Dormancy-inducing 3D-engineered matrix uncovers mechanosensitive and drug protective FHL2-p21 signaling axis

Abstract

Resected tumors frequently relapse with distant metastasis, despite systemic treatment. Cellular quiescence has been identified as an important mechanism underlying such drug resistance enabling late relapse. Nonetheless, hurdles associated with detection and isolation of disseminated cancer cells (DCCs) in disease-free patients urge the need for in vitro models of quiescent cells suited for drug screening campaigns. Here, we explore a quiescence-inducing 3D-engineered matrix based on ultraviolet light-initiated thiol-ene-crosslinked alginate hydrogels, which generate mechanical confinement and induce growth arrest and survival against chemotherapy in cancer cells. As underlying mechanism, we identified stiffness-dependent nuclear localization of the four-and-a-half LIM domains 2 (FHL2) protein, leading to p53-independent high p21Cip1/Waf1 nuclear expression, validated in murine and human tissue. Suggestive of a resistance-causing role, cells in the quiescence-inducing matrix became sensitive against chemotherapy upon FHL2 downregulation. Thus, our biomaterial-based approach will enable systematic screens for novel compounds suited to eradicate potentially relapsing, dormant cancer cells.