PhD Defense | Eloïse Bouges | Radiotherapy response modelling in patient-derived tumor organoids and integration into a microphysiological system for colorectal cancer research

Radiotherapy response modelling in patient-derived tumor organoids and integration into a microphysiological system for colorectal cancer research 

Colorectal cancer is the third most common cancer worldwide, and radiotherapy remains a core therapeutic strategy for rectal tumors. Yet, predicting patient response and treatment optimization remains limited by most preclinical models of the gastrointestinal tract. Mouse models capture systemic and immune context but differ from humans in radiosensitivity and tissue architecture, while 2D immortalized cell lines lack the three-dimensional structure, cellular heterogeneity, and patient-specific genetic background of real tumors. As a result, neither model reliably reproduces human tumor-specific epithelial damage or the cumulative response to fractionated irradiation as delivered in the clinic. This PhD project contributed to bridging the gap between simple in vitro systems and the physiological complexity of human colorectal tumors at a time when most drugs fail during clinical trials and increasing regulatory support for alternatives to animal experimentation are driving innovation in preclinical research. It participated to the New Approach Methodologies (NAMs) strategy by establishing a PDTO-derived rectal epithelial model to represent fractionated irradiation and compatible with both fluid flow and biotic exposure, capturing molecular level radiation responses undetectable by conventional viability or barrier assays. Beyond advancing the understanding of colorectal cancer responses to radiation, this microphysiological system platform provides a foundation for future applications in radiotherapy optimization. Its ability to capture molecular and phenotypic responses at clinically relevant exposure levels, in a fully controlled closed environment, makes it a promising tool for the preclinical evaluation of novel radiopharmaceuticals and radioligand therapies.

Promoters:

Prof. Sarah Lebeer, University of Antwerp

Dr. Jianbo Zhang, University of Amsterdam

SCK CEN mentors:

Dr. Felice Mastroleo