Role of topographic cues on cancer cell proliferation

Speaker: Parthiv Kant CHAUDHURI (Graduate Student, MBI, NUS)
Date: 7 Jul 2017, Friday
Time: 4:30pm
Venue: MBI, T-lab, level 5 seminar rooms

Supervisor(s): Prof LIM Chwee Teck (main supervisor), A/P LOW Boon Chuan (co-supervisor)

Abstract: Metastasis from a primary epithelial tumor is one of the main causes of cancer related deaths. While the roles of biochemical cues on the metastatic cascade are well known, mounting evidences suggest that physical cues such as extracellular matrix (ECM) stiffness, dimensionality and topography also direct cancer cell behaviour. Although the role of stiffness on proliferative response of cancer cells has been well studied, little is known about the effect of topographic cues in guiding cancer cell proliferation.

Here, we examined the effect of topographic cues on cancer cell proliferation by fabricating micron scale topographic features. Firstly, we studied the role of topographic cues of the primary breast tumor microenvironment in influencing proliferation. We observed that the proliferation response of non-cancer breast epithelial cells (MCF-10A) but not of metastatic (MDA-MB-231) and non-metastatic (MCF-7) 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. However, isotropic features such as micropillars do not reduce the proliferation of MCF-10A, indicating that the anisotropic environmental cues are essential for this process. Interestingly, micrograting mediated reduction of proliferation is prevented in the presence of acto-myosin contraction inhibitory drugs, namely, Y-27632 and blebbistatin, thereby confirming the activation of Rho-ROCK-Myosin in this phenomenon. Beside the primary breast tumor microenvironment, we also focused on the role of the topographic cues that mimicked the secondary breast tumor microenvironment. Bone, which is composed of a porous matrix, is one of the principal secondary locations for breast cancer. However, little is known about the effect of this porous microenvironment in regulating cancer cell proliferation. Here, we examined how the depth of the pores could transduce a mechanical signal and reduce the proliferation of non-cancer and malignant breast cancer cells. Interestingly, cells extended actin-rich protrusions, such as invadopodia to sense the depth of the matrix pore and activate actomyosin contractility to decrease MCF-10A proliferation. However, in MDA-MB-231, depth sensing inactivates Rho-Rac regulated actomyosin contractility and phospho-ERK signaling. Inhibiting contractility on this porous matrix using blebbistatin further reduced MDA-MB-231 proliferation. Taken together, we observe the existence of Mechanically Induced Dormancy (MID) where topographical cues could inhibit the proliferation of non-cancer and malignant breast cancer cells through differential regulation of actomyosin contractility.

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