Studies on the heterogeneity and function of molecules critical in colorectal cancer progression
Idan Carmi
Molecular Medicine Division
Dr. Várnai Péter
SE NET tanácsterem
2026-03-30 10:30:00
Human molecular genetics and genetic diagnostics
Dr. Wiener Zoltán
Dr. Wiener Zoltán
Dr. Wachtl Gerda Gabriella
Vellainé Dr. Takács Krisztina
Dr. Bödör Csaba
Dr. Uzonyi Barbara
Dr. Jakus Zoltán
CRC is one of the most prevalent and lethal malignancies worldwide. Despite substantial progress in treatment, patient outcomes remain highly variable due to pronounced intra-tumoral heterogeneity and complex tumor-stroma interactions. Using patient-derived 3D organoids, we investigated cancer stem cell heterogeneity, the role of the serotonin receptor HTR2B in tumor behavior, and the impact of fibroblast-mediated extracellular matrix (ECM) remodeling on tumor plasticity and invasion.
CRC organoids displayed stable heterogeneity for classical cancer stem cell markers, including CD44, CD133, and PTK7. CD44high and CD133high subpopulations exhibited enhanced proliferative potential and organoid-forming capacity, confirming their hierarchical advantage. CMS marker expression was also heterogeneous, with epithelial CDX2 and mesenchymal HTR2B defining distinct but partially overlapping subpopulations, indicating hybrid epithelial-mesenchymal phenotypes that may underlie CRC plasticity.
Serotonin metabolism played a context-dependent role in CRC: although serotonin production was minimal, HTR2B expression was elevated, particularly under nutrient-limited conditions. HTR2B activation reduced cell survival during glucose deprivation, suggesting interaction with mTORC1 signaling. Consistently, mTORC1 inhibition reduced both HTR2B and NOTCH3 expression, linking metabolic stress to pathways regulating EMT and survival.
Fibroblast co-culture and collagen-rich matrices induced partial EMT, increased HTR2B expression, and promoted tumor invasion. HTR2Bhigh cells localized to the invasive front while retaining epithelial markers, supporting invasion through a permissive ECM rather than complete EMT.
Collectively, these findings show that CRC cells integrate metabolic, mechanical, and paracrine cues to sustain phenotypic diversity and invasive potential. HTR2B emerges as a key regulator connecting stress adaptation, fibroblast-driven ECM remodeling, and tumor invasion. Understanding these interconnected mechanisms provides new insight into CRC plasticity and may identify therapeutic opportunities targeting the HTR2B-mTORC1-NOTCH3 axis in aggressive, CMS4-like tumors.
