Studies on the role of PTEN in tumorigenesis and development of chemoresistance in a miR30-based transgene murine model of conditional PTEN inactivation
Final Report Abstract
The PTEN (phosphatase and tensin homolog) gene is part of the phosphoinositol 3 kinase (PI3K) pathway, which is one of the most frequently deregulated signalling cascades in human cancers and is often target of deletions and mutations in leukemia and lymphoma. However, it remains unclear to which extent malignancies are dependent upon the sustained absence of PTEN. To address this problem, we used tetracycline-responsive promoter driven RNA interference (RNAi) to specifically regulate the expression of PTEN. By recombination of the PTEN shRNA into embryonic stem (ES) cells and pairing the mice generated from these ES cells with transactivator (tTA) lines directing shRNA expression to lymphoid cells, we achieved consistent knockdown of PTEN in B- and T-cells. The double transgenic mice (carrying both the shRNA and the tTA) developed T-cell lymphomas (TCL), which recapitulated the phenotype observed in PTEN knock-out mice. To probe the role of PTEN in tumor maintenance, we serially transplanted shPTEN-induced TCL and treated one cohort of mice with doxycycline to reactivate PTEN expression. Interestingly, PTEN reactivation significantly prolonged survival by dramatically reducing the extent of tumor infiltration into liver and small intestine, but did not affect tumor growth in hematopoietic tissues such as lymph nodes and spleen. Thus, continuous PTEN suppression does not seem to be required for tumor maintenance in this model, which could be due to other genetic alterations found in these tumors like e.g. overexpression of the myc oncogene. Strikingly, PTEN loss strongly increases tumor cell infiltration into non-hematopoietic tissues. Our studies suggest that PTEN acts as a brake on PI3K signalling originating from chemokine receptors, and loss of PTEN leads to the amplification of signals from the tumor environment. The results from this project highlight the importance of PTEN in modulating cell-external signalling and suggest a context-dependent role for PTEN in tumor suppression, paving the way for new therapeutic approaches to malignancies with PTEN inactivation.
Publications
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Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007 Feb 8;445(7128):656-60
Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW
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Senescence of activated stellate cells limits liver fibrosis. Cell. 2008 Aug 22;134(4):657-67
Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, Yee H, Zender L, Lowe SW
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Functional identification of tumor-suppressor genes through an in vivo RNA interference screen in a mouse lymphoma model. Cancer Cell. 2009 Oct 6;16(4):324-35
Bric A, Miething C, Bialucha CU, Scuoppo C, Zender L, Krasnitz A, Xuan Z, Zuber J, Wigler M, Hicks J, McCombie RW, Hemann MT, Hannon GJ, Powers S, Lowe SW
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(2011). A rapid and scalable system for studying gene function in mice using conditional RNA interference. Cell 145, 145-58
Premsrirut PK, Dow LE, Kim SY, Camiolo M, Malone CD, Miething C, Scuoppo C, Zuber J, Dickins RA, Kogan SC, Shroyer KR, Sordella R, Hannon GJ, Lowe SW
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A tumour suppressor network relying on the polyamine–hypusine axis. Nature. 2012 Jul 12;487(7406):244-8
Scuoppo C., Miething C., Lindqvist L., Reyes J., Ruse C., Appelmann I., Yoon S., Krasnitz A., Teruya-Feldstein J., Pappin D., Pelletier J., Lowe SW
