Adult Stem Cell Niches & Tumor Microenvironment
We are working to unravel the biological complexity of tissue homeostasis since its disintegration underlies cancer and disease. Control over structural scaffolds, stem & progenitor cell populations, and instructive signals is essential for healthy aging of tissues. We excel at developing cutting-edge systems including genetically engineered mouse models and primary human cell mutagenesis platforms. We are known for our discoveries in proteolytic regulation of cell signalling, adult stem cell dynamics, and new cancer driver genes that govern tumorigenesis. We are translating our findings to benefit cancer therapy, prevention and cure.
Adult stem cells and Tissue homeostasis
We aim to understand how extrinsic factors regulate stem cell populations in adult tissues. We discovered that progesterone induces adult mammary stem cell expansion via intricate paracrine signalling across distinct epithelial cell populations (Nature 2010; Stem Cell Reports 2015; JAMA Oncology 2015). Sex hormone-driven mechanisms, and their control over breast biology, are our current focus towards developing new means for breast cancer screening, prevention and therapy. Stem cell fate also depends on cellular interactions with its niche. We study how natural protease inhibitors function to construct adequate structural and soluble constituents critical for sustaining and expanding stem cell pools (Nature Cell Biology 2015).
Secreted and cell surface proteases are invariably altered in all human cancers where they impact structural matrix integrity and inflammation. We have developed genetic mouse models and cell systems to globally perturb metalloproteinase networks. This allows us to study their function in cancer initiation and progression, as well as dissect underlying molecular mechanisms. We have shown that proteolysis provides an innate control over powerful signal transduction pathways including TNF, EGFR and Notch signalling during inflammation, tissue regeneration and tumor-stromal interactions (Nature Reviews Immunology 2013; Nature Cell Biology 2014; Immunity 2012; J Clinical Investigation 2010). We are investigating these processes in breast as well as liver and pancreatic cancers (Oncogene 2015).
Cancer Gene Discovery
To complement the global efforts towards cancer gene discovery, we have developed new approaches using Sleeping Beauty transposon mutagenesis for primary human cells in forward genetic screens. Beginning with specific human cells, such as bone-derived cells, we generate de novo, tractable human cancers in mice and then use genomic methods to identify candidate genes that can drive specific cancers or tumor subtypes (Nature Genetics 2014). We have also developed cross-species genomics to leverage other organisms to broaden our reach for discovering new cancer driver genes. Here, we are especially committed to osteosarcoma, a bone cancer that afflicts younger populations and compromises their quality of life (Science Translational Medicine 2015; J Clinical Investigation 2010).
For more detailed information visit the Khokha lab homepage.