STRATEGIC OBJECTIVES 

· Previous studies have shown that control of cellular mechanics and mitotic spindle orientation are essential for adult organs and cancer development. We will address the mechanistic response of intestinal cells in target one and the orientation of the mitotic spindle in target two, which could yield key insights for CRC treatment.

· In recent years, our laboratory has developed and patented new three-dimensional (3D) micropatterned organotypic systems to model epithelial polarity and tubulogenesis in a robust and systematic way. Our projects use these "organ-on-a-chip" systems to grow human intestinal organoids in micropatterns. We take advantage of this organoid model to analyze the biochemical and biomechanical properties of epithelial organoids during intestinal development and address their impact on cancer development and progression.

· Protein absorption in neonates depends on intracellular digestion by LREs in the ileum and is essential during the early postnatal stages. Our previous work characterized the basic properties of these cells in nutrient absorption and nutrition (Herranz et al. in preparation). In the coming years we will continue to deepen our understanding of these intestinal cells and their relationship to autophagy, cell metabolism, and paracellular communication, all of which are essential for intestinal development and homeostasis, and their related conditions such as CRC.

· We will explore the use of the high absorption capacity of LREs to facilitate the entry of nanocarriers orally. Oral administration of biological drugs, including peptides, monoclonal antibodies, and nucleic acids, represents a very interesting drug delivery mechanism, both for patients and industry. This proposal will provide new approaches for the administration of biological drugs through biological barriers such as the intestinal tract. Many laboratories around the world are focused on improving nanotechnology to design new nanocarriers to deliver these biologic drugs. Instead, we are focusing on a completely new and innovative strategy: enhancing the absorption of these biologics by reprogramming adult enterocytes that mimic features of neonatal LRE, with high protein absorption.

· Deregulation of the metabolism of immune cells, such as T cells, seems key to the development of diseases such as cancer or autoimmunity. Despite the role of B lymphocytes in these diseases, little is known about how their metabolism is deregulated in pathological situations and more importantly, how this deregulation gives rise to disease. Our objective is to characterize the role of metabolism as a regulator of the activation and differentiation of B cells under normal physiological conditions, in order to later understand its role in the pathology and identify new biomarkers of the disease and possible therapeutic targets. We will use two different disease models, inflammatory bowel disease, and diffuse large B-cell lymphoma.

In summary, we hope that the combination of these gut-on-a-chip models with in vivo physiological systems will offer new ways to understand gut morphogenesis, patterning, homeostasis, and its relationship to human diseases such as cancer.

RESEARCH LINES

1. Characterize the role of lysosome-rich enterocytes (LRE) in the early stages of development, metabolism, and effect on intestinal homeostasis. IP: Fernando Martin Belmonte.

2. Cellular strategy to improve drug absorption for cancer treatment. IP: Fernando Martin Belmonte.

3. Characterize the role of B cell immunometabolism in the immune response. Nuria Martinez-Martin.

4. Characterize the role of smoothelin-like2 (smtnl2) in the reorganization of the cytoskeleton, and in the progression of carcinoma in intestinal tissues. IP: Fernando Martin Belmonte.