Understanding the biology of cancer metastases is critical to improving the treatment of cancer. A key challenge in these efforts has been the lack of cancer models that can recapitulate metastasis biology, especially organ- specificity, a hallmark of cancer metastasis. Therefore, there is an urgent need for the development of novel models of cancer metastasis that can reflect organ specificity of tumor metastasis. Our group has been applying tissue engineering technologies to develop in vitro engineered cancer metastasis model. We hypothesized that decellularized tissue can recapitulate the organ microenvironment of cancer metastasis and can be utilized as strata for culturing tumor cells. We used an innovative decellularization technology, where the process retains soluble extracellular proteins in the organs (decellularized tissue are termed biomatrix), to engineer cancer metastasis. Using multiple cancer cell lines, we found that tumor cells can spontaneously form colonies on biomatrices that are common sites of metastasis (“good soil”/liver and lung). Importantly, the biology of these tumor colonies and treatment response reflect organ-specificity. We were also able to culture circulating tumor cells from patients using liver and lung biomatrices. Excitingly, we also found that tumor cells were unable to proliferate on “bad soil” biomatrices. Further study also revealed that the soluble matrix proteins are largely responsible for the lack of proliferation of tumor cells on these biomatrices. Based on our preliminary data, we hypothesize that we can develop an in vitro cancer metastasis model system using biomatrices and this model system can reflect organ-specificity. We further theorize that our proposed model of cancer metastasis represents a powerful tool for cancer biology research and hold high potential for precision oncology. In this application, we aim to further develop and validate our metastasis model. We plan to use kidney cancer as a disease model. Kidney cancer was chosen because its unique metastatic pattern: it can metastasize to organs that are rarely sites of metastasis, such as pancreas. Our proposal has 3 specific aims. The first aim will generate a comprehensive panel of biomatrices to model sites of cancer metastasis. We will conduct validation studies to confirm the model system can recapitulate organ-specificity. Second aim will focus on demonstrating the biomatrix metastasis model’s ability to improve precision oncology. Last aim will focus on identifying soluble matrix proteins that prevent metastasis formation. Success with our research will result in powerful new tools for cancer research.