McGrail Daniel J, Kieu Quang Minh N, Iandoli Jason A, Dawson Michelle R
School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, 311 Ferst Dr, Atlanta, GA 30332, USA.
Phys Biol. 2015 Feb 23;12(2):026001. doi: 10.1088/1478-3975/12/2/026001.
Despite major advances in the characterization of molecular regulators of cancer growth and metastasis, patient survival rates have largely stagnated. Recent studies have shown that mechanical cues from the extracellular matrix can drive the transition to a malignant phenotype. Moreover, it is also known that the metastatic process, which results in over 90% of cancer-related deaths, is governed by intracellular mechanical forces. To better understand these processes, we identified metastatic tumor cells originating from different locations which undergo inverse responses to altered matrix elasticity: MDA-MB-231 breast cancer cells that prefer rigid matrices and SKOV-3 ovarian cancer cells that prefer compliant matrices as characterized by parameters such as tumor cell proliferation, chemoresistance, and migration. Transcriptomic analysis revealed higher expression of genes associated with cytoskeletal tension and contractility in cells that prefer stiff environments, both when comparing MDA-MB-231 to SKOV-3 cells as well as when comparing bone-metastatic to lung-metastatic MDA-MB-231 subclones. Using small molecule inhibitors, we found that blocking the activity of these pathways mitigated rigidity-dependent behavior in both cell lines. Probing the physical forces exerted by cells on the underlying substrates revealed that though force magnitude may not directly correlate with functional outcomes, other parameters such as force polarization do correlate directly with cell motility. Finally, this biophysical analysis demonstrates that intrinsic levels of cell contractility determine the matrix rigidity for maximal cell function, possibly influencing tissue sites for metastatic cancer cell engraftment during dissemination. By increasing our understanding of the physical interactions of cancer cells with their microenvironment, these studies may help develop novel therapeutic strategies.
尽管在癌症生长和转移的分子调节因子表征方面取得了重大进展，但患者生存率在很大程度上停滞不前。最近的研究表明，细胞外基质的机械信号可以驱动向恶性表型的转变。此外，众所周知，导致超过90%的癌症相关死亡的转移过程受细胞内机械力的支配。为了更好地理解这些过程，我们鉴定了源自不同位置的转移性肿瘤细胞，它们对改变的基质弹性有相反的反应：MDA-MB-231乳腺癌细胞更喜欢刚性基质，而SKOV-3卵巢癌细胞更喜欢顺应性基质，这通过肿瘤细胞增殖、化疗耐药性和迁移等参数来表征。转录组分析显示，在更喜欢坚硬环境的细胞中，与细胞骨架张力和收缩性相关的基因表达更高，无论是将MDA-MB-231与SKOV-3细胞进行比较，还是将骨转移性与肺转移性MDA-MB-231亚克隆进行比较时都是如此。使用小分子抑制剂，我们发现阻断这些途径的活性可减轻两种细胞系中刚性依赖性行为。探测细胞对下层底物施加的物理力表明，尽管力的大小可能与功能结果没有直接关联，但其他参数，如力的极化，确实与细胞运动性直接相关。最后，这种生物物理分析表明，细胞收缩性的内在水平决定了实现最大细胞功能的基质刚性，这可能会影响转移癌细胞在播散过程中植入的组织部位。通过增进我们对癌细胞与其微环境物理相互作用的理解，这些研究可能有助于开发新的治疗策略。
