Oral Presentation 25th Lorne Cancer Conference 2013

Senescence and melanoma: dissecting mechanism and screening for novel therapeutic targets (#10)

Daniel Peeper 1
  1. Division of Molecular Oncology, Netherlands Cancer Institute, , Amsterdam

The BRAF protein kinase is frequently mutated (commonly V600E) in melanoma and a number of other tumor types. Remarkably, BRAFE600 is also found in the vast majority of benign melanocytic nevi (moles). Nevi typically show little proliferative activity and in rare cases progress to malignant melanoma. Previously, we reported that BRAFE600 is associated with the activation of tumor suppressors (including p16INK4A) and induction of long-term, senescence-like cell cycle arrest of nevi (1, 2). Similar results on oncogene-induced senescence (OIS) in vivo have now been reported across a wide variety of model systems, and in the context of several oncogenes and tumor suppressor genes.

   In spite of the common long-term arrested state of nevus cells, we observed that nevi often display a mosaic immunopositivity for p16INK4A. This may imply that alongside p16INK4A other factors contribute to the senescent state of BRAFE600-expressing untransformed cells. In addition to taking a candidate gene approach, we are combining gene expression analysis, systematic RNAi and unbiased functional screens to identify such factors. This integrative oncogenomics approach has identified novel signaling networks involved in OIS. For example, we found that the inflammatory transcriptome is induced in the context of oncogenic stress. This is dependent on the activity of the transcription factor CEPBb as well as several of its effector genes, including specific interleukins (3, 4, 5). We also identified a mechanism by which nevi progress to melanomas, involving activation of the PI3K pathway (6). Based on these data, we have begun to build a framework, comprising several transcription factors, which fulfill a central role in melanoma suppression.

  Furthermore, we have set out to screen for novel therapeutic targets in melanoma, using function-based screens in combination with next-generation sequencing. Although recently new modes of therapeutic interference have become available, often resistance emerges. The need for, perspective and challenges of combinatorial therapy will be discussed.

  1. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, Majoor DM, Shay JW, Mooi WJ, Peeper DS. Nature. 2005 Aug 4;436(7051):720-4.
  2. Oncogene-induced cell senescence--halting on the road to cancer. Mooi WJ, Peeper DS. N Engl J Med. 2006 Sep 7;355(10):1037-46.
  3. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, Aarden LA, Mooi WJ, Peeper DS. Cell. 2008 Jun 13;133(6):1019-31
  4. Senescence-messaging secretome: SMS-ing cellular stress. Kuilman T, Peeper DS. Nat Rev Cancer. 2009 Feb;9(2):81-94. Epub 2009 Jan 9
  5. Kuilman, T., Michaloglou, C., Mooi, W. J. & Peeper, D. S. The essence of senescence. Genes Dev 24, 2463–2479 (2010).
  6. Vredeveld, L. C. W. et al. Abrogation of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanomagenesis. Genes Dev (2012).doi:10.1101/gad.187252.112