Extracellular matrix stiffness causes systematic variations in proliferation and chemosensitivity in myeloid leukemias

Significance Most chemotherapy drugs treat, but do not cure, cancer patients due to resistance. New high-throughput screening assays are emerging to better predict drug efficacy by recapitulating tumor microenvironments with three-dimensional hydrogels. Our platform exploits the mechanical tunability of alginate hydrogels to introduce biophysical cues into screening assays. The utility of this approach is demonstrated with the findings of unique modes of growth modulation by matrix stiffness and mechanosensitivity of drug actions in different myeloid leukemia subtypes. The same hydrogels were then adapted to confirm in vivo that matrix softening accelerates cancer growth kinetics and causes resistance to standard chemotherapy. We anticipate that this integrative workflow will be broadly useful to discover drugs that target cancer cells in different physical environments.