Tissue Regeneration and Cancer

YZ Group Webpage Banner_re

Research Areas

p53 Activity in vivo

Our group is focused on investigating p53 activity in vivo. p53 is stabilized and post-translationally modified to serve its transcriptional activation function. The rapid response of p53 by various stresses and drugs in vivo makes it possible to provide reliable mouse models to verify the efficacy of novel developed p53 activators for cancer therapy. Using the capacity that proteasome inhibitors can stabilize proteins in multiple mouse organs and xenograft human tumor cells, we provide optimized methods to help test novel developed antibodies.

p53 in Regeneration and Carcinogenesis

Point missense mutations in the coding region of TP53 are the most common specific genetic alteration found in human cancer. Using Li-Fraumeni Syndrome mouse models, our group found elevated mutant p53 protein levels in non-cancerous mouse tissues, this work led to the possible discovery of early events occurred in carcinogenesis of multiple organs. Recently, we also found p53 can be activated in stem/progenitor cells of various organs which reveals its possible importance in tissue homeostasis and regeneration. Our group will continue to unravel the role of p53 in mechanisms of carcinogenesis of gastrointestinal and hematopoietic malignancies.
YZ Group Webpage Fig3_re637032630056032412

p53 Immune Function

We are also currently exploring roles for p53 in hematopoiesis and tumour immunology. Analyses of Li-Fraumeni Syndrome mice and mice treated with proteasome inhibitors have revealed p53 expression/stabilization in bone marrow, spleen and gut-associated lymphoid tissues. Using multi-parameter flow cytometry and NGS, we aim to characterize p53 in cycling hematopoietic stem cells and multipotent progenitor subpopulations and follow lineage development in lymphoid tissues. We are also exploring whether p53 activity is relevant in tumour-infiltrating immune cells using Li-Fraumeni Syndrome mice and 3D organoid models of gastrointestinal tumours.                           

Fig4_p53 in immune response resized

Intratumor Heterogeneity 

Lastly, p53 IHC staining patterns within tumors are complex and heterogeneous, possibly reflecting specific TP53 mutations and underlying mechanisms that promote tumorigenesis. We aim to evaluate p53 expression patterns in different types of human tumors to develop a reliable p53 IHC classification scheme for inferring p53 mutations, thereby uncover the mechanisms of p53 heterogeneous expression and develop biomarkers for selecting p53 dependent cancer therapeutic approaches.

YZ Group Webpage Fig5_re

Current members

Group Leader 

XUE Yuezhen, Senior Research Scientist

Group Members

Boris San Luis, Research fellow

He Pingping, Senior Research Officer 

Teena Thakur, Research Officer 

Siti Aishah Binte Rahmat, Research Officer 

Recent publications

  1. Puan KJ ∆, San Luis B ∆, Yusof NB, Kumar D, Andiappan AK, Lee W, Chan JD, Dollner T, Lee B, Hou HW, Poidinger M, Wang D, Rotzschke O*. Fucosyltransferase 6 deficiency compromises basophil function by abrogating their sialyl-Lewis X expression. 2019, f or submission. ( ∆co-first author).
  2. Xue Y, San Luis B, Lane DP*. Intratumour heterogeneity of p53 expression; causes and consequences. J Pathol. 2019 Nov;249(3):274-285 doi: 10.1002/path.5328.
  3. Xue Y*, Barker N, Hoon S, He P, Thakur T, Abdeen SR, Maruthappan P, Ghadessy FJ, Lane DP. Bortezomib Stabilizes and Activates p53 in Proliferative Compartments of both Normal and Tumor Tissues in Vivo. Cancer Res. 2019, 79(14): 3595-3607. (Cover Figure in the Jul 15 issue)
  4. Yuen TY*, Brown CJ, Xue Y, Tan YS, Ferrer Gago FJ, Lee XE, Neo JY, Yong , Thean D, Kaan HYK, Partridge AW, Verma CS, Lane DP, Johannes CW. Stereoisomerism of All-Hydrocarbon Stapled Peptide Inhibitors of the p53-Mdm2 Interaction: an Assessment of Synthetic Strategies and Activity Profiles. Chem Sci. 2019, 10(26):6457-6466.
  5. Hwang LA, Phang BH, Liew OW, Iqbal J, Koh XH, Koh XY, Othman R, Xue Y , Richards AM, Lane DP*, Sabapathy K*. Monoclonal Antibodies against Specific p53 Hotspot Mutants as Potential Tools for Precision Medicine. Cell Rep. 2018, 22(1):299-312.
  6. Y Xue, A Raharja, W Sim, E S M Wong, S A B Rahmat and D P Lane*. The hot-spot p53R172H mutant promotes formation of giant spermatogonia triggered by DNA damage. Oncogene. 2017, 36(14):2002-2013.
  7. Meuris F, Carthagena L, Jaracz-Ros A, Gaudin F, Cutolo P, Deback C, Xue Y , Thierry F, Doorbar J, Bachelerie F* . The CXCL12/CXCR4 Signaling Pathway: A New Susceptibility Factor in Human Papillomavirus Pathogenesis. PLoS Pathog. 2016, 12(12):e1006039. doi: 10.1371/journal.ppat.1006039.
  8. Penny HL, Sieow JL, Adriani G, Yeap WH, Ee PSC, San Luis B, Lee B, Lee T, Mak SY, Ho YS, Lam KP, Ong CK, Huang RYJ, Ginhoux F, Rotzschke O, Kamm RD, Wong SC*. Warburg metabolism in tumor-conditioned macrophages promote metastasis in human pancreatic ductal adenocarcinoma. Oncoimmunology. 2016, 5(8):e1191731.
  9. Eng HY, Wang CI, Xue Y , Lee CY, Binte Zulkifli S, Chiam PC, Ghadessy FJ, Lane DP*. Enhanced antigen detection in immunohistochemical staining using a 'digitized' chimeric antibody. Protein Eng Des Sel. 2016, 29(1):11-21.
  10. Xue Y *, Toh SY, He P, Lim T, Lim D, Pang CL, Abastado JP, Thierry F. HPV16-E2 induces prophase arrest and activates the cellular DNA damage response in vitro and in precursor lesions of cervical carcinoma. Oncotarget. 2015, 6(33):34979-91.
  11. Goh AM ∆, Xue Y ∆, Leushacke M, Li L, Wong JS, Chiam PC, Rahmat SA, Mann MB, Mann KM, Barker N, Lozano G, Terzian T, Lane DP*. Mutant p53 accumulates in cycling and proliferating cells in the normal tissues of p53 R172H mutant mice. Oncotarget. 2015, 6(20):17968-80 ( ∆co-first author).
  12. Haase D, Puan KJ, Starke M, Lai TS, Soh MY, Karunanithi I, San Luis B, Poh TY, Yusof N, Yeap CH, Phang CY, Chye WS, Chan M, Koh MB, Goh YT, Bertin-Maghit S, Nardin A, Ho LP, Rotzschke O*. Large-scale isolation of highly pure untouched; regulatory T cells in a GMP environment for adoptive cell therapy. J Immunother. 2015, 38(6):250-8.
  13. Andiappan AK, Melchiotti R, Poh TY,Nah M,Puan KJ,Vigano E,Haase D,YusofNB, San Luis B, Lum J, Kumar D, Foo S, Zhuang L, Vasudev A, Irwanto A, Lee B, Nardin A, Lui H, Zhang F, Connolly J, Liu J, Mortellaro A, Wang DY, Poidinger M, Larbi A, Zolezzi F, Rotzschke O*. Genome-wide analysis of the genetic regulation of gene expression in human neutrophils. Nat Commun. 2015, 6:7971.
  14. San Luis B and Carpino N*. Insight into the Sts-1-mediated regulation of T cell receptor (TCR) signaling through the use of novel substrate-trapping Sts-1 phosphatase variants. FEBS J. 2014, 281(3):696-707.
  15. Chen J, Xue Y, Poidinger M, Lim T, Chew SH, Pang CL, Abastado JP*, Thierry F. Mapping of HPV transcripts in four human cervical lesions using RNAseq suggests quantitative rearrangements during carcinogenic progression. Virology. 2014, 462-463:14-24.
  16. Pang CL, Toh SY, He P, Teissier S, Ben Khalifa Y, Xue Y , Thierry F*. A functional interaction of E7 with B-Myb-MuvB complex promotes acute cooperative transcriptional activation of both S- and M-phase genes. Oncogene. 2014, 33(31):4039-49.
  17. San Luis B, Nassar N, Carpino N*. New insight into the catalytic mechanism of histidine phosphatases revealed by a functionally essential arginine within the active sites of the Sts phosphatases. Biochem J. 2013, 453:27-35.
  18. Xue Y, Lim D, Zhi L, He P, Abastado JP, Thierry F*. Loss of HPV16 E2 protein expression without disruption of the E2 ORF correlates with carcinogenic progression. Open Virol J. 2012, 6:163-72.
  19. San Luis B, Sondgeroth B, Nassar N, Carpino N*. Sts-2 is a phosphatase that negatively regulates zeta-associated protein (ZAP)-70 and T cell receptor signaling pathways. J Biol Chem. 2011, 286: 15943-54.
  20. Tan CL, Gunaratne J, Lai D, Carthagena L, Wang Q, Xue YZ , Quek LS, Doorbar J, Bachelerie F, Thierry F, Bellanger S*. HPV-18 E2^E4 chimera: 2 new spliced transcripts and proteins induced by keratinocyte differentiation. Virology. 2012, 429(1):47-56.
  21. Bellanger S, Tan CL, Xue YZ , Teissier S, Thierry F*. Tumor suppressor or oncogene? A critical role of the human papillomavirus (HPV) E2 protein in cervical cancer progression. Am J Cancer Res. 2011, 1(3):373-389.
  22. Xue Y, Bellanger S, Zhang W, Lim D, Low J, Lunny D, Thierry F*. HPV16 E2 is an immediate early marker of viral infection, preceding E7 expression in precursor structures of cervical carcinoma. Cancer Res. 2010, 70(3):5316-5325.