It is predicted that pancreatic ductal adenocarcinoma (PDAC) will become the second most lethal cancer in the US by 2030. PDAC includes a fibrous-like stroma, desmoplasia, encompassing most of the tumor mass, which is produced by cancer-associated fibroblasts (CAFs) and includes their cell-derived extracellular matrices (CDMs). Since elimination of desmoplasia has proven detrimental to patients, CDM reprogramming, as opposed to stromal ablation, is therapeutically desirable. Hence, efforts are being made to harness desmoplasia's anti-tumor functions. We conducted biomechanical manipulations, using variations of pathological and physiological substrates in vitro, to culture patient-harvested CAFs and generate CDMs that restrict PDAC growth and spread. We posited that extrinsic modulation of the environment, via substrate rigidity, influences CAF's cell-intrinsic forces affecting CDM production. Substrates used were polyacrylamide gels of physiological (~1.5 kPa) or pathological (~7 kPa) stiffnesses. Results showed that physiological substrates influenced CAFs to generate CDMs similar to normal/control fibroblasts. We found CDMs to be softer than the corresponding underlying substrates, and CDM fiber anisotropy (i.e., alignment) to be biphasic and informed via substrate-imparted morphological CAF aspect ratios. The biphasic nature of CDM fiber anisotropy was mathematically modeled and proposed a correlation between CAF aspect ratios and CDM alignment; regulated by extrinsic and intrinsic forces to conserve minimal free energy. Biomechanical manipulation of CDMs, generated on physiologically soft substrates, leads to reduction in nuclear translocation of pERK1/2 in KRAS mutated pancreatic cells. ERK2 was found essential for CDM-regulated tumor cell spread. In vitro findings correlated with in vivo observations; nuclear pERK1/2 is significantly high in human PDAC samples. The study suggests that altering underlying substrates enable CAFs to remodel CDMs and restrict pancreatic cancer cell spread in an ERK2 dependent manner.

中文翻译：

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刚性控制人类促纤维增生基质的各向异性，使胰腺癌细胞能够通过细胞外信号调节激酶 2 进行扩散。

据预测，到 2030 年，胰腺导管腺癌 (PDAC) 将成为美国第二大致死性癌症。PDAC 包括纤维状基质、结缔组织，包围大部分肿瘤块，由癌症相关成纤维细胞 (CAF) 产生）并包括其细胞衍生的细胞外基质（CDM）。由于消除结缔组织增生已被证明对患者有害，因此与基质消融相反，CDM 重编程在治疗上是可取的。因此，人们正在努力利用结缔组织增生的抗肿瘤功能。我们利用体外病理和生理基质的变化进行生物力学操作，以培养患者收获的 CAF 并生成限制 PDAC 生长和扩散的 CDM。我们假设环境的外在调节通过基质刚性影响 CAF 的细胞内在力，从而影响 CDM 的产生。使用的基质是具有生理硬度（~1.5 kPa）或病理硬度（~7 kPa）的聚丙烯酰胺凝胶。结果表明，生理底物影响 CAF 生成与正常/对照成纤维细胞相似的 CDM。我们发现 CDM 比相应的底层基材更柔软，并且 CDM 纤维各向异性（即排列）是双相的，并通过基材赋予的形态 CAF 纵横比来了解。对 CDM 光纤各向异性的双相性质进行了数学建模，并提出了 CAF 纵横比与 CDM 排列之间的相关性；受外在和内在力量的调节，以保存最小的自由能。对在生理软基质上生成的 CDM 进行生物力学操作，可减少 KRAS 突变胰腺细胞中 pERK1/2 的核转位。ERK2被发现对于CDM调节的肿瘤细胞扩散至关重要。体外研究结果与体内观察结果相关；核 pERK1/2 在人类 PDAC 样本中显着升高。该研究表明，改变底层底物使 CAF 能够重塑 CDM，并以 ERK2 依赖性方式限制胰腺癌细胞扩散。