Microenvironmental Stiffness Induces Metabolic Reprogramming in Glioblastoma

The mechanical properties of solid tumors influence tumor cell phenotype and ability to invade into surrounding tissues. Using bioengineered scaffolds to provide a matrix microenvironment for patient-derived glioblastoma (GBM) spheroids, this study demonstrates that a soft, brain-like matrix induces GBM cells to shift to a glycolysis-weighted metabolic state which supports invasive behavior. We first show that orthotopic murine GBM tumors are stiffer than peri-tumoral brain tissues, but tumor stiffness is heterogenous where tumor edges are softer than the tumor core. Then, we developed three-dimensional scaffolds with µ-compressive moduli resembling either stiffer, tumor core or softer, peri-tumoral brain tissue. We demonstrate that the softer matrix microenvironment induces a shift in GBM cell metabolism toward glycolysis which manifests in lower proliferation rate and increased migration activities. Finally, we show that these mechanical cues are transduced from the matrix via CD44 and integrin receptors to induce metabolic and phenotypic changes in cancer cells. Overall design: To investigate the role of stiffness on glioblastoma , patient derived cells were encapsulated in hydrogels with mechanical properties mimicking the tumor stiffness and the peritumoral brain tissue

实体瘤的机械力学特性可影响肿瘤细胞的表型及其侵袭周围组织的能力。本研究通过生物工程支架为患者来源的胶质母细胞瘤（glioblastoma, GBM）球体构建基质微环境，证实柔软的脑源性基质可诱导胶质母细胞瘤细胞转向以糖酵解为主的代谢状态，进而支持其侵袭行为。我们首先证实，原位小鼠胶质母细胞瘤的硬度高于肿瘤周围脑组织，但肿瘤内部硬度存在异质性：肿瘤边缘的硬度低于肿瘤核心区域。随后，我们制备了具有不同微压缩模量的三维支架，分别模拟较硬的肿瘤核心组织与较软的肿瘤周围脑组织。研究表明，较柔软的基质微环境可诱导胶质母细胞瘤细胞的代谢转向糖酵解，表现为增殖速率降低、迁移活性增强。最后，我们证实这类机械信号可通过CD44与整合素受体从基质传递至肿瘤细胞，进而引发癌细胞的代谢与表型改变。总体实验设计：为探究基质硬度对胶质母细胞瘤的作用，本研究将患者来源的肿瘤细胞包埋于水凝胶中，该水凝胶的机械特性可模拟肿瘤组织与肿瘤周围脑组织的硬度。