Overview

The critical role of stroma in cancer development and normalization

Historically, cancer research has emphasized the uncontrolled proliferation of cells forming tumors, neglecting the crucial role of the tumor microenvironment. In vitro 3D and in vivo experiments have demonstrated the decisive role of stroma in cancer development and normalization. Specifically, recombination experiments involving the selective exposure of stroma and epithelium showed that an exposed stroma is sufficient to drive tumor formation, even when combined with a non-exposed epithelium. In contrast, an exposed epithelium combined with a non-exposed stroma leads to normal morphogenesis. These findings highlight the stroma not as a passive element but as an active participant in tumor formation and a key target for normalization-based therapies.

Advanced supra-cellular modeling to guide cancer normalization

Onteis' strategy is based on a supra-cellular perspective, focusing on the reorganization of the tumor microenvironment rather than direct cell destruction. Unlike classical approaches that target individual molecular pathways, cancer normalization requires a framework that accounts for emergent and novel tissue-level regularities. Variation plays a central role in this process since biological systems are not defined by fixed rules but by dynamic constraints that evolve over time. Onteis’ platform leverages multilevel and multiscale modeling to identify structural "hits" within the stroma and epithelium, facilitating the restoration of tissue-level organization and function. This approach provides a robust foundation for developing targeted, non-cytotoxic therapies designed to improve the therapeutic index (efficacy/toxicity) compared to conventional treatments.