New research is focussing on understanding the genetic causes and architecture of acral melanoma - an understudied disease that is the most common type of melanoma in Mexico.
Dr Daniela Robles Espinoza, an International Fellow at the Sanger Institute, and Assistant Professor at National Autonomous University of Mexico, has recently been awarded a Wellcome Career Development Fellowship – funding designed to support the future leaders of international research. Based in Mexico, her team studies the genetic causes and architecture of acral melanoma. Acral melanoma is the most common type of melanoma in Mexico and other countries in Latin America, Africa and Asia. Despite this, there are few studies focused on the disease. And more generally, there are very few genetic studies focusing on Latin American individuals. As a result, samples from Latin American people are underrepresented in genetic data repositories – something Daniela aims to change. Here, she tells us about her work, and what the new Fellowship award will enable.
By Dr Daniela Robles Espinoza
Latin America is a large, complex region formed of multiple countries, each composed of a myriad of cultures, languages, socioeconomic and political contexts and genetic ancestries. Although around eight per cent of the world’s population live in this megaregion, there are very few genetic studies focusing on Latin American individuals. One result of this is a gross underrepresentation of samples from Latin American people in genetic data repositories. The reasons for these disparities in research outcomes are varied, including difficulty in aligning the priorities of the research and medical communities, lack of human and economic resources and insufficient specialised infrastructure to support large projects.
We know that disease incidence and outcome are influenced by our genetics and the environment we live in, and so in my mind it’s crucial that we study the causes and evolution of disease in Latin American individuals. Ideally, this should be in research projects led by Latin American teams in collaboration with international partners. Such studies would contribute to our understanding of disease biology and would hopefully help form human resources and establish much-needed infrastructure to support the development of local, large research projects.
It is with these ideas in mind that I established my research team back in 2015 at the International Laboratory for Human Genome Research (LIIGH), part of the National Autonomous University of Mexico (UNAM), in the central city of Queretaro. We started to work in collaboration with local institutions such as the National Cancer Institute of Mexico (INCan) and the National Institute of Genomic Medicine (INMEGEN), and international partners such as the Wellcome Sanger Institute and the National Cancer Institute of Brazil (INCA).
Daniela (middle of bottom row) with her research group
Daniela (middle of bottom row) with her research group
Our focus so far has been on the study of acral melanoma (AM), the most common type of melanoma in Mexico and other countries in Latin America, Africa and Asia. AM has been understudied compared to other types of melanoma due to the small fraction of cases it represents in countries such as the UK, the USA and Australia, and because of this, its causes are still unknown and no effective treatments are available for patients living with the disease.
Our team was able to put together a cohort of nearly 100 AM Mexican patients and we have generated whole exome and whole genome, transcriptome, proteomics and genotyping data from samples donated by the patients. We are now working on integrating these data to characterise the cancer and find predictors of disease outcomes. We are also collaborating with our Brazilian partners to create a collection of patient-derived xenograft (PDX) models. These are made when fragments of tumour are inoculated in immunosuppressed mice and are used to study disease evolution and identify therapeutic targets. We hope that these studies contribute to describing the architecture of the disease in Mexico and Brazil and help train people and establish infrastructure in our local institutions.
These studies and other ideas formed the basis of my application for a Wellcome Career Development Award, which was granted in 2023. With Wellcome’s support, we are now starting studies on the somatic architecture of disease in Latin America, focusing in the beginning on acral melanoma and liver diseases, a new research line in our lab. We are starting to characterize the driver mutations and genes, as well as mutational signatures and the genes that these tumours express. Liver diseases are increasingly common around the world and, in Mexico, it is estimated that perhaps 50 per cent of the population may live with nonalcoholic fatty liver disease (NAFLD). I am thankful to Dr Christian Molina-Aguilar, a postdoctoral researcher in our lab who started this research and conducted our first experiments and analyses, which also formed part of the application to Wellcome.
We plan to study the somatic architecture of tissues (e.g. melanoma tumours or liver biopsies from NAFLD patients) to identify whether specific genetic events are selected for under different disease conditions. We aim to investigate the contribution that ethnicity and lifestyle make to the somatic profile of tumours and pre-cancerous liver lesions, and to investigate the dynamics of anti-tumour drug response in Latin American patients using our collection of PDX models and other experiments.
During the development of this project, we will also train people in genomic analysis and other data integration techniques and will work with our collaborators to establish the infrastructure needed to develop these projects. We will also work closely with Dr Peter Campbell and Dr Dave Adams from the Sanger Institute, who will initially provide access to machines and other tools needed to start the project and advise and contribute to training and research internships.
We will be working with other teams in Mexico, Brazil, the US and the UK, including Drs D. Timothy Bishop (University of Leeds), Andrés Moreno-Estrada (LANGEBIO-CINVESTAV), Natalia Nuño-Lámbarri (Médica Sur Clinic and Foundation Hospital), Alfredo Hidalgo-Miranda (INMEGEN), Mauricio Díaz-Muñoz (INB-UNAM), Patrícia A. Possik (INCA), Maria Teresa Landi (NCI NIH), Héctor Martínez-Said (INCan) and Diego Aguilar-Ramírez (University of Oxford). I am very thankful to them and to our current and previous funders, including UNAM, the National Council for Science and Technology of Mexico, Wellcome, the Wellcome Sanger Institute, the Melanoma Research Alliance, the Medical Research Council, the Forbeck Research Foundation and the Academy of Medical Sciences for believing in us and allowing us to generate data that now allows us to have more stable research funding for the next eight years.
We hope that the benefits of this award can be shared broadly, by the generation of novel data from Latin American patients, the formation of new scientific partnerships and in training researchers and technicians. We are very excited to start work!
