The tumor microenvironment (TME) plays a significant role in cancer progression and thus modeling it will advance our understanding of cancer growth dynamics and response to therapies. Most in vitro models are not exposed to intact body physiology, and at the same time, fail to recapitulate the extensive features of the tumor stroma. conversely, animal models do not accurately capture the human tumor architecture. We address these deficiencies with biofabricated colorectal cancer (cRc) tissue equivalents, which are built to replicate architectural features of biopsied cRc tissue. our data shows that tumor-stroma co-cultures consisting of aligned extracellular matrix (ECM) fibers and ordered micro-architecture induced an epithelial phenotype in cRc cells while disordered ecM drove a mesenchymal phenotype, similar to well and poorly differentiated tumors, respectively. Importantly, co-cultures studied in vitro, and upon implantation in mice, revealed similar tumor growth dynamics and retention of architectural features for 28 days. Altogether, these results are the first demonstration of replicating human tumor ecM architecture in ex vivo and in vivo cultures. Tumors are products of their environment. They send signals that can have significant effects on local tissue, and they receive signals from nearby cells and extracellular matrix (ECM) that can alter their progression 1-3. Despite the importance of a tumor's environment, current strategies for prognostication of tumors are centered around analyses of the tumor cells in isolation, such as morphological assessment or proliferative index calculation 4,5. Although these metrics are correlated to tumor progression, they do not capture the dynamics between a tumor and its surrounding space leading to inaccuracies when attempting to predict tumor progression and chemotherapeutic response 6,7. New technologies that improve prognostication will have a significant effect on patient mortality and lead to development of novel therapeutics which target and control tumor cells specifically, sparing healthy tissue from the deleterious effects of contemporary chemotherapeutics 8,9. Recent studies have identified the tumor microenvironment (TME) as a major contributing factor to cancer development and growth. The combination of paracrine factors, stromal cells such as endothelial, macrophages and tumor associated fibroblasts (TAFs), ECM proteins, and tissue mechanics coalesce into the perfect environment for a cancer to thrive and evade treatment 2,3. Of particular interest to our research: a number of studies have shown that tissue biomechanics 10-12 and ECM architectures 13,14 can alter and guide cancer cell phenotype, as well as alter therapeutic response. These findings indicate the TME as a potential target for innovative anti-cancer cell, or cancer-modulating, therapies. To devise TME targeting therapies, in vitro models of the TME need to be developed and validated. Many groups, including ours, have used tissue engineering techniques to fabricate tumor constructs that ...
