The "seed-soil" concept of cancer metastasis postulates the dependent interactions between "seed" (i.e. cancer cells) with soil (i.e. host-microenvironment)1, which transform our understanding of cancer from a disease of tumor cells into a disease of imbalance2. Extracellular matrix (ECM) is the most abundant tumor microenvironment playing critical role in cancer metastasis and tissue tension homeostasis; while undergoing structural rearrangement. Metastasis involves in invasion of primary tumor cells through basement membrane and ECM to circulatory system. Basement membrane displays thixotropic properties during tumor cell-endothelial cell interaction and tumor cell migration. Therefore, incorporation of a thixotropic (time-dependent shear thinning property) component, such as natural silk protein silk fibroin nanofibrils into the ECM gel network serve as more realistic modeling of tumor microenvironment in vitro. The nanofibrils of silk with thixotropic property can easily be obtained via fibrillar self-assembly and centrifugation. The regulation of thixotropic properties of silk nanofibrils is presently under investigation in order to understand the regulation of the mechano-transducing property of fabricated ECM in future. The goal of this work is to elaborate the cross-talk between ECM-cancer cells in order to develop ECM targeting therapeutics and the insight of metastatic process.