Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

New avenues to inhibit mutant p53-driven metastasis (#115)

Paul M Neilsen 1 , Rachel J Suetani 1 , David F Callen 1
  1. Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA 5005, Australia

The p53 tumor suppressor plays a pivotal role in the prevention of neoplastic transformation, with half of all human tumours harbouring mutations in TP53. Such mutations not only lead to the expression of a protein unable to impart its normal tumour suppressor ability, but also endow the mutant p53 protein with newly acquired oncogenic properties that drive invasion and metastasis. Although it is widely established that mutant p53-expressing tumours have a high capacity to metastasize and are associated with poor outcomes, the key molecular mechanisms utilised by mutant p53 are largely unknown.

We have developed a panel of H1299 carcinoma derivatives that can inducibly re-express various mutant p53 proteins into a p53 null background. In vivo induction of mutant p53 in the primary H1299 xenograft tumour was associated with increased distant metastases. Induction of mutant p53 drove an EMT and was associated with an increase invasive capacity in vitro; properties consistent with the pro-metastatic phenotype1,2. We show that mutant p53 functions as an aberrant transcription factor to selectively alter the expression of key cancer-related genes3 . Remarkably, the majority of mutant p53 target genes identified from this study are also direct targets of the metastasis suppressor, p63. We show that mutant p53 forms an oncogenic complex with p63 at the promoters of p63 target genes, resulting in disruption of the anti-metastatic p63-signalling pathway. Key direct targets of mutant p53-p63 include Dicer2 , miR-1554  and DKK13 . Surprisingly, the majority of mutant p53 target genes were secreted products. This aberrant ‘secretome’ driven by mutant p53 was predicted to promote bone destruction, as exposure of normal primary human osteoblasts to this mutant p53 secretome altered the expression of key genes that maintains bone homestasis. As such, we predict that the secreted products from mutant p53-expressing tumours may create a ‘pre-metastatic niche’ in the bone.

  1. Noll JE, Jeffery J, Al-Ejeh F, Kumar R, Khanna KK, Callen DF and Neilsen PM. Mutant p53 drives invasion and multinucleation through a process that is suppressed by ANKRD11. Oncogene. 2011. Oct 10. PMID 21986947.
  2. Muller PAJ, Trinidad AG, Timpson P, et al, Lane DP, Sansom O, Neilsen PM, Norman JC and Vousden KH. Mutant p53 induces MET signalling to drive cell scattering and invasion by inhibiting TAp63 and Dicer. Oncogene. In press (accepted 18th March 2012).
  3. Neilsen PM, Noll JE, Suetani RJ, Ho K, Schulz RB, Al-Ejeh F, Evdokiou A, Lane DP and Callen DF. Mutant p53 uses p63 as a molecular chaperone to alter gene expression and induce a pro-invasive secretome. Oncotarget. 2011; 2(12):1203-17.
  4. Neilsen PM, Noll JE, Mattiske S, Bracken CP, Gregory PA, Schulz RB, Lim SP, Kumar R, Suetani RJ, Goodall GJ and Callen DF. Mutant p53 drives invasion in breast tumors through up-regulation of miR-155. Oncogene. 2012. In press (accepted June 2012).