Abstract 1104: The role of DLL4 in cancer immune-surveillance and its pathogenicity in p53-dysregulated environment

Abstract

Abstract Recent advances in cancer studies reveal that tumorigenesis results from an accumulation of mutational and epigenetic changes that alter normal cell growth and survival pathways. Li-Fraumeni syndrome (LFS) is a clinically and genetically heterogeneous inherited cancer syndrome characterized by mutation of the TP53 tumor suppressor gene (locus 17p13.1). The p53 transcription factor responds to diverse cellular stresses by regulating target genes that induce apoptosis, cell cycle arrest, DNA repair, and senescence. LFS can provide powerful insights into our understanding of somatic mutations present in sporadic cancers as well as the de-regulation of cell signaling pathways. We will be using LFS cells and mice as models to build on our previous discovery that showed a balanced reciprocal translocation between chromosomes 11q23 and 15q15 in LFS patients' skin fibroblast cells. In our present study, analysis of the breakpoint region reveals that in LFS, breast cancer (MCF7) and neuroblastoma (IMR32) cell lines, there is a dramatically increased activation in the expression of cancer susceptibility candidate 5 gene (CASC5), a part of kinetochore-microtubule attachments associated with cell proliferation. Furthermore, there was an abrogation in the expression of a critical protein, Delta-like ligand-4 (DLL4), in LFS normal skin fibroblasts of TP53 mutation carriers and non-carriers. There was also a down-regulation of DLL4 in unrelated breast cancer and neuroblastoma cell lines by DNA hypermethylation. DLL4 is a ligand for Notch family of receptors with crucial functions in normal development, immune surveillance and tissue homeostasis. TP53 and CTCF (a transcription factor involved in chromatin architecture) have a direct activator effect at the DLL4 promoter. Notch/DLL4 plays a key role in the generation of hematopoietic stem cells during embryonic development and regulates the T cell lineage and subsequent stages of thymopoiesis. WNT2 is also down-regulated in LFS cell lines and abolished in MCF7. Whereas Notch signaling controls cell fate specification in a variety of cell contexts during embryonic and postnatal development, Wnt signaling plays a critical role in cell differentiation and proliferation. Both Notch and Wnt pathways are activated by oncogenic mutations and dysregulated in cancer. The long-term objective of this research is to develop a critical understanding of the mechanisms by which p53 regulates cancer immune-surveillance through cross-talk with the tumor microenvironment so that therapeutic agents can be developed to curtail cancer progression. Citation Format: Zhixing Yao, Zaki A. Sherif. The role of DLL4 in cancer immune-surveillance and its pathogenicity in p53-dysregulated environment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1104. doi:10.1158/1538-7445.AM2014-1104