Metabolism and Cancer

Group leader: Pedro Miguel Rodrigues, PhD

Biogipuzkoa HRI, Ikerbasque Research Fellow pedromiguel.rodriguesvieira@bio-gipuzkoa.eus
Dr. Pedro M. Rodrigues has training in Molecular and Cellular Biology from the New University of Lisbon (2011) and obtained his doctorate in Pharmacy in 2017, from the University of Lisbon (Portugal). In 2018, he joined the Health Research Institute Biogipuzkoa (San Sebastián), in the Liver Diseases group to carry out his postdoctoral studies, under the direction of Prof. Jesús M. Bañales. During this period, he has been deeply involved in the study of the molecular mechanisms that govern the development of liver tumors, searching for new therapeutic targets and non-invasive biomarkers. In 2019, he was awarded the competitive Sara Borrell contract (ISCIII; 2020-2022) which allowed him to continue his postdoctoral studies in the same group. Currently, he is a Miguel Servet Researcher, Ikerbasque Research Fellow and Head of the Metabolism & Cancer Group at HRI Biogipuzkoa, dedicating himself to the study of the molecular mechanisms that govern the progression of metabolic diseases towards liver cancer. He has directed 4 Doctoral Theses and 2 Master’s Thesis, he is Principal Investigator of more than 10 projects financed by national organizations (ISCIII, LaCaixa, AECC, Basque Government, Provincial Council of Gipuzkoa) and international organizations (Portuguese Foundation for Science and Technology, AMMF UK and PSC Support UK), and is co-inventor of 1 patent. Dr. Rodrigues has more than 50 scientific articles in high-impact journals (NEJM, Nature, JCI, Gut, Nature Reviews Gastroenterology & Hepatology, Journal of Hepatology, Hepatology, Ann Rev Pathol) and is a Member of the Editorial Committee or Associate Editor from scientific journals (Frontiers in Pharmacology, Cancers and Hepatology Communications). He has received various national and international awards for his scientific career, such as the UEG Rising Star 2022 award, from the United European Gastroenterology (UEG), which distinguishes young (<40 years old) emerging leaders in the field of gastroenterology, and the Cells 2022 Young Investigator Award. Dr. Rodrigues was a member and Grant Awarding Coordinator in the COST EURO-CHOLANGIO-NET Action (2021-2023) and was a member of the UEG Young Talent Group (2020-2022). Currently, he is part of the EASL Young Investigator Task Force (2023-2026) and coordinator of WG2 on the COST Precision-BTC-Network Action (2023-2027).

Strategic Objectives

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a spectrum of liver lesions ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH). While simple steatosis is usually benign and the earliest stage, MASH is a more malignant state that tends to progress to cirrhosis and liver cancer, contributing to the morbidity and mortality of patients. The pathogenesis of MASLD is complex and multifactorial, and there remains no unifying pathogenic mechanism for its progression. However, MASLD is closely associated with obesity, insulin resistance, dyslipidemia and hypertension, which usually lead to metabolic rearrangement and chronic inflammation, establishing a procarcinogenic environment. Likewise, although viral infections and alcohol abuse have until now been the main risk factors for liver cancer, MASLD is now the liver cancer risk factor with the greatest clinical impact. Thus, patients with MASLD not only have a higher risk of developing hepatocellular carcinoma (HCC), but are also more likely to develop biliary tumors, or cholangiocarcinoma (CCA). However, the progression of MASLD to liver cancer is poorly studied and the molecular mechanisms responsible for this progression are completely unknown. The main objective of the Metabolism and Cancer group is to promote research inspired by the needs of patients with MASLD, promoting research into the molecular mechanisms underlying the development and progression of the disease, with the intention of identifying new predictive/diagnostic/biomarker for patients, as well as new therapeutic targets that enable the generation of new drugs. In this sense, there are several lines of research that are directed towards this end.

 

Main lines of research

Our main objective is to carry out a detailed study of the pathogenesis of MASLD and investigate the role of epigenetic, cellular and metabolic alterations in the progression of MASLD to liver cancer, with the aim of developing new liquid biopsy tools and relevant therapeutic targets and effective drugs.

  • Detailed study of the progression from MASLD to CCA: While the progression of MASLD to HCC is widely known and there is enormous interest in this field, CCA associated with MASLD is currently an understudied entity. Epidemiological and cohort studies have clearly demonstrated the increased risk of patients with MASLD for developing CCA. Recent data clearly suggest a notable proportion of MASLD in individuals with CCA included in the International CCA Registry. However, these studies only show the association between MASLD and CCA, but so far no more detailed studies have been carried out. Why is it so important to study the progression of MASLD to CCA? Because the prevalence of MASLD is increasing alarmingly around the world, in parallel with the increase in the number of CCA cases. Therefore, a notable increase in the number of CCA cases associated with MASLD is expected in the next decade. However, this field of research remains completely unexplored and, at present, the molecular mechanisms underlying the development of CCA in patients with NAFLD are completely unknown. Likewise, in our group, we aim to develop and characterize new experimental models of CCA associated with MASLD that allow detailed cellular and molecular study of the progression from MASLD to CCA.
  • Study of the heterogeneity of MASLD and the molecular mechanisms associated with progression to liver cancer: the clinical and histological presentation of MASLD is very heterogeneous (thin versus obese individuals; slow progressors versus rapid progressors, etc.). Contrary to what was postulated, the progression of MASLD is not linear, since a quite notable proportion (one third) of liver tumors arise in a non-cirrhotic context, which contrasts with what is observed in other etiologies (> 90% of tumors arise in patients with liver cirrhosis). Furthermore, it is also not known why among individuals with progressive MASLD (i.e., who develop cancer), some develop HCC and others CCA. Likewise, we intend to study why some patients progress to cancer, while others remain in earlier stages of the disease. We also want to understand why some patients with MASLD develop HCC while others develop CCA. To do this, we try to study the epigenetic mechanisms (microRNAs, histone modifications) that can explain these alterations.
  • Study of the impact of the lipid microenvironment on the growth of liver tumors and association with patient prognosis: Previous studies indicate that the most proliferative and aggressive CCA cells depend on the uptake of lipoproteins and extracellular lipids to have a more aggressive phenotype. Likewise, our objective is to study how a fat-rich liver microenvironment, typical in patients with MASLD, affects the growth of CCA and HCC tumors, and how it is associated with patient prognosis and response to therapies.
  • Identification and validation of new predictive, diagnostic and prognostic biomarkers for MASLD: Both HCC and CCA are generally asymptomatic in early stages and are usually diagnosed in advanced stages. Therefore, the silent growth of these tumors seriously compromises their early detection, limiting patients’ access to potentially curative options (i.e., tumor resection). Serum tumor biomarker analysis (AFP and CA19-9) is the only liquid biopsy tool currently used clinically to aid in the diagnosis of HCC and CCA, but its diagnostic power is suboptimal, especially in early tumor stages. Furthermore, there is an alarming lack of accurate non-invasive biomarkers to predict the development and early diagnose these tumors in patients with MASLD. In this regard, biofluids such as blood, bile or urine may contain precise non-invasive biomarkers of particular interest. Likewise, our objective is to identify and validate new circulating biomarkers (proteins, miRNAs, lipids, metabolites) that can help predict the development of HCC and CCA in patients with MASLD, as well as help their diagnosis and predict their survival and response to treatments.

 

Team Members

Name Surname Center E-mail
Ainhoa Lapitz Dambolenea Biogipuzkoa HRI ainhoa.lapitzdambolenea@bio-gipuzkoa.eus
Anne Echebarria Estebanez Biogipuzkoa HRI ANNE.ECHEBARRIAESTEBANEZ@bio-gipuzkoa.eus
Irune Lasa Elosegui Biogipuzkoa HRI IRUNE.LASAELOSEGUI@bio-gipuzkoa.eus
Santiago Iturbe Rey Biogipuzkoa HRI SANTIAGO.ITURBEREY@bio-gipuzkoa.eus

Scientific Output