Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee; Jeju National University College of Medicine, Jeju, Republic of Korea.
Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Pathology, Jeju National University College of Medicine, Jeju, Republic of Korea.
Gastroenterology. 2024 Jan;166(1):117-131. doi: 10.1053/j.gastro.2023.09.040. Epub 2023 Oct 4.
BACKGROUNDS & AIMS: Precancerous metaplasia progression to dysplasia can increase the risk of gastric cancers. However, effective strategies to specifically target these precancerous lesions are currently lacking. To address this, we aimed to identify key signaling pathways that are upregulated during metaplasia progression and critical for stem cell survival and function in dysplasia.
To assess the response to chemotherapeutic drugs, we used metaplastic and dysplastic organoids derived from Mist1-Kras mice and 20 human precancerous organoid lines established from patients with gastric cancer. Phospho-antibody array analysis and single-cell RNA-sequencing were performed to identify target cell populations and signaling pathways affected by pyrvinium, a putative anticancer drug. Pyrvinium was administered to Mist1-Kras mice to evaluate drug effectiveness in vivo.
Although pyrvinium treatment resulted in growth arrest in metaplastic organoids, it induced cell death in dysplastic organoids. Pyrvinium treatment significantly downregulated phosphorylation of ERK and signal transducer and activator of transcription 3 (STAT3) as well as STAT3-target genes. Single-cell RNA-sequencing data analyses revealed that pyrvinium specifically targeted CD133/CD166 stem cell populations, as well as proliferating cells in dysplastic organoids. Pyrvinium inhibited metaplasia progression and facilitated the restoration of normal oxyntic glands in Mist1-Kras mice. Furthermore, pyrvinium exhibited suppressive effects on the growth and survival of human organoids with dysplastic features, through simultaneous blocking of the MEK/ERK and STAT3 signaling pathways.
Through its dual blockade of MEK/ERK and STAT3 signaling pathways, pyrvinium can effectively induce growth arrest in metaplasia and cell death in dysplasia. Therefore, our findings suggest that pyrvinium is a promising chemotherapeutic agent for reprogramming the precancerous milieu to prevent gastric cancer development.
癌前化生进展为异型增生会增加胃癌的风险。然而，目前缺乏专门针对这些癌前病变的有效策略。为了解决这个问题，我们旨在确定在化生进展过程中上调的关键信号通路，这些通路对异型增生中的干细胞存活和功能至关重要。
为了评估化疗药物的反应，我们使用 Mist1-Kras 小鼠衍生的化生和异型增生类器官以及 20 个人胃癌前类器官系进行研究。通过磷酸化抗体阵列分析和单细胞 RNA 测序来鉴定受吡嗪酰胺（一种潜在的抗癌药物）影响的靶细胞群和信号通路。我们将吡嗪酰胺给予 Mist1-Kras 小鼠，以评估其在体内的药效。
尽管吡嗪酰胺治疗导致化生类器官生长停滞，但它诱导异型增生类器官细胞死亡。吡嗪酰胺治疗显著下调 ERK 和信号转导和转录激活因子 3（STAT3）的磷酸化以及 STAT3 靶基因。单细胞 RNA 测序数据分析显示，吡嗪酰胺特异性靶向 CD133/CD166 干细胞群以及异型增生类器官中的增殖细胞。吡嗪酰胺抑制化生进展，并促进 Mist1-Kras 小鼠中正常胃黏膜的恢复。此外，吡嗪酰胺通过同时阻断 MEK/ERK 和 STAT3 信号通路，对具有异型增生特征的人源类器官的生长和存活具有抑制作用。
通过双重阻断 MEK/ERK 和 STAT3 信号通路，吡嗪酰胺可以有效地诱导化生的生长停滞和异型增生的细胞死亡。因此，我们的研究结果表明，吡嗪酰胺是一种有前途的化疗药物，可用于重新编程癌前微环境，以预防胃癌的发生。
