RT Journal Article
SR Electronic
T1 Tumor cell-organized fibronectin is required to maintain a dormant breast cancer population
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 686527
DO 10.1101/686527
A1 Lauren E. Barney
A1 Christopher L. Hall
A1 Alyssa D. Schwartz
A1 Akia N. Parks
A1 Christopher Sparages
A1 Sualyneth Galarza
A1 Manu O. Platt
A1 Arthur M. Mercurio
A1 Shelly R. Peyton
YR 2019
UL http://biorxiv.org/content/early/2019/07/01/686527.abstract
AB Tumors can undergo long periods of dormancy, with cancer cells entering a largely quiescent, non-proliferative state before reactivation and outgrowth. For a patient, these post-remission tumors are often drug resistant and highly aggressive, resulting in poor prognosis. To understand the role of the extracellular matrix (ECM) in regulating tumor dormancy, we created an in vitro cell culture system that combines carefully controlled ECM substrates with nutrient deprivation to observe entrance into and exit from dormancy with live imaging. We saw that cell populations capable of surviving entrance into long-term dormancy were heterogeneous, containing quiescent, cell cycle arrested, and actively proliferating cells. Cell populations that endured extended periods of serum-deprivation-induced dormancy formed an organized, fibrillar fibronectin matrix via αvβ3 and α5β1 integrin adhesion, ROCK-generated tension, and TGFβ2 stimulation. We surmised that the fibronectin matrix was primarily a mediator of cell survival, not proliferation, during the serum-deprivation stress, bacause cancer cell outgrowth after dormancy required MMP-2-mediated fibronectin degradation. Given the difficulty of animal models in observing entrance and exit from dormancy in real-time, we propose this approach as a new, in vitro method to study factors important in regulating dormancy, and we used it here to elucidate a role for fibronectin deposition and MMP activation.