Background: Metastasis is the primary cause of death of cancer patients. Disseminated tumor cells (DTCs) leave the primary tumor and seed target organs originating metastasis, years or decades after treatment. This delay in growth is mediated by a process called tumor dormancy. The extracellular matrix (ECM)-tumor cell interactions have been shown to regulate the hallmark of cancer; from primary tumor growth to migration, invasion and metastasis. However, how ECM sensing and remodeling can induce and sustain dormancy of DTCs is unclear. Moreover, whether DTCs assemble dormancy-supportive ECM niches to sustain their phenotype is also an unanswered question. We will explore the hypothesis that ECM remodeling by dormant cells contribute to tumor dormancy by constructing a dormant ECM niche rich in collagen III (COL III). Hypothesis: Our overall hypothesis states that dormant cancer cells can construct their own ?dormancy- supportive niche? by remodeling and depositing a COL III rich ECM that sustain their phenotype. Objective: The overall goal of this project is two-fold: 1) to understand the role of the COL III ECM on the formation of dormancy-supportive niches and 2) to determine how the interaction with the collagen III ECM through DDR1 regulates the dormancy-to-reactivation transition.
Specific Aims : #1: To determine how fibrillar collagen III networks contribute to establish a dormancy-supportive niche. #2: To identify the molecular mechanisms through which collagen receptor DDR1 modulates assembly of a pro-quiescence ECM. Study design/Methods: 1) The approaches available to study the biology of dormant cells in real-time in vivo are limited. We propose to use high-resolution imaging tools combined with dormancy models to study tumor cell-ECM interactions during dormancy. We have been developing an imaging approach that includes: i) Multiphoton imaging and second harmonic generation (SHG) and ii) activity reporters for dormancy-related specific pathways to measure changes in p38/ERK signaling and cell cycle status during dormancy. 2) To analyze the ECM composition and remodeling we use quantitative proteomics in collaboration with Dr. Naba. Relevance: This project is innovative both at the conceptual and at the methodological level. We propose to study the following aspects of metastasis: 1) how DTCs create a dormant ECM niche enriched in COL III to sustain dormancy; 2) the role of COL III/DDR1 interaction in regulating dormancy; 3) how IFNg/STAT1 signaling regulates tumor dormancy through ECM remodeling; 4) how disruption of a pro-quiescence ECM proteome and increase in LTBP1 mediate dormancy-to-reactivation transition. We expect our studies to have a significant impact on biomedicine because they will uncover the mechanisms regulating dormant cell-ECM interactions, which will be an efficient way of identifying targets to prevent metastasis.
This project investigates the mechanisms of tumor cell-extracellular matrix (ECM) interactions during dormancy. Outcomes will reveal how cancer cells remodel the ECM to create a COL III rich dormancy-supportive niche and the role of COLIII/DDR1 in this process. Findings will be applied towards finding novel anti-metastatic targets.
