The tumor microenvironment has been demonstrated to play a crucial role in modulating cancer progression. Amongst various cell types within the tumor microenvironment, cancer associated fibroblasts (CAFs) are in abundance, serving to modulate the biophysical properties of the stromal matrix, through excessive deposition of extracellular matrix (ECM) proteins, and lead to enhanced tumor progression. There is still a critical need to develop a fundamental framework on the role of tumor-stromal cell interactions on desmoplasia and tumorigenicity. Herein, we developed a 3D microengineered organotypic tumor-stroma model incorporated with breast cancer cells surrounded by CAF-embedded collagen matrix. We integrated our platform with atomic force microscopy (AFM) to study the dynamic changes in stromal stiffness during active tumor invasion.

Our findings primarily demonstrated enhanced tumor progression in presence of CAFs. Furthermore, we highlighted the crucial role of crosstalk between tumor cells and CAFs on stromal desmoplasia, where we identified the role of tumor-secreted PDGF-AA/-BB on elevated matrix stiffness. Inhibition of the activity of PDGFRs in CAFs led to attenuation of stromal stiffness. Overall, our work presents a well-controlled tumor microenvironment model capable of dissecting specific biophysical and biochemical signaling cues which lead to stromal desmoplasia and tumor progression.

肿瘤微环境已被证明在调节癌症进展中起着至关重要的作用。在肿瘤微环境中的各种细胞类型中，癌症相关成纤维细胞 (CAF) 大量存在，通过细胞外基质 (ECM) 蛋白的过度沉积来调节基质基质的生物物理特性，并导致肿瘤进展加快。仍然迫切需要制定一个关于肿瘤-基质细胞相互作用对结缔组织增生和致瘤性作用的基本框架。在此，我们开发了一种 3D 微工程器官型肿瘤基质模型，其中包含被 CAF 嵌入的胶原基质包围的乳腺癌细胞。我们将我们的平台与原子力显微镜 (AFM) 相结合，以研究活动性肿瘤侵袭期间基质硬度的动态变化。

我们的研究结果主要证明了在存在 CAF 的情况下肿瘤进展增强。此外，我们强调了肿瘤细胞和 CAF 之间的串扰对间质结缔组织增生的关键作用，我们确定了肿瘤分泌的 PDGF-AA/-BB 对升高的基质刚度的作用。CAF 中 PDGFR 活性的抑制导致基质硬度减弱。总的来说，我们的工作提出了一个控制良好的肿瘤微环境模型，能够剖析导致间质结缔组织增生和肿瘤进展的特定生物物理和生化信号线索。