Mechanobiology Institute, National University of Singapore , 5A Engineering Drive 1, Singapore 117411, Singapore.
Cell Signaling and Developmental Biology Laboratory, Department of Biological Sciences, National University of Singapore , Singapore 117543, Singapore.
ACS Nano. 2017 Jul 25;11(7):7336-7348. doi: 10.1021/acsnano.7b03452. Epub 2017 Jul 3.
Bone, which is composed of a porous matrix, is one of the principal secondary locations for cancer. However, little is known about the effect of this porous microenvironment in regulating cancer cell proliferation. Here, we examine how the depth of the pores can transduce a mechanical signal and reduce the proliferation of noncancer breast epithelial cells (MCF-10A) and malignant breast cancer cells (MDA-MB-231 and MCF-7) using micrometer-scale topographic features. Interestingly, cells extend 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 reduces MDA-MB-231 proliferation. Our findings support the notion of mechanically induced dormancy through depth sensing, where invadopodia-mediated depth sensing can inhibit the proliferation of noncancer and malignant breast cancer cells through differential regulation of actomyosin contractility.
骨骼由多孔基质组成，是癌症的主要继发部位之一。然而，人们对这种多孔微环境如何调节癌细胞增殖知之甚少。在这里，我们使用微米级形貌特征研究了孔的深度如何传递机械信号并减少非癌乳腺上皮细胞 (MCF-10A) 和恶性乳腺癌细胞 (MDA-MB-231 和 MCF-7) 的增殖。有趣的是，细胞会伸出富含肌动蛋白的突起，如侵袭伪足，以感知基质孔的深度，并激活肌动球蛋白收缩力以减少 MCF-10A 的增殖。然而，在 MDA-MB-231 中，深度感应会使 Rho-Rac 调节的肌动球蛋白收缩力和磷酸化 ERK 信号失活。在这种多孔基质上使用 blebbistatin 抑制收缩力会进一步降低 MDA-MB-231 的增殖。我们的研究结果支持通过深度感应诱导休眠的观点，其中侵袭伪足介导的深度感应可以通过差异调节肌动球蛋白收缩力来抑制非癌和恶性乳腺癌细胞的增殖。
