Guenther Alexis A, Ahn Suyeon, Min Jimin, Zhang Changqing, Lee Hyuk-Joon, Yang Han-Kwang, Sung Bong Hwan, Weaver Alissa M, Choi Eunyoung
Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
Cell Mol Gastroenterol Hepatol. 2025;19(6):101490. doi: 10.1016/j.jcmgh.2025.101490. Epub 2025 Mar 5.
BACKGROUND & AIMS: Epithelial cancer onset occurs through sequential stages of cell lineage conversion and functional dysregulation. Dysplasia is a precancerous lesion defined as a direct precursor to cancer and is histologically defined as a transition stage between pre-cancer and cancer, but molecular and biological mechanisms controlling its transformation to malignancy are underdetermined. Here, we discover the crucial role of the actin stabilization and exosome secretion-regulatory protein cortactin in dysplastic cell transformation to adenocarcinoma.
We engineered a CRISPR/Cas9-based cortactin knock-out (KO) dysplasia organoid model established from dysplastic tissue and examined malignant roles of cortactin during gastric cancer development in vitro and in vivo.
Although dysplastic cell identity remained unchanged, the cortactin KO organoids exhibited a decrease in cellular organization and multicellular protrusions, which are considered aggressive features when observed in vitro. When injected into the flank of nude mice, cortactin KO cells failed malignant transformation into adenocarcinoma and solid tumor formation with reduced recruitment of fibroblasts and macrophages. In addition, cortactin KO cells showed diminished exosome secretion levels, and adenocarcinoma development was impaired when exosome secretion was inhibited in cortactin wild-type dysplastic cells.
These data suggest that cortactin is a functional element of membrane dynamics, malignant changes, and exosome secretion in dysplastic cells, and solid gastric tumor formation associated with alteration of the tumor microenvironment.
上皮癌的发生是通过细胞谱系转化和功能失调的连续阶段进行的。发育异常是一种癌前病变，被定义为癌症的直接前体，在组织学上被定义为癌前和癌症之间的过渡阶段，但控制其向恶性转化的分子和生物学机制尚未完全明确。在此，我们发现肌动蛋白稳定和外泌体分泌调节蛋白皮层肌动蛋白在发育异常细胞向腺癌转化中起关键作用。
我们构建了一种基于CRISPR/Cas9的皮层肌动蛋白敲除（KO）发育异常类器官模型，该模型由发育异常组织建立，并在体外和体内研究了皮层肌动蛋白在胃癌发生过程中的恶性作用。
尽管发育异常细胞的特征保持不变，但皮层肌动蛋白敲除的类器官在细胞组织和多细胞突起方面表现出减少，这些在体外观察时被认为是侵袭性特征。当注射到裸鼠侧腹时，皮层肌动蛋白敲除的细胞无法恶性转化为腺癌，也无法形成实体瘤，同时成纤维细胞和巨噬细胞的募集减少。此外，皮层肌动蛋白敲除的细胞外泌体分泌水平降低，当在皮层肌动蛋白野生型发育异常细胞中抑制外泌体分泌时，腺癌的发生受到损害。
这些数据表明，皮层肌动蛋白是发育异常细胞中膜动力学、恶性变化和外泌体分泌的功能元件，与肿瘤微环境改变相关的实体胃肿瘤形成有关。
