Extracellular matrix regulates hallmark features of cancer through biochemical and mechanical signals, although mechanistic understanding of these processes remains limited by lack of models that recreate physiology of tumors. To tissue-engineer models that recapitulate three-dimensional architecture and signaling in tumors, there is a pressing need for new materials permitting flexible control of mechanical and biophysical features. We developed a hybrid hydrogel system composed of collagen and alginate to model tumor environments in breast cancer and other malignancies. Material properties of the hydrogel, including stiffness, microstructure and porosimetry, encompass parameters present in normal organs and tumors. The hydrogel possesses a well-organized, homogenous microstructure with adjustable mechanical stiffness and excellent permeability. Upon embedding multicellular tumor spheroids, we constructed a 3D tumor invasion model showing follow-the-leader migration with fibroblasts leading invasion of cancer cells similar to in vivo. We also demonstrated effects of CXCL12-CXCR4 signaling, a pathway implicated in tumor progression and metastasis, in a dual-tumor spheroid invasion model in 3D hydrogels. These studies establish a new hydrogel platform with material properties that can be tuned to investigate effects of environmental conditions on tumor progression, which will advance future studies of cancer cell invasion and response to therapy.

Statement of Significance

Our manuscript describes a novel design of hybrid hydrogel system composed of collagen and alginate modeling 3D tumor environments in breast cancer. The hydrogel possesses a well-organized, homogenous microstructure with adjustable mechanical stiffness. Upon embedding tumor spheroids, we successfully showed a 3D tumor invasion model showing follow-the-leader migration with fibroblasts leading invasion of cancer cells similar to in vivo. To the best of our knowledge, this is the first study showing two spheroids invade simultaneously and forming bridge-like connection and effects of chemical gradients in 3D hydrogel environment. This research provides a new model for tumor-stromal interactions in cancer cell migration and establishes a novel hydrogel system for analyzing physical and biochemical signals regulating cancer progression and response to therapy.

中文翻译：

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混合藻酸胶原蛋白水凝胶作为3D肿瘤球体入侵的平台

细胞外基质通过生化和机械信号调节癌症的标志性特征，尽管对这些过程的机械理解仍然由于缺乏重建肿瘤生理学的模型而受到限制。对于概括了三维结构和肿瘤信号的组织工程模型，迫切需要能够灵活控制机械和生物物理特征的新材料。我们开发了一种由胶原蛋白和藻酸盐组成的混合水凝胶系统，可以对乳腺癌和其他恶性肿瘤的肿瘤环境进行建模。水凝胶的材料特性，包括刚度，微观结构和孔隙率，涵盖了正常器官和肿瘤中存在的参数。水凝胶具有组织良好，均质的微观结构，具有可调节的机械刚度和出色的渗透性。体内。我们还在3D水凝胶的双肿瘤球体入侵模型中证明了CXCL12-CXCR4信号传导的作用，该信号传导涉及肿瘤的进展和转移。这些研究建立了一个具有材料特性的新水凝胶平台，可以对其进行调节以研究环境条件对肿瘤进展的影响，这将推动未来癌细胞侵袭和对治疗反应的研究。

重要声明

我们的手稿描述了混合水凝胶系统的新颖设计，该系统由胶原蛋白和藻酸盐模拟乳腺癌中的3D肿瘤环境组成。水凝胶具有组织良好，均质的微观结构，并具有可调节的机械刚度。嵌入肿瘤球体后，我们成功地显示了3D肿瘤入侵模型，该模型显示了与成纤维细胞的先导性迁移，从而导致了类似于体内的癌细胞入侵。据我们所知，这是第一项研究，表明两个球体同时侵入并在3D水凝胶环境中形成桥状连接和化学梯度效应。