Periodic Reporting for period 1 - ETICAN (ECM and TFEB interplay: from building multidisciplinary devices to unravelling the missing link in cancer)
Reporting period: 2023-11-01 to 2025-10-31
Cancer progression is not driven solely by genetic mutations within tumor cells, but also by the physical and biochemical properties of their surrounding microenvironment, known as the extracellular matrix (ECM). Over the past decades, increasing evidence has shown that changes in ECM stiffness, composition, and architecture actively shape tumor growth, invasion, and resistance to therapy. In bladder cancer, one of the most expensive cancers to manage in Europe due to its high recurrence rate, the role of ECM mechanics remains insufficiently understood. The ETICAN project addresses this gap by investigating how ECM mechanics and chemistry regulate tumor behavior through their interaction with transcription factor EB (TFEB), an emerging oncogenic regulator of lysosomal function and lipid metabolism. By reconstructing the bladder cancer ECM using tunable, synthetic biomaterials, ETICAN recreates physiologically relevant tumor microenvironments that allow systematic study of tumor–ECM interactions. The overall objective of ETICAN is to elucidate the reciprocal crosstalk between ECM properties and TFEB signaling and to determine how this interaction drives tumor adaptation, invasiveness, and therapy response. Ultimately, the project aims to generate knowledge and tools that support precision oncology by enabling patient-specific tumor modeling and improved therapeutic targeting.
ETICAN successfully combined biomaterials engineering, cancer cell biology, and advanced imaging to develop a scalable tumoroid-based platform for studying tumor–microenvironment interactions. A comprehensive mechanical and biochemical fingerprint of bladder cancer ECM was established using patient-derived biopsies.
A major technological achievement was the development of a biomimetic “nest” platform based on microengineered polyethylene glycol hydrogels. This system enables the rapid generation of over 100,000 patient-derived tumoroids within 24 hours and allows precise tuning of microenvironment stiffness. The platform is compatible with high-throughput workflows and advanced imaging, enabling real-time analysis of tumor mechanics and metabolism. Using this system, ETICAN demonstrated that ECM stiffness activates a mechanotransductive program involving TFEB, lipid metabolism reprogramming, and altered integrin trafficking. These findings revealed a feedback loop linking tissue mechanics, cellular metabolism, and invasive behavior.
A major technological achievement was the development of a biomimetic “nest” platform based on microengineered polyethylene glycol hydrogels. This system enables the rapid generation of over 100,000 patient-derived tumoroids within 24 hours and allows precise tuning of microenvironment stiffness. The platform is compatible with high-throughput workflows and advanced imaging, enabling real-time analysis of tumor mechanics and metabolism. Using this system, ETICAN demonstrated that ECM stiffness activates a mechanotransductive program involving TFEB, lipid metabolism reprogramming, and altered integrin trafficking. These findings revealed a feedback loop linking tissue mechanics, cellular metabolism, and invasive behavior.
ETICAN goes beyond existing organoid models by integrating controlled mechanical cues with patient-derived tumor biology at scale. The identification of a TFEB–lipid–integrin axis provides a novel conceptual framework connecting mechanobiology, metabolism, and membrane trafficking in cancer progression.
The biomimetic nest technology represents a breakthrough for personalized medicine, offering a rapid and reproducible approach for functional drug testing directly on patient material. Beyond bladder cancer, the platform has demonstrated applicability to multiple solid tumors, opening new avenues for translational cancer research and industrial uptake.
The biomimetic nest technology represents a breakthrough for personalized medicine, offering a rapid and reproducible approach for functional drug testing directly on patient material. Beyond bladder cancer, the platform has demonstrated applicability to multiple solid tumors, opening new avenues for translational cancer research and industrial uptake.