Regaining control of cancer at biological borders

Descripción del proyecto

Nuevos conocimientos sobre el traspaso de las fronteras tisulares en la metástasis

La transición epitelial mesenquimal (TEM) es un proceso biológico por el cual las células epiteliales, caracterizadas por una estrecha adhesión célula-célula, pierden sus rasgos epiteliales y adquieren características mesenquimales. Esta transición es esencial en diversos procesos fisiológicos y patológicos, incluida la metástasis. El objetivo del proyecto BorderControl, financiado por el Consejo Europeo de Investigación, es estudiar cómo interactúan las células cancerosas con las células endoteliales para superar las barreras fisiológicas y propagarse a otros tejidos. Los investigadores emplearán técnicas punteras para identificar las señales moleculares que regulan la TEM. Se prevé que la identificación de nuevos biomarcadores y dianas terapéuticas dé lugar a aplicaciones clínicas y mejore los resultados del tratamiento antineoplásico.

Objetivo

During dissemination, cancer cells must face and overcome several physiological borders, including the immediate stroma for local invasion and the endothelium for long-distance metastasis. At these critical junctures, cell plasticity between epithelial (E) and mesenchymal (M) states could determine metastasis potential. Based on our preliminary data, ideally-positioned cues emanating from the normal stroma contain the tumour in situ. Once this first border is breached, rare cancer cell-endothelial interactions trigger further dissemination through the vascular border. Moreover, cancer cell plasticity is vital throughout this process, enabling optimal response to distinct border microenvironments.

In BorderControl, we will build on our cutting-edge cell biology expertise and close collaboration with clinicians to define the molecular signals underlying these border crossings and gain unprecedented information on how cancer cells overwhelm these natural defences. Starting with patient tissues, we will spatially profile the tumour-stroma border to identify receptor-ligand pairs that regulate invasion. We will use microfluidics to image, catch and profile cancer cell crossings at endothelial hotspots and determine key molecular regulators of the process in endothelial and cancer cells. Building on our novel discovery of endosomally regulated E-M cell states, we will test how E-M transitions impact border-breaching potential. These novel concepts will be investigated with interdisciplinary methods (scRNAseq, synthetic biology, colour barcoded HTS) and our new technologies (dynamically tuneable multicell-type migration and invasion imaging platforms) to determine the specific interactions/mechanisms regulating border crossings. Finally, we will take the molecular level discoveries from the cancer-limiting borders back to the patients, assessing clinical relevance using designer TMAs, and expect to uncover novel biomarkers and therapeutically actionable targets.