE, Yu H, Xu R, Huang W. CAMK2γ in intestinal epithelial cells modulates colitis-associated colorectal carcinogenesis via enhancing STAT3 activation. Oncogene. 2017 Mar 20. doi: 10.1038/onc.2017.16.
Hong AW, Meng Z, Yuan HX, Plouffe SW, Moon S, Kim W, Jho EH, Guan KL. Osmotic stress-induced phosphorylation by NLK at Ser128 activates YAP. EMBO Rep. 2017 Jan;18(1):72-86. doi: 10.15252/embr.201642681.
2016-
Plouffe SW, Meng Z, Lin KC, Lin B, Hong AW, Chun JV, Guan KL. Characterization of Hippo Pathway Components by Gene Inactivation. Mol Cell. 2016 Dec 1;64(5):993-1008. doi: 10.1016/j.molcel.2016.10.034.
Meng Z, Ma X, Du J, Wang X, He M, Gu Y, Zhang J, Han W, Fang Z, Gan X, Van Ness C, Fu X, Schones DE, Xu R, Huang W. CAMK2γ antagonizes mTORC1 activation during hepatocarcinogenesis. Oncogene. 2016 Nov 7. doi: 10.1038/onc.2016.400.
Feng X, Liu P, Zhou X, Li MT, Li FL, Wang Z, Meng Z, Sun YP, Yu Y, Xiong Y, Yuan HX, Guan KL. Thromboxane A2 Activates YAP/TAZ to Induce Vascular Smooth Muscle Cell Proliferation and Migration. J Biol Chem. 2016 Jul 5. pii: jbc.M116.739722
Meng Z, Moroishi T, Guan KL. Mechanisms of Hippo pathway regulation. Genes Dev. 2016 Jan 1;30(1):1-17. doi: 10.1101/gad.274027.115. Review.
2015-
Meng Z, Moroishi T, Mottier-Pavie V., Plouffe SW, Hansen CG, Hong AW, Park HW, Mo JS, Lu W, Lu S, Flores F, Yu FX, Halder G, Guan KL. MAP4K Family Kinases Act in Parallel to MST1/2 to Activate LATS1/2 in the Hippo Pathway. Nat Commun. 2015 Oct 5;6:8357. doi: 10.1038/ncomms9357.
Mo JS, Meng Z, Kim YC, Park HW, Kim S, Guan KL. AMPK mediates cellular energy stress to regulate YAP and the Hippo pathway. Nat Cell Biol. 2015 Apr;17(4):500-10.
Park HW, Kim YC, Yu B, Moroishi T, Mo JS, Plouffe SW, Meng Z, Lin KC, Yu FX, Alexander CM, Wang CY, Guan KL. Alternative Wnt Signaling Activates YAP/TAZ. Cell. 2015 Aug 13;162(4):780-94. doi: 10.1016/j.cell.2015.07.013.
Moroishi T, Park HW, Qin B, Chen Q, Meng Z, Plouffe SW, Taniguchi K, Yu FX, Karin M, Pan D, Guan KL. A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis. Genes Dev. 2015 Jun 15;29(12):1271-84. doi: 10.1101/gad.262816.115.
Fu X, Dong B, Tian Y, Lefebvre P, Meng Z, Wang X, Pattou F, Han W, Wang X, Lou F, Jove R, Staels B, Moore DD, Huang W. MicroRNA-26a regulates insulin sensitivity and metabolism of glucose and lipids. J Clin Invest. 2015 Jun;125(6):2497-509. doi: 10.1172/JCI75438. Epub 2015 May 11.
Gu Y, Zhou H, Gan Y, Zhang J, Chen J, Gan X, Li H, Zheng W, Meng Z, Ma X, Wang X, Xu X, Xu G, Lu X, Liang Y, Zhang X, Lu X, Huang W, Xu R. Small-molecule induction of phospho-eIF4E sumoylation and degradation via targeting its phosphorylated serine 209 residue. Oncotarget. 2015 Jun 20;6(17):15111-21.
Han W, Fu X, Xie J, Meng Z, Gu Y, Wang X, Li L, Pan H, Huang W. miR-26a enhances autophagy to protect against ethanol-induced acute liver injury. J Mol Med 2015 Apr 17.
Yu FX, Meng Z, Plouffe SW, Guan KL. Hippo pathway regulation of gastrointestinal tissues. Annu Rev Physiol. 2015 Feb 10;77:201-27. (review)
Before 2015
Chow A, Zhou W, Liu L, Fong MY, Champer J, Van Haute D, Chin AR, Ren X, Gugiu BG, Meng Z, Huang W, Ngo V, Kortylewski M, Wang SE. Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-κB. Sci Rep. 2014 Jul 18;4:5750.
Liu G, Yu FX, Kim YC, Meng Z, Naipauer J, Looney DJ, Liu X, Gutkind JS, Mesri EA, Guan KL. Kaposi sarcoma-associated herpesvirus promotes tumorigenesis by modulating the Hippo pathway. Oncogene. 2014 Sep 8;0.
Yu FX, Luo J, Mo JS, Liu G, Kim YC, Meng Z, Zhao L, Peyman G, Ouyang H, Jiang W, Zhao J, Chen X, Zhang L, Wang CY, Bastian BC, Zhang K, Guan KL. Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP. Cancer Cell. 2014 Jun 16;25(6):822-30.
Fu X, Meng Z, Liang W, Tian Y, Wang X, Han W, Lou G, Wang X, Lou F, Yen Y, Yu H, Jove R, Huang W. miR-26a enhances miRNA biogenesis by targeting Lin28B and Zcchc11 to suppress tumor growth and metastasis. Oncogene. 2014 Aug 21;33(34):4296-306.
Lou G, Ma X, Fu X, Meng Z, Zhang W, Wang YD, Van Ness C, Yu D, Xu R, Huang W.
GPBAR1/TGR5 mediates bile acid-induced cytokine expression in murine Kupffer cells. PLoS One. 2014 Apr 22;9(4):e93567. doi: 10.1371/journal.pone.0093567.
Meng Z, Li T, Ma X, Wang X, Van Ness C, Gan Y, Zhou H, Tang J, Lou G, Wang Y, Wu J, Yen Y, Xu RZ, Huang W. Berbamine inhibits the growth of liver cancer cells and cancer initiating cells by targeting Ca2+/Calmodulin-dependent protein kinase II. Mol Cancer Ther. 2013 Oct;12(10):2067-77.
Chen T, Meng Z, Gan Y, Gu Y, Wang X, Zhang Y, Xu X, Tang J, Zhou H, Zhang X, Gan X, Xu G, Huang L, Zhang X, Fang Y, Zheng S, Jin J, Huang W, Xu R. The viral oncogene Np9 acts as a critical molecular switch for co-activating β-catenin, ERK, Akt and Notch1 and promoting the growth of human leukemia stem/progenitor cells. Leukemia. 2013 Jul;27(7):1469-78.
Wang X, Fu X, Van Ness C, Meng Z, Ma X, Huang W. Bile Acid Receptors and Liver Cancer. Curr Pathobiol Rep. 2013 Mar 1;1(1):29-35. (Review)
Gu Y, Chen T, Meng Z, Gan Y, Xu X, Zhang Y, Lou G, Li H, Gan X, Xu G, Tang J, Zhou H, Huang L, Zhang X, Fang Y, Zheng S, Huang W, Xu R. CaMKII γ, a critical regulator of multiple cancer signaling pathways, is a target of the natural product berbamine. Blood. 2012 Dec 6;120(24):4829-39. *, equal contribution.
Meng Z, Wang X, Gan Y, Zhang Y, Zhou H, Van Ness C, Wu J, Lou G, 7, Yu H, He C, Xu R, Huang W. Deletion of IFNγ enhances hepatocarcinogenesis in FXR knockout mice. J Hepatol. 2012 Nov;57(5):1004-12.
Liu N, Meng Z, Lou G, Zhou W, Wang X, Zhang Y, Zhang L, Liu X, Yen Y, Lai L, Forman BM, Xu Z, Xu R, Huang W. Hepatocarcinogenesis in FXR-/- Mice Mimics Human HCC Progression That Operates through HNF1α Regulation of FXR Expression. Mol Endocrinol. 2012 May;26(5):775-85.
Lee CG, Kim YW, Kim EH, Meng Z, Huang W, Hwang SJ, Kim SG. Farnesoid X Receptor Protects Hepatocytes From Injury by Repressing miR-199a-3p, Which Increases Levels of LKB1. Gastroenterology. 2012 May;142(5):1206-1217.e7.
Li X, Deng R, He W, Liu C, Wang M, Young J, Meng Z, Du C, Huang W, Chen L, Chen Y, Martin P, Forman S, Zeng D. Loss of B7-H1 expression by recipient parenchymal cells leads to expansion of infiltrating donor CD8+ T cells and persistence of graft-versus-host disease. J Immunol. 2012 Jan 15;188(2):724-34.
Meng Z, Liu N, Fu X, Wang X, Wang YD, Chen WD, Zhang L, Forman BM, Huang W. Insufficient bile acid signaling impairs liver repair in CYP27(-/-) mice. J Hepatol. 2011 Oct;55(4):885-95.
Chen X, Lou G, Meng Z, Huang W. TGR5: A Novel Target for Weight Maintenance and Glucose Metabolism. Exp Diabetes Res. 2011;2011:853501. (Review)
Chen X, Meng Z, Wang X, Zeng S, Huang W. The nuclear receptor CAR modulates alcohol-induced liver injury. Lab Invest. 2011 Aug;91(8):1136-45.
Chen WD, Wang YD, Meng Z, Zhang L, Huang W. Nuclear bile acid receptor FXR in the hepatic regeneration. Biochim Biophys Acta. 2011 Aug;1812(8):888-92. (Review)
Meng Z, Fu X, Chen X, Zeng S, Tian Y, Jove R, Xu R, Huang W. miR-194 is a marker of hepatic epithelial cells and suppresses metastasis of liver cancer cells in mice. Hepatology. 2010 Dec;52(6):2148-57.
Meng Z, Wang Y, Wang L, Jin W, Liu N, Pan H, Liu L, Wagman L, Forman BM, Huang W. FXR regulates liver repair after CCl4-induced toxic injury. Mol Endocrinol. 2010 May;24(5):886-97.
Zhang L, Huang X, Meng Z, Dong B, Shiah S, Moore DD, Huang W. Significance and mechanism of CYP7a1 gene regulation during the acute phase of liver regeneration. Mol Endocrinol. 2009 Feb;23(2):137-45
Meng Lab at University of Miami 