The Arnes group investigates how molecular determinants of cellular identity, with a particular focus in non-coding RNAs, regulate the initiation and progression of pancreatic cancer.
The group is interested in understanding how long non-coding RNAs interact with transcription factors and chromatin modifiers to regulate gene expression and cellular plasticity in development and disease. The long-term goal is to devise cancer therapies based in altering the activity of transcriptional regulators of pancreas differentiation.
Acinar cells in the pancreas can adopt alternative cell fates upon injury. Although considered a physiological process of tissue homeostasis, it renders the tissue susceptible to cancer. Cell-type-specific noncoding regulatory elements maintain the identity and function of mature cell types. Although we have a clear picture of the steady-state transcriptional and epigenetic landscape in development and cancer, the molecular regulators of cell fate transitions are not well understood. We aim to elucidate the molecular underpinnings of cell fate decisions in pancreas development and cancer.
We want to address two fundamental questions: What is the role of pervasively transcribed RNA in the regulation of genome function? How do noncoding regulatory elements interplay to regulate gene expression and cellular differentiation in development and disease?
Long noncoding RNAs are necessary for pancreas development
- We showed that gene regulatory elements are not randomly distributed in the genome and instead localize to the vicinity of lineage-specific transcription factors.
- Subset of lncRNAs are conserved in evolution, dynamically regulated in development, and dysregulated in disease. However, for most of them, the function remains yet unknown
- lncRNAs are necessary for the control of developmental competence in the differentiation of pancreatic lineages
Pancreatic ductal adenocarcinoma is a disease of differentiation and molecular regulators of cellular identity are potent tumor suppressors
- We used an integrative analysis of genomic and clinical data from PDAC tumour samples to define a catalogue of lncRNAs associated with genetic traits of pancreatic cancer and associated with clinical outcome.
- lncRNAs define molecular subtypes of pancreatic cancer with implications in disease progression and patient stratifications
- molecular subtypes are dynamic, and regulated at least in part by lncRNAs, opening a window of opportunity to understand and target tumor heterogeneity in pancreatic cancer
- Understand the gene regulation of pancreas regeneration and susceptibility to cancer
- Investigate the molecular mechanisms controlling tumor heterogeneity and resistance to therapy in pancreatic ductal adenocarcinoma
- Understanding how long noncoding RNAs interact with transcription factors and chromatin modifiers to regulate gene expression and cell fate decision in development and cancer
We use genetic mouse models of PDAC, acinar explants, and human embryonic stem cells to model pancreas development and the early stages of the disease. We combine the results with comparative human data in pathological specimens. We use a combination of gene expression, chromatin accessibility, and single-cell RNA sequencing in time-resolved experiments to define drivers of precancerous lesions and the molecular mechanisms of tumor heterogeneity.
Rabadan, R. et al. Identification of relevant genetic alterations in cancer using topological data analysis. Nature communications 11, 3808, doi:10.1038/s41467-020-17659-7 (2020).
Singer, R. A. et al. The Long Noncoding RNA Paupar Modulates PAX6 Regulatory Activities to Promote Alpha Cell Development and Function. Cell metabolism 30, 1091-1106 e1098, doi:10.1016/j.cmet.2019.09.013 (2019).
Font-Cunill, B., Arnes, L., Ferrer, J., Sussel, L. & Beucher, A. Long Non-coding RNAs as Local Regulators of Pancreatic Islet Transcription Factor Genes. Frontiers in genetics 9, 524, doi:10.3389/fgene.2018.00524 (2018).
Arnes, L. et al. Comprehensive characterisation of compartment-specific long non-coding RNAs associated with pancreatic ductal adenocarcinoma. Gut 68, 499-511, doi:10.1136/gutjnl-2017-314353 (2019).
Arnes, L., Akerman, I., Balderes, D. A., Ferrer, J. & Sussel, L. betalinc1 encodes a long noncoding RNA that regulates islet beta-cell formation and function. Genes & development 30, 502-507, doi:10.1101/gad.273821.115 (2016).
Arnes, L. & Sussel, L. Epigenetic modifications and long noncoding RNAs influence pancreas development and function. Trends in genetics : TIG 31, 290-299, doi:10.1016/j.tig.2015.02.008 (2015).