SelfOrg · Addressing the role of self-organization in tumor heterogeneity and plasticity

Addressing the role of self-organization in tumor heterogeneity and plasticity

Colorectal cancer (CRC) remains a major health challenge, with a survival rate of 15% in stage IV cases due to therapy resistance and tumor relapse. A key barrier to effective treatment is the high degree of intratumor heterogeneity and plasticity. These features enable the coexistence of diverse cancer cell populations within a tumor, each of them specialized in key functions such as proliferation, invasion or resistance to treatment. Additionally, phenotypic plasticity grants these cancer cells flexibility to dynamically tune their phenotype, to the extent that a single surviving cell can regenerate a full heterogeneous tumor. Despite their crucial role in CRC pathology, the biological mechanisms driving tumor heterogeneity and plasticity remain poorly understood. Current research suggests that tumor plasticity is driven by microenvironmental cues, where external signals induce specific cell states within localized tumor niches. However, my preliminary data reveal that cancer cells also possess an intrinsic ability to self-organize and establish heterogeneity even in the absence of external signals. SelfOrg will tackle the unexplored contribution of self-organization to tumor heterogeneity and plasticity. To do so, I will combine quantitative measurements in bioengineered human organoids with physiologically relevant mouse tumor models to dissect the intrinsic mechanochemical signals regulating tumor heterogeneity. The project is divided in three main aims: - Aim 1: To quantitatively characterize the self-organization of colon organoids representing different stages of tumor progression. - Aim 2: To identify the molecular mechanisms driving tumor self-organization and their role in vivo. - Aim 3: To quantify the heterogeneity in self-organization of a PDO biobank and to assess its correlation with tumor clinicopathological features. Overall, SelfOrg will dissect how intrinsic mechanochemical interactions among epithelial cells drive the formation of a homeostatic tissue and how this program deteriorates during tumor progression. Through a quantitative biology framework, we will systematically quantify, classify, and mechanistically understand the self-organization programs that pattern human tumors, uncover how they interact with the microenvironment, and assess their predictive value for patient outcomes. Ultimately, EvoSelf will establish self-organization as a fundamental principle of tumor biology

Data: CORDIS, © European Union