Mechanics of a multilayer epithelium instruct tumour architecture and function.
Mechanics of a multilayer epithelium instruct tumour architecture and function.
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DOI：
10.1038/s41586-020-2695-9
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发表时间：
2020-09
期刊：
影响因子：
64.8
通讯作者：
Fuchs E
中科院分区：
文献类型：
--
作者：
Fiore VF;Krajnc M;Quiroz FG;Levorse J;Pasolli HA;Shvartsman SY;Fuchs E
正常组织结构的丧失是致癌转化的标志。在发育中的生物体中，组织结构在形态发生期间由机械力塑造。然而，肿瘤发生过程中组织结构的起源和后果仍然难以捉摸。在皮肤中，癌前基底细胞癌形成“芽”，而浸润性鳞状细胞癌开始为“褶皱”。在这里，使用计算建模，遗传操作和生物物理测量，我们确定这些肿瘤架构的生物物理基础和生物后果。细胞增殖和肌动球蛋白收缩性在单层上皮中而不是多层上皮中主导组织结构。同时，在复层表皮中，基底膜的软化和增强的重塑促进肿瘤出芽，而基底膜的硬化促进折叠。另外的关键力量来自祖细胞的分层和分化。肿瘤特异性基底上硬度梯度产生的致癌病变进展向恶性肿瘤，我们计算预测将改变肿瘤基底膜上的伸展张力。这一预测的病理生理后果是深远的。遗传性降低基底膜的硬度增加了膜张力，并增强了体内浸润性鳞状细胞癌的进展。我们的研究结果表明，从多层上皮细胞的上下祖细胞施加的机械力可以塑造癌前肿瘤的结构并影响肿瘤的进展。有关研究设计的更多信息，请参阅本文链接的自然研究报告摘要。
Loss of normal tissue architecture is a hallmark of oncogenic transformation. In developing organisms, tissues architectures are sculpted by mechanical forces during morphogenesis. However, the origins and consequences of tissue architecture during tumorigenesis remain elusive. In skin, premalignant basal cell carcinomas form ‘buds’, while invasive squamous cell carcinomas initiate as ‘folds’. Here, using computational modelling, genetic manipulations and biophysical measurements, we identify the biophysical underpinnings and biological consequences of these tumour architectures. Cell proliferation and actomyosin contractility dominate tissue architectures in monolayer, but not multilayer, epithelia. In stratified epidermis, meanwhile, softening and enhanced remodelling of the basement membrane promote tumour budding, while stiffening of the basement membrane promotes folding. Additional key forces stem from the stratification and differentiation of progenitor cells. Tumour-specific suprabasal stiffness gradients are generated as oncogenic lesions progress towards malignancy, which we computationally predict will alter extensile tensions on the tumour basement membrane. The pathophysiologic ramifications of this prediction are profound. Genetically decreasing the stiffness of basement membranes increases membrane tensions in silico and potentiates the progression of invasive squamous cell carcinomas in vivo. Our findings suggest that mechanical forces–exerted from above and below progenitors of multilayered epithelia–function to shape premalignant tumour architectures and influence tumour progression. Further information on research design is available in the Nature Research Reporting Summary linked to this paper.
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影响因子：
4
作者：
Daley, William P.;Yamada, Kenneth M.
通讯作者：
Yamada, Kenneth M.
影响因子：
7.7
作者：
Crest, Justin;Diz-Munoz, Alba;Bilder, David
通讯作者：
Bilder, David
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1126/science.1171643
发表时间：
2009-06-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Discher DE;Mooney DJ;Zandstra PW
通讯作者：
Zandstra PW
影响因子：
11.4
作者：
Li, J;Tzu, J;Marinkovich, MP
通讯作者：
Marinkovich, MP