An effective multistage mouse model of esophageal carcinogenesis for preclinical and computational pathology applications

Abstract

The use of carcinogen-induced multistage carcinogenesis animal models of esophageal squamous cell carcinoma (CIMCM of ESCC) is limited by prolonged timelines, high toxicity, and excessive mutational burden. In this study, we report the establishment of an effective mouse CIMCM of ESCC by using 4-nitroquinoline-1-oxide (4NQO) as a carcinogen and sorafenib (SOR) as a tumor promoter. We show that SOR specifically activates the Raf-MEK-ERK signaling pathway in normal esophageal stratified squamous epithelium cells, thereby promoting tumor progression. This CIMCM of ESCC accurately recapitulates the multistage process of ESCC carcinogenesis from precancerous lesions to invasive carcinoma, with shortened time and high efficiency. Pathological, molecular, cellular and multiomic analyses show that the CIMCM of ESCC significantly reduces the tumor mutation burden to levels detected in human ESCC samples, while preserving key genetic driver mutations and abnormal transcriptomic/protein expression profiles. Notably, the CIMCM of ESCC demonstrates that the tissue microenvironment plays an important role in ESCC carcinogenesis, as the application of mechanical injury to the esophageal SSE of the CIMCM results in the inflammatory-related response, site-specific tumor formation and high tumor incidence. Since the CIMCM of ESCC provides valuable samples from different stages of tumor initiation and progression, the pathological whole slide images of the CIMCM of ESCC are applied to the computational pathology, which enables the detection, segmentation and annotation of the ESCC initiation and progression with pathologist-level accuracy. Taken together, this mouse CIMCM of ESCC provides a versatile platform for ESCC early diagnosis, basic and preclinical research and therapeutic strategy.