Dissecting and Targeting Latent Metastasis
Abstract
Award DOD W81XWH-12-1-0074 is designed to address this problem. In Year 01 of this award, we developed models of latent metastasis of breast cancer and lung cancer. We isolated latency competent cancer (LCC) cells by in vivo selection of early-stage human tumor cell populations in mice. In Year 02, we investigated the metastatic properties of these models. In parallel, we discovered the roles of Serpins and L1CAM in the early seeding of the brain and other organs by breast cancer cells. In Year 03 of this award, we have achieved the first level of completion of the tasks set forth in our DOD W81XWH-12-1-0074 application. We have used our newly developed models of metastatic latency to show that LCC cells are a distinct class of stem-like cancer cells, which primed to enter quiescence and evade innate immunity after infiltrating distant organs. LCC cells express SOX transcription factors that impart tumor-initiating stem/progenitor cell identity. It has been long believed that dormant DTCs enter quiescence by the action of growth inhibitory signals from the host stroma. However, organs that host DTCs support cell proliferation as part of normal tissue homeostasis and regenerative processes, raising questions as to whether growth inhibitory signals from the stroma alone could explain latent metastasis. Indeed, our work shows that LCC cells actively enter a slow-cycling state by producing DKK1, an inhibitor of the stem cell growth factor WNT, leading to withdrawal and the cells from the proliferative cycle. The WNT signaling pathway is a key driver of proliferation of stem and progenitor cells, both normal and neoplastic. Moreover, we show that this self-imposed slow-cycling state involves the downregulation of ULBP ligands and other activators of natural killer (NK) lymphocytes, thus leading to evasion of NK cell-mediated cancer cell clearance.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2015
- Accession Number
- ADA623878
Entities
People
- Joan Massagué Solé
Organizations
- Memorial Sloan Kettering Cancer Center