Transcriptional regulation by NR5A2 couples cell differentiation and inflammation in the pancreas

Date

Oct 30, 2018

Time

9:30 AM - 10:30 AM

Speaker

Isidoro Cobo

Affiliation

Spanish National Cancer Research Centre, CNIO, Madrid

Series

CMCB Life Sciences Seminar

Language

en

Main Topic

Biologie

Other Topics

Biologie, Medizin

Host

Prof. Dr. Michael Sieweke

Description

AbstractChronic inflammation is a major risk factor for the development of several tumour types Inflammation acts as a double-edged sword: on one hand, it is a precise mechanism that allows proper response upon damage. However, when de-regulated or persistent, inflammation can promote tumour development. NR5A2 is indispensable for complete pancreatic acinar cell differentiation and homeostasis. SNPs in the vicinity of the NR5A2 locus have been associated with higher risk of developing pancreatic cancer. In this work, I have demonstrated that, in addition to its role in pancreas homeostasis, NR5A2 restrains an inflammatory program in the pancreas. In this regard, reduced NR5A2 expression both in normal mouse and human pancreas, leads to a basal pre-inflammatory state that resembles that one observed in the early stages of pancreatitis. During the pre-inflammatory state, NR5A2 is genomically relocated from the promoter of acinar differentiation genes to the promoter of inflammatory genes in a process that is dependent on AP-1 proteins. Our work opens the possibility of identifying scenarios of pre-inflammation in other tissues even when histology and functionality seems normal. In addition, I have drilled down into the tumour supressor role of NR5A2. I have found that the combination of mutant KRas activation and Nr5a2 heterozigosity in pancreatic epithelial cells leads to the formation of aggressive cystic lesions, in the absence of exogenous pancreatitis induction. 5 most recent papersThe molecular Basis of Radial Interacalation during Tissue Spreading in Early Development. András Szabó,1 Isidoro Cobo,1 Sharif Omara, Sophie McLachlan, Ray Keller, and Roberto Mayor,∗ 1 Equal contributors. Developmental Cell, 2016 May 9; 37(3): 213-225. Nr5a2 couples differentiation and inflammation in the pancreas. Isidoro Cobo, Paola Martinelli, Marta Flández, Latifa Bakiri, Mingfeng Shang, Enrique Carrillo-de-Santa-Pau, Jinping Jia, Liv Themmesen, Torunn Bruland, Natalia del Pozo, Sara Olson, Jill Smith, William R. Bamlet, Gloria M Petersen, Núria Malats, Laufey T Amundadottir, Erwin F. Wagner and Francisco X Real. Nature, 2018. 554(7693):533-537. c-Myc downregulation is required for preacinar to acinar maturation and pancreatic homeostasis. Victor J. Sánchez-Arévalo, Luis C. Fernandez, Enrique Carrillo-de-Santa-Pau, Laia Richart, Isidoro Cobo, Jerowslak Cendrowski, Ulises Moreno, Natalia del Pozo, Diego Megías, Bernardette Bréant, Cristopher Wright, Mark Magnuson and Francisco X. Real. Gut, 2016-312306. Nr5a2 heterozygosity cooperates with KRas in the development of aggressive cystic tumours. Isidoro Cobo, Mar Iglesias, Marta Flández, Miriam Llorente, Natalia del Pozo and Francisco X. Real (manuscript in preparation). Nfic is a novel Nr5a2 interactor and regulator of the acinar program. Isidoro Cobo, Julia Melia, Sumit Paliwal, Irene Millán, Fernando García, Javier Muñoz, Joo-Cheol Park and Francisco X. Real. (manuscript in preparation).

Links

• to announcement of the organizer

Last modified: Oct 30, 2018, 1:06:18 AM