Modelling intrahepatic cholangiocarcinoma microenvironment for drug screening

• Grant number: 25/03407-1
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: June 01, 2025
• End date: November 30, 2025
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Lidia Maria Rebolho Batista Arantes
• Grantee: Victor Gabriel Paes
• Supervisor: Silvia Affo
• Host Institution: Hospital do Câncer de Barretos. Fundação Pio XII (FP). Barretos , SP, Brazil
• Institution abroad: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain
• Associated to the scholarship: 24/05090-2 - Evaluation of PD-1, TIM-3 and LAG-3 checkpoint inhibitors in 3D models of irradiated head and neck tumor cell cultures, BP.MS

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive liver cancer with limited treatment options and poor prognosis. The tumor microenvironment (TME) significantly influences iCCA progression, drug resistance, and immune evasion. Single-cell and multiomics studies have revealed complex interactions between cancer cells, hepatic stellate cells (HSCs), cancer-associated fibroblasts (CAFs), immune cells, and endothelial cells. Moreover, CAFs are responsible for extracellular matrix (ECM) deposition, which creates a fibrotic niche supporting tumor growth and contributes to the immunosuppressive TME in iCCA. CAFs exhibit high plasticity and heterogeneity, modulating pathways in angiogenesis, immune evasion, and chemoresistance. Despite the recent advancements, effective therapies remain limited for iCCA, mainly due to the lack of experimental models replicating the complexity of the TME. Therefore, the primary objective of this study is to explore novel methods for iCCA TME modelling, to provide a foundation for future drug screening studies. This will be achieved by generating 3D assembloids in vitro, incorporating various cell types within the TME of iCCA, enabling the testing of different therapeutic compounds. Ultimately, the interactions within the EMT will be further evaluated in vivo using transgenic mice models. Mimicking the TME serves as a starting point for advancing our understanding of disease mechanisms and accelerating therapeutic development, not only to improve clinical outcomes for iCCA patients, but also with potential for application across other tumor types, offering tailored solutions to address the specific needs of each disease.