Epithelial polarity and cancer
Centro de Biología Molecular “Severo Ochoa” CSIC-UAM (CBMSO)
DESCRIPTION OF THE OFFER
The mechanisms tube formation, or tubulogenesis, are diverse across epithelial organ systems, but they all result in the formation of a central single lumen. Lumen formation occurs through the coordinated series of distinct cellular processes, including intracellular trafficking, de novo apical membrane biogenesis, lumen enlargement, and finally, its resolution in one caviy. Most of the molecular mechanisms associated with lumen formation derive from studies in cellular models that though very informative cannot recapitulate the complexity of a three-dimensional organ. Furthermore, one of the most important factors that control lumen formation is the interaction with the microenvironment, and 2D cultures behave very differently from their tissues of origin, thus limiting their potential in biomedical research. In this project we will study the cellular mechanisms controlling lumen formation and cell differentiation in developmental gut vertebrates. In particular, we will address (I) the mechanisms of lumen resolution in vertebrates. To that end, we will use a combination of studies in the gastrointestinal tract of zebrafish, and 3D organotypic systems. Indeed, our laboratory has developed a new 3D organotypic system in micropatterns to address tubulogenesis that recreates more faithfully the in vivo physiological conditions of epithelial morphogenesis. Next, we will analyze (II) the biochemical and biomechanical properties of intestinal lumen formation and address their impact on cancer development and progression. For this purpose, we will develop a new 3D organoid platform to grow intestinal cells derived from human epithelial samples to characterize the 3D forces exerted by intestinal tubes during their formation under normal and pathological conditions.
Finally, we will also study (III) the mechanism associated with the differentiation and specification of a specialized population of absorptive cells in the vertebrate gut. Early in embryonic development, the undifferentiated intestinal epithelium is patterned into the different functional cell types along the proximal-to-distal axis. We have recently identified that Plasmolipin (Pllp), a developmentally-regulated gene, is essential for the differentiation of the Lysosome-Rich-Enterocytes (LREs), a specialized population of absorptive cells present in the ileum, which are necessary for protein absorption and intracellular digestion during early postnatal stages in vertebrates. We will study the role of LREs in absorption and nutrition using Pllp KO animal models.
In summary, we propose a multidisciplinary project at the frontier between cell biology, development, physics, and bioengineering to better understand the molecular mechanisms associated with tubule formation and patterning in intestinal morphogenesis and their relationship with human pathologies. The combination of these reliable organ-on-a-chip models with in vivo systems, as proposed in GUTFORM, will offer new ways to understand intestinal tube formation and differentiation in higher organisms. Our extensive experience in these combined approaches puts us in an excellent position to boost progress in this field. A better understanding of epithelial tubulogenesis is highly relevant as deciphering the interplay between the cellular biology, the differentiation and mechanics of intestinal tubulogenesis will help for the development of new therapeutic targets to treat important human diseases.
Biomolecules & Cell D.
Nuria Martinez Martin