Heterogeneous microenvironmental stiffness regulates pro-metastatic functions of breast cancer cells.
Heterogeneous microenvironmental stiffness regulates pro-metastatic functions of breast cancer cells.
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异质的微环境刚度调节乳腺癌细胞的促异常功能。
DOI：
10.1016/j.actbio.2021.07.009
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发表时间：
2021-09-01
影响因子：
9.7
通讯作者：
Luker GD
中科院分区：
文献类型：
--
作者：
Liu C;Li M;Dong ZX;Jiang D;Li X;Lin S;Chen D;Zou X;Zhang XD;Luker GD
除了在癌细胞中观察到的分子和表型变异外，肿瘤微环境中还发生了肿瘤内异质性。乳腺肿瘤活检中不同肿瘤内位置的相关刚度图表明，刚度从核心到外围增加。但是，如何调节癌细胞在肿瘤进展中的关键功能的不同局部ECM刚度尚不清楚。尽管增加的组织刚度是乳腺癌进展的确定驱动力，但2D培养物的结论与3D环境中癌细胞的新数据不符。过去对3D培养的乳腺癌的许多研究都无法概括真正的乳腺肿瘤的刚度或肿瘤微环境中存在的各种局部刚度。在这项研究中，我们开发了一系列具有可调节刚度的胶原蛋白/藻酸盐杂交水凝胶，以匹配乳腺肿瘤的核心，中间和外围区域。我们使用这种水凝胶系统来研究不同局部刚度对乳腺癌细胞形态，增殖和迁移的影响。刚度不同的水凝胶中细胞的RNA测序揭示了癌症进展的多个细胞过程的变化，包括血管生成和代谢。我们发现，在软环境中，肿瘤细胞富集了YAP1和AP1信号转导相关的基因，而僵硬环境中的肿瘤细胞通过上调纤连蛋白1（FN1）和基质金属蛋白酶9（MMP9）的表达而变得更加促血管生成。这项系统的研究定义了乳腺肿瘤中存在的环境僵硬范围如何调节癌细胞，从而为肿瘤界面的肿瘤发生和疾病进展提供了新的见解。
Besides molecular and phenotypic variations observed in cancer cells, intratumoral heterogeneity also occurs in the tumor microenvironment. Correlative stiffness maps of different intratumor locations in breast tumor biopsies show that stiffness increases from core to periphery. However, how different local ECM stiffness regulates key functions of cancer cells in tumor progression remains unclear. Although increased tissue stiffness is an established driver of breast cancer progression, conclusions from 2D cultures do not correspond with newer data from cancer cells in 3D environments. Many past studies of breast cancer in 3D culture fail to recapitulate the stiffness of a real breast tumor or the various local stiffnesses present in a tumor microenvironment. In this study, we developed a series of collagen/alginate hybrid hydrogels with adjustable stiffness to match the core, middle, and peripheral zones of a breast tumor. We used this hydrogel system to investigate effects of different local stiffness on morphology, proliferation, and migration of breast cancer cells. RNA sequencing of cells in hydrogels with different stiffness revealed changes in multiple cellular processes underlying cancer progression, including angiogenesis and metabolism. We discovered that tumor cells in a soft environment enriched YAP1 and AP1 signaling related genes, whereas tumor cells in a stiff environment became more pro-angiogenic by upregulating fibronectin 1 (FN1) and matrix metalloproteinase 9 (MMP9) expression. This systematic study defines how the range of environmental stiffnesses present in a breast tumor regulates cancer cells, providing new insights into tumorigenesis and disease progression at the tumor-stroma interface.
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影响因子：
4.9
作者：
Bonnesoeur, Sarah;Morin-Grognet, Sandrine;Labat, Beatrice
通讯作者：
Labat, Beatrice
DOI：
10.1126/science.1191035
发表时间：
2010-08-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gilbert PM;Havenstrite KL;Magnusson KE;Sacco A;Leonardi NA;Kraft P;Nguyen NK;Thrun S;Lutolf MP;Blau HM
通讯作者：
Blau HM
影响因子：
3.7
作者：
Dvorak KM;Pettee KM;Rubinic-Minotti K;Su R;Nestor-Kalinoski A;Eisenmann KM
通讯作者：
Eisenmann KM
细胞介导的纤维募集驱动工程原纤维微环境中的细胞外基质机械感应。
影响因子：
41.2
作者：
Baker BM;Trappmann B;Wang WY;Sakar MS;Kim IL;Shenoy VB;Burdick JA;Chen CS
通讯作者：
Chen CS
影响因子：
9.7
作者：
Brancato, Virginia;Gioiella, Filomena;Netti, Paolo A.
通讯作者：
Netti, Paolo A.