ECM and TFEB interplay: from building multidisciplinary devices to unravelling the missing link in cancer

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Over the last 30 years, researchers have shown that tumor cells not only need to accumulate oncogenic genetic alterations, but also rely on permissive cues from a surrounding extracellular matrix (ECM) for malignant progression. However, reconstructing the tumor niche in vitro has not been easy due to the complexity of its intertwined physico- biochemical properties and the limitation of the available biomimetic scaffolds. Furthermore, preclinical studies have mainly focused on druggable targets at the intracellular signaling level and overlooked the implication of the ECM. To overcome these hurdles, we will unravel the ECM mechano-chemical contribution in tumorigenesis and its continuum interaction with tumor cells in 3 steps. First, we will deconstruct bladder cancer ECM through in-depth analysis of its physical and biochemical features. This will provide us a blueprint to follow, in order to build a tailored microenvironment for bladder tumoroids. Then, we will reassemble ECM properties in a new generation of tunable materials, functionalized with ECM proteins secreted by bladder cancer cells in vitro. Using our developed tumoroid model, we will finally chart the reciprocal crosstalk between extracellular cues and transcription factor EB (TFEB), an emerging oncogene and regulator of tumor microenvironment. By bridging the gap between ECM and TFEB regulation, we anticipate to catalyse the success of cancer prevention and therapy leveraging new druggable targets at the level of the reciprocal feedback between the evolving ECM and tumor cells.