MICROTOPOGRAPHY INDUCES DIFFERENTIAL SENSITIVITY ON CANCER CELL PROLIFERATION VIA RHO-ROCK-MYOSIN CONTRACTILITY
Parthiv Kant Chaudhuri1, Catherine Qiurong Pan1, Boon Chuan Low1,2, Chwee Teck Lim1,2
1Mechanobiology Institute, National University of Singapore, Singapore;
2National University of Singapore, Singapore
The microenvironment that surrounds the cells is composed of the extracellular matrix (ECM) that provides myriads of mechanical and biochemical cues, which can dictate cellular behavior and phenotype. During breast cancer progression, the ECM fibers align themselves in parallel orientation that helps the migration of the cancer cells away from the primary tumor. Here, we examined the effect of microtopographic cues on cancer and non-cancer cell proliferation by fabricating micron scale topographic features. We observed that the proliferation response of non-cancer breast epithelial cells (MCF-10A) but not of metastatic (MDA-MB-231) and non-metastatic (MCF7) breast cancer cells; decreases on the microgratings (gratings widths of 2, 3 and 4 μm) across all the ECM proteins, namely, fibronectin, collagen and laminin. Interestingly, microgratings mediated proliferation reduction is prevented in presence of acto-myosin contraction inhibitory drugs, namely, Y-27632 and blebbistatin, thereby confirming the activation of RhoROCK-Myosin contractility in this phenomenon. In conclusion, we observe the existence of Mechanically Induced Dormancy (MID) where topographical cues induces proliferation inhibitory response to the normal epithelial cells but the malignant cells could successfully overcome this inhibitory barrier and continue uncontrolled proliferation. This study reveals a novel mechanism by which normal cells sense external topographical cues and restricts their proliferation in an environment that promotes tumor growth and spreading. Determining how tumor cells bypass this mechanism of MID may be paramount in the development of novel anti-cancer strategies that target cellular mechanisms altered by physical or mechanical cues during cancer progression. Promising chemotherapeutic agents targeting cellular contractile machineries has already started to emerge, and more are expected to come.