Investigation of therapeutic targets of altered Hippo-signalling in liver cancer
Final Report Abstract
The p53 tumor suppressor coordinates a series of anti-proliferative responses that restrict the expansion of malignant cells and, as a consequence, p53 is lost or mutated in the majority of human cancers. We could show that loss of p53 enables dedifferentiation of mature hepatocytes into nestin-positive progenitor-like cells, which are poised to differentiate into hepatocellular carcinomas (HCCs) or cholangiocarcinomas (CCs) in response to lineage-specific mutations that target Wnt and Notch signaling, respectively. Moreover, our results demonstrate that p53 restricts expression of the stem and progenitor cell-associated protein nestin in an Sp1/3 transcription factor-dependent manner and that nestin is required for tumor initiation in vivo. Therefore, we uncover an unexpected role for p53 dependent tumor suppression in restricting dedifferentiation of terminal differentiated cells.
Publications
- Non-cell-autonomous tumor suppression by p53. Cell. 2013 Apr 11;153(2):449-60
Lujambio A, Akkari L, Simon J, Grace D, Tschaharganeh,DF, Bolden JE, Zhao Z, Thapar V, Joyce JA, Krizhanovsky V, Lowe SW
- CDK9 mediated transcriptional elongation is required for Myc addiction in hepatocellular carcinoma. Genes Dev. 2014 Aug 15,28(16):1800-14
Huang CH, Lujambio A, Zuber J, Tschaharganeh DF, Doran MG, Evans MJ, Kitzing T, Zhu N, de Stanchina E, Sawyers CL, Armstrong SA, Lewis JS, Sherr CJ, Lowe SW
(See online at https://doi.org/10.1101/gad.244368.114) - Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor ß signaling. Cell. 2014 Apr 10;157(2):382-94
Weissmueller S, Manchado E, Saborowski M, Morris JP 4th, Wagenblast E, Davis CA, Moon SH, Pfister NT, Tschaharganeh, DF, Kitzing T, Aust D, Markert EK, Wu J, Grimmond SM, Pilarsky C, Prives C, Biankin AV, Lowe SW
(See online at https://doi.org/10.1016/j.cell.2014.01.066) - p53 dependent Nestin regulation links tumor suppression to cellular plasticity in liver cancer. Cell. 2014 Jul 31;158(3):579-92
Tschaharganeh DF, Xue W, Calvisi DF, Evert M, Michurina TV, Dow LE, Banito A, Katz SF, Kastenhuber ER, Weissmueller S, Huang CH, Lechel A, Andersen JB, Capper D, Zender L, Longerich T, Enikolopov G, Lowe SW
(See online at https://doi.org/10.1016/j.cell.2014.05.051)
