SEMINAR: Juan Rodríguez Vita / Alfonso Benítez Páez

24feb12:0013:00SEMINAR: Juan Rodríguez Vita / Alfonso Benítez Páez

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12:00 – 12:30 Juan Rodríguez Vita

HAPLN-1 increases peritoneal carcinomatosis by inducing tumor cell hyperplasticity in pancreatic ductal adenocarcinoma

Pancreatic Ductal Adenocarcinoma (PDAC) frequently metastasizes into the peritoneum forming peritoneal carcinomatosis, which are so far not treatable effectively. Metastasis-initiating cells need to acquire beneficial traits including cell plasticity, immune evasion, dormancy state control and organ colonization. These characteristics can be summarized in broad terms into two main processes, epithelial-to-mesenchymal transition (EMT) and stemness. Hyaluronic acid (HA), an extracellular matrix component, is a crucial factor in regulating these processes in PDAC, but it is so far not successfully targetable. Analyzing publicly available databases by gene set enrichment analysis (GSEA), a signature related to HA binding was enriched in tumor samples compared to normal tissue. Hyaluronan And Proteoglycan Link Protein 1 (HAPLN1) was the top contributor to the enrichment score, being the 8th most enriched gene overall. We found that higher HAPLN1 expression correlated with shorter overall survival and that HAPLN1high patients had both, basal subtype and EMT signatures enriched. Moreover, these patients had a signature for peritoneal metastasis significantly enriched, suggesting a higher risk for peritoneal carcinomatosis. To study the role of HAPLN1 on PDAC in vitro, we stably overexpressed HAPLN1 in the murine PDAC cell line KPC. KPC-HAPLN1 cells expressed more EMT markers, more stem-related genes and changed the proteoglycan production from Aggrecan to Versican, which is known to be pro-metastatic. We found that spheroid formation, a feature of stemness, was improved in KPC-HAPLN1 vs KPC. Additionally, embedding these spheroids into matrigel led to an increased invasion of KPC-HAPLN1 cells. KPC-HAPLN1 cells improved KPC cell invasion capacities when co-cultured, indicating a paracrine effect. In vivo, intraperitoneal injection of luciferase expressing KPC cells resulted in higher luciferase activity when tumor cells expressed HAPLN1. Analyzing the peritoneal lavage (PL) from these mice, we obtained significantly more tumor cells in KPC-HAPLN1 injected mice. RNAseq data of tumor cells isolated from tumor nodules and PL showed that KPC-HAPLN1 cells acquired an increased metastatic potential and a strong immunomodulatory phenotype. Thus, we evaluated the immune cell composition of the PL by flow cytometry. Neutrophil and monocyte percentages were drastically reduced in KPC-HAPLN1 bearing mice. On the contrary, these mice had a significant increase in macrophages, which showed a reduction in pro-inflammatory gene expression. We conclude that HAPLN1 expression in tumor cells promotes a hyperplastic phenotype that facilitates invasion and colonization of the peritoneum, among others by creation of a pro-tumoral immune microenvironment.


12:30 – 13:00 Alfonso Benítez Páez

Diet-host-microbiome interactions underlying metabolic disease.

The last decade has been crucial to advancing the understanding of the human microbiome and how it influences our physiological development and function from birth to adulthood. Implications of the human microbiome in the development and progression of many human diseases and their interactions with lifestyle factors such as the diet are under the spotlight. Although strong evidence is being accumulated supporting the direct influence of the human microbiome in several pathophysiological processes, to date, there are no conclusive results about causality and its contribution to the onset and pathogenic mechanisms of highly prevalent disorders such as obesity and co-morbidities, metabolic impairment, intestinal inflammatory diseases, or cognitive and brain function impairments. Therefore, the research intended in our laboratory corresponds with a leading ambition to assess, from the molecular basis point of view and applying comprehensive multiomics approaches, the role of the gut microbiome components, at the cellular and sub-cellular levels, in the development of obesity and metabolic co-morbidities.



24.02.2022 12:00 - 13:00(GMT+02:00)


Centro de Investigación Príncipe Felipe

Eduardo Primo Yúfera, 3 Valencia Spain

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