Analyzing the role of genetic alterations on metaplasia or dysplasia development and progression to cancer in esophageal carcinogenesis

• Applicant: Professor Dr. Michael Quante
• Subject Area: Gastroenterology ; General Genetics and Functional Genome Biology ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 567324837

Esophageal adenocarcinoma (EAC) is one of the few solid tumors with rising incidence and poor prognosis. Traditionally, Barrett’s Esophagus (BE) has been considered a precursor to EAC; however, emerging transcriptomic evidence suggests that EAC may arise directly from undifferentiated gastric progenitor cells, challenging the conventional metaplasia-dysplasia-carcinoma sequence. Instead, metaplasia may serve as a protective adaptation to chronic inflammation, while genetic alterations such as TP53 loss and KRAS activation disrupt epithelial homeostasis and drive early tumor initiation. The interplay between genetic mutations, inflammation, and the tumor microenvironment likely dictates whether progenitor cells undergo protective metaplastic differentiation or malignant transformation. This study aims to elucidate the genetic and microenvironmental factors underlying BE progression to EAC through three integrated approaches. Aim 1 focuses on generating and characterizing a mutation-driven EAC transgenic mouse model, employing Cre-mediated recombination in Lgr5+ progenitor cells within the inflammatory L2-IL-1β model. The effects of TP53, RB1, KRAS, and CDKN2A mutations on metaplasia, dysplasia, and tumor progression will be examined. Aim 2 investigates how the tumor microenvironment influences genetic and phenotypic changes using RNA sequencing (RNA-seq) and mass cytometry (CyTOF) to identify key cytokine signaling pathways and cellular interactions. Aim 3 explores epithelial-immune interactions in mouse-derived 3D organoid models, assessing immune surveillance and escape mechanisms in early carcinogenesis. By integrating genetic, inflammatory, and immune perspectives, this research will advance the understanding of BE and EAC pathogenesis. The findings will provide critical insights into early detection, risk stratification, and novel therapeutic targets, with translational implications for prevention and treatment strategies in high-risk patients.

• DFG Programme: Research Grants