Utilizing cell line-derived organoids to evaluate the efficacy of a novel LIFR-inhibitor, EC359 in targeting pancreatic tumor stroma.

Q2 Biochemistry, Genetics and Molecular Biology
Bradley R Hall, Andrew Cannon, Christopher Thompson, Bindu Santhamma, Alejandra Chavez-Riveros, Rakesh Bhatia, Hareesh B Nair, Klaus Nickisch, Surinder K Batra, Sushil Kumar
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引用次数: 16

Abstract

Survival of pancreatic cancer (PC) patient is poor due to lack of effective treatment modalities, which is partly due to the presence of dense desmoplasia that impedes the delivery of chemotherapeutics. Therefore, PC stroma-targeting therapies are expected to improve the efficacy of chemotherapeutics. However, in vitro evaluation of stromal-targeted therapies requires a culture system which includes components of both tumor stroma and parenchyma. We aim to generate a cell line-derived 3D organoids to test the efficacy of stromal-targeted, LIFR-inhibitor EC359. Murine PC (FC1245) and stellate (ImPaSC) cells were cultured to generate organoids that recapitulated the histological organization of PC with the formation of ducts by epithelial cells surrounded by activated fibroblasts, as indicated by CK19 and α-SMA staining, respectively. Analysis by qRT-PCR demonstrated a significant downregulation of markers of activated stroma, POSTN, FN1, MMP9, and SPARC (p<0.0001), when treated with gemcitabine in combination with EC359. Concurrently, collagen proteins including COL1A1, COL1A2, COL3A1, and COL5A1 were significantly downregulated (p <0.0001) after treatment with gemcitabine in combination with EC359. Overall, our study demonstrates the utility of cell lines-derived 3D organoids to evaluate the efficacy of stroma-targeted therapies as well as the potential of EC359 to target activated stroma in PC.

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利用细胞系衍生的类器官评估一种新型lifr抑制剂EC359靶向胰腺肿瘤基质的疗效。
由于缺乏有效的治疗方式,胰腺癌(PC)患者的生存率很低,部分原因是存在致密的结缔组织增生,阻碍了化疗药物的传递。因此,PC基质靶向治疗有望提高化疗药物的疗效。然而,基质靶向治疗的体外评估需要一个包括肿瘤基质和实质成分的培养系统。我们的目标是生成一种细胞系衍生的3D类器官,以测试基质靶向的lifr抑制剂EC359的功效。小鼠PC细胞(FC1245)和星状细胞(ImPaSC)分别通过CK19和α-SMA染色显示,上皮细胞被活化的成纤维细胞包围形成导管,形成了具有PC组织结构的类器官。qRT-PCR分析显示,活化基质、POSTN、FN1、MMP9和SPARC标记物显著下调
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来源期刊
Genes and Cancer
Genes and Cancer Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
3.90
自引率
0.00%
发文量
6
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