Pancreas Cancer Research Lab, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, SE 141 86 Huddinge, Sweden.
Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany.
Int J Mol Sci. 2024 Aug 29;25(17):9369. doi: 10.3390/ijms25179369.
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is almost entirely resistant to conventional chemotherapy and radiation therapy. A significant factor in this resistance appears to be the dense desmoplastic stroma, which contains various cancer-associated fibroblast (CAF) populations. However, our understanding of the communication between tumor cells and CAFs that contributes to this aggressive malignancy is still developing. Recently, we used an advanced three-dimensional heterospecies, heterospheroid co-culture model to investigate the signaling between human pancreatic tumor Panc1 cells and mouse pancreatic stellate cells (mPSCs) through global expression profiling. Upon discovering that was significantly upregulated in Panc1 cells during co-culture, we decided to explore the role of CCN1 using CRISPR-Cas9 knockout technology. Panc1 cells lacking CCN1 showed reduced differentiation and decreased sensitivity to gemcitabine, primarily due to lower expression of genes involved in gemcitabine transport and metabolism. Additionally, we observed that stimulation with TGF-β1 and lysophosphatidic acid increased expression in Panc1 cells and induced a shift in mPSCs towards a more myofibroblastic CAF-like phenotype.
胰腺导管腺癌（PDAC）是一种致命的疾病，几乎完全对常规化疗和放疗有抗性。这种抗性的一个重要因素似乎是密集的纤维变性基质，其中包含各种癌症相关成纤维细胞（CAF）群体。然而，我们对肿瘤细胞与促进这种侵袭性恶性肿瘤的 CAF 之间的交流的理解仍在不断发展。最近，我们使用先进的三维异质种、异质球体共培养模型，通过全局表达谱分析研究人胰腺肿瘤 Panc1 细胞与小鼠胰腺星状细胞（mPSC）之间的信号传递。在发现共培养过程中 Panc1 细胞中显著上调后，我们决定使用 CRISPR-Cas9 敲除技术探索 CCN1 的作用。缺乏 CCN1 的 Panc1 细胞表现出分化减少和对吉西他滨的敏感性降低，主要是由于参与吉西他滨转运和代谢的基因表达降低。此外，我们观察到 TGF-β1 和溶血磷脂酸刺激可增加 Panc1 细胞中 CCN1 的表达，并诱导 mPSC 向更具肌成纤维 CAF 样表型的转变。
