Synthetic lethality in the context of chromosome 8p deletion in liver cancer
Final Report Abstract
The project “Synthetic lethality in the context of chromosome 8p deletion in liver cancer” funded under the “Forschungsstipendien” program was aimed at understanding the molecular function of recurrent broad copy number alterations in human tumors and how they could be therapeutically translated. At the beginning of this project in 2011 broad cancer-associated deletions have been mainly interpreted according to the classical Knudsen “two-hit” model to inactivate a single tumor suppressor gene. Studying chromosome 8p as an example for recurrent broad chromosome deletions in epithelial tumors, we initially used integrated genomic analysis in combination with in vivo RNAi screening in a mouse model of hepatocellular carcinoma (HCC) to test the hypothesis that large deletions can harbor multiple tumor suppressor genes that cooperate in tumorigenesis. Indeed, we identified a number of 8p genes whose knockdown promoted tumor growth in vivo and validated Fbxo25, Fgl1 and Trim35 as novel HCC candidate tumor suppressor genes. Moreover, investigating the cooperativity between these newly identified tumor suppressors and Dlc1, a previously described HCC tumor suppressor, revealed that the 8p tumor suppressor genes synergistically act to promote tumorigenesis. Further analysis of Trim35, a member of the tripartite motif-containing family and potential E3 ligase, functionally validated it’s tumor suppressive role in HCC development and progression and implicated it’s molecular role in regulating cytokinesis. Furthermore, exploration of the therapeutic potential of broad chromosome 8p deletions using RNAi-based screening in human HCC cell lines implicated that, indeed, those large copy number aberrations exhibit specific vulnerabilities potentially useful for therapeutic intervention. In summary, this study addressing synthetic lethal interactions of 8p-dependent HCC led to the identification of a number of cooperating tumor suppressor genes highlighting the concept that recurrent broad copy number alterations contain a distinct number of cancer genes that synergistically drive tumorigenesis. Thus, the biological effect of these genomic events goes beyond the alteration of any individual gene and should be considered as a distinct genomic event. Furthermore, vulnerabilities created by such broad copy number aberrations promise novel pharmacological and therapeutical avenues for targeted anti-cancer therapy.
Publications
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(2011), Nucleating actin for invasion. Nat. Rev. Cancer 11:177-187
Nuernberg, A., Kitzing, T. and Grosse, R.
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(2012), A cluster of cooperating tumorsuppressor gene candidates in chromosomal deletions. PNAS 109:8212-8217
Xue W., Kitzing T., Roessler S., Zuber J., Krasnitz A., Schultz N., Revill K., Weissmueller S., Rappaport A.R., Simon J., Zhang J., Hicks J., Zender L., Wang X.W., Powers S., Wigler M. and Lowe S.W.
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(2012), Cooperating Tumor Suppressor Genes on Chromosome 8p Predict Survival Outcome in Hepatocellular Carcinoma. Eur J Cancer 48:S139-S139
Kitzing T., Xue W., Roessler S., Krasnitz A., Schultz N., Wang X.W., Wigler M. and Lowe S.W.
