多层上皮组织机械力影响肿瘤的结构和功能
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多层上皮组织机械力影响肿瘤的结构和功能
2017-10-15

本期文章:《自然》:Online/在线发表

美国洛克菲勒大学Elaine Fuchs研究组发现多层上皮组织机械力影响肿瘤的结构和功能。相关论文于2020年9月2日在线发表在《自然》杂志上。

在本研究中,研究人员使用计算机建模、遗传操作和生物物理测量的方法,确定了与皮肤相关肿瘤结构的生物物理基础和生物学影响。在单层而不是多层上皮组织中,细胞增殖和肌动球蛋白收缩主导组织结构。同时,在分层的表皮中,基底膜软化和增强的重塑促进肿瘤出芽,而基底膜变硬则促进折叠产生。附加关键作用力来源于祖细胞的分层和分化。随着致癌性病变向恶性进展,会产生肿瘤特异的上基底硬度梯度,研究人员通过计算可以预测这种改变肿瘤基底膜的拉伸张力。

这种预测方法具有深远的病理和生理意义。生物信息学研究显示利用遗传方法降低基底膜的硬度会增加膜张力,并增强体内浸润性鳞状细胞癌的进展。该发现表明,从多层上皮祖细胞的上方和下方施加机械力会影响恶变前肿瘤的结构并影响肿瘤的进展。

据悉,丢失正常组织结构是致癌转化的标志。处在发育中的个体,在形态发生过程中机械力可重塑组织结构。然而,在肿瘤发生过程中组织结构的来源和产生的后果仍亟待阐明。在皮肤器官中,基底细胞癌在癌变前形成“芽”,而浸润性鳞状细胞癌则以“皱褶”开始。

附:英文原文

Title: Mechanics of a multilayer epithelium instruct tumour architecture and function

Author: Vincent F. Fiore, Matej Krajnc, Felipe Garcia Quiroz, John Levorse, H. Amalia Pasolli, Stanislav Y. Shvartsman, Elaine Fuchs

Issue&Volume: 2020-09-02

Abstract: Loss of normal tissue architecture is a hallmark of oncogenic transformation1. In developing organisms, tissues architectures are sculpted by mechanical forces during morphogenesis2. 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.

DOI: 10.1038/s41586-020-2695-9

Source: https://www.nature.com/articles/s41586-020-2695-9

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
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