Abstract
The evolutionarily conserved Notch signaling pathway regulates crucial aspects of development and tissue homeostasis. This thesis contributes research towards understanding a role of non-canonical Notch signaling in the tumor-stroma interaction of breast cancer, provides a bioinformatics-based technology to study these interactions, and proposes a novel mouse model of the liver disease in Alagille syndrome.
In Paper I, we report a novel target for non-canonical Notch signaling in breast cancer, the cytokine IL-6. In human breast cancer cell lines, we observe increased IL-6 mRNA and protein levels when Notch signaling is amplified, in turn activating the JAK/STAT pathway in a p53-dependent, but CSL-independent fashion, via IKKα and IKKβ of the NF-κB pathway. These data add a new facet to the existing body of knowledge on hyperactivated Notch signaling in promoting inflammation in breast tumors.
In Paper II, we present and validate a new bioinformatics-based approach of species-specific sequencing (S3). Using an intermixed human tumor and mouse stroma cell population from xenografted cells, we demonstrate a way to decode transcriptomes, separated by their species-specific differences, with 99% accuracy. This technique circumvents current problems in mechanically separating mixed tissue, and paves the way to efficiently analyze in vivo cell-cell interactions.
In Paper III, we characterize a mouse strain, with a missense mutation in the Jagged1 gene, as a potential model for the rare genetic disorder Alagille syndrome. We show that this model recapitulates pathologies in the liver, heart, lens and kidney observed in Alagille patients, and identify dysregulated biliary morphogenesis caused by this mutation. We also use the S3 technology, developed in Paper II, to investigate signaling specifically in receptor-expressing cells by wild type and mutated Jagged1.
In summary, the work presented in this thesis sheds new light on the role of Notch signaling in breast cancer and liver disease, and provides a novel technology to facilitate the detailed study of cell-cell interactions.
