한빛사논문
- 조회442
Hyesung Kim 1,2,3 ∗, Bogun Jang 1,2,4 ∗, Changqing Zhang 1,2, Brianna Caldwell 1,2, Do-Joong Park 5,6, Seong-Ho Kong 5,6, Hyuk-Joon Lee 5,6, Han-Kwang Yang 5,6, James R. Goldenring 1,2,7,8, Eunyoung Choi 1,2,8
1Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
2Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
3Jeju National University College of Medicine, Jeju, Republic of Korea
4Department of Pathology, Jeju National University College of Medicine, Jeju, Republic of Korea
5Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
6Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
7Nashville VA Medical Center, Nashville, TN, USA
8Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
∗These authors contributed equally.
Corresponding author: Eunyoung Choi, PhD
Abstract
Backgrounds & aims: Pre-cancerous metaplasia progression to dysplasia can increase the risk of gastric cancers. However, effective strategies to specifically target these pre-cancerous lesions are currently lacking. To address this, we aimed to identify key signaling pathways which are upregulated during metaplasia progression and critical for stem cell survival and function in dysplasia.
Methods: To assess the response to chemotherapeutic drugs, we utilized metaplastic and dysplastic organoids derived from Mist1-Kras mice and twenty human pre-cancerous organoid lines established from gastric cancer patients. Phospho-antibody array analysis and scRNA-seq were performed to identify target cell populations and signaling pathways affected by Pyrvinium, a putative anti-cancer drug. Pyrvinium was administered to Mist1-Kras mice to evaluate drug effectiveness in vivo.
Results: While pyrvinium treatment resulted in growth arrest in metaplastic organoids, it induced cell death in dysplastic organoids. Pyrvinium treatment significantly downregulated phosphorylation of ERK and STAT3 as well as STAT3-target genes. scRNA-seq 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 the MEK/ERK and STAT3 signaling pathways.
Conclusions: 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 pre-cancerous milieu to prevent of gastric cancer development.
논문정보
- Research article
- 2023년 10월 (BRIC 등록일 2023-10-11)
- 국내+국외 연구진
- 의약학 > 종양의학
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