Welcome to the
IdISBa Cancer Epigenetics Lab
Cancer Epigenetics Lab
We are the Cancer Epigenetics Lab, at the Cancer Cell Biology Group. We are located at the Son Espases Hospital (Mallorca, Spain) as a part of the Health Research Institute of the Balearic Islands (IdISBa). Our lab was founded in 2018, when Dr. Marzese was incorporated as principal investigator thanks to a Miguel Servet grant. We are a mixed lab, where we combine computational biology tools with molecular and cellular biology techniques.
What is Epigenetics?
Epigenetics is the study of heritable changes in gene expression and cellular traits that occur without alterations to the underlying DNA sequence. These changes are often driven by chemical modifications to DNA, such as DNA methylation, and modifications of the DNA-associated proteins, such as histones. Thus, these modifications which can influence how genes are turned on or off and play a crucial role in regulating various biological processes, development, and adaptation to environmental factors.
These epigenetic marks are different between cell types, and they are also modulated during disease progression, such as cancer.
Llinàs-Arias P, Íñiguez-Muñoz S, Cancers, 2021
How do we work?
Most of our projects start with a gap, an idea, or an issue detected by clinicians that must be addressed.
First, we begin with data mining, wherein we collect and curate vast datasets from various sources, including epigenomics, genomics, and transcriptomics. Our workflow emphasizes multi-omic data integration, allowing us to merge different layers of biological information along with the clinicopathological data, providing a comprehensive view of the molecular underpinnings of complex biological processes.
Once we collect evidence enough, we move our investigation toward the wet lab, where we test our hypothesis using cell line models. We have generated stable cell lines using CRISPR/Cas9 or lentiviral systems to either increase or reduce the expression of genes of interest. These models are further used to generate high throughput data and perform functional experiments. Apart from that, we also characterize DNA alterations - including mutations or DNA methylation - as well as RNA and protein expression from patient-derived samples.
In conclusion, our approach underscores the synergy between clinical insight and advanced biological research. The integration of computational and experimental methods equips us with a comprehensive understanding of complex biological processes, ultimately bridging the translational gap and advancing our ability to develop innovative solutions for clinical challenges.
Our research: breast cancer
Our investigation is nowadays mainly focused on the aggressive forms of breast cancer. Despite the research advances in breast cancer treatment some particularly aggressive manifestations of the disease still show a dismal prognosis. Triple Negative Breast Cancer (TNBC) is characterized by the absence of estrogen and progesterone receptors, as well as the lack of HER2 amplification. This is a heterogeneous molecular subtype of breast cancer with the lowest survival, due to the lack of specific treatments and the enhanced metastasis rates.
We have studied the effects of chemotherapy on gene expression in TNBC patients (Orozco et al., Ann Surg Oncol 2019), the epigenetic subtypes in TNBC (DiNome et al., Ann Surg Oncol 2019), and we also summarized all the subtypes found on this particular breast cancer (Ensenyat-Mendez and Llinàs-Arias et al., Frontiers Oncol 2021).
The greater metastatic rates prompted us to look into the epigenetic role in TNBC. We unraveled a novel mechanism involved in the invasion (Llinàs-Arias et al., preprint available) and we generated multi-omic data in our TNBC cell line models (Llinàs-Arias and Ensenyat-Méndez et al., BMC Genomics Data 2023).
The rise of immunotherapy as a therapeutic approach for TNBC (Llinàs-Arias and Íñiguez-Muñoz et al., 2021) motivated us to generate a classifier to distinguish which patients may respond to immune checkpoint inhibitors (Ensenyat-Méndez et al., Commun Med (Lond) 2023). We are currently working on this line with the support of the CONTIGO Foundation in the MERIT project. We are deciphering how aberrant splicing contributes to immune evasion in TNBC.
Apart from TNBC, we are also interested in discovering the differential traits of other aggressive forms of breast cancer, such as secondary breast cancer (Graff-Baker et al., Ann Surg Oncol 2018), as well as the ethnicity-associated divergences in breast cancer (Ensenyat-Méndez and Solivellas-Pieras et al., JAMA Netw Open 2023). We also took advantage of epigenetics to generate classifiers to determine lymph node invasion based on the DNA methylation on the primary site (Orozco et al., Ann Surg Oncol 2022 and Ensenyat-Mendez et al., Ann Surg Oncol 2022).
Other cancers
We have also been involved in other tumors, especially in glioblastoma, the most aggressive form of brain cancer. We published different studies in this disease. We generated a machine learning-based classifier (Ensenyat-Méndez et al., BioData Min 2021), we characterized a particularly aggressive subpopulation of cancer stem cells (Sesé et al., Cancers (Basel) 2022) and we summarized the relevance of IEs in GBM biology (Sesé et al., Clin Epigenetics 2021).
Our team has also collaborated in studies focused on melanoma (Chagani S et al.m J Invest Dermatol 2023; Carrier et al., Clin Epigenetics 2022) and appendiceal cancer Garland-Kledzik et al., (Ann Surg Oncol 2022).
Current research lines
Understand the molecular basis of breast cancer invasion.
Decipher the immune evasive mechanisms of breast cancer.
Characterize the molecular differences between patient subgroups.
Generate molecular classifiers to predict response to treatment.
Identify alterations affecting non-coding regions.
Chromatin insulation orchestrates matrix metalloproteinase gene cluster expression reprogramming in aggressive breast cancer tumors
Pere Llinàs‐Arias, Miquel Ensenyat‐Méndez, Sandra Íñiguez‐Muñoz, Javier I. J. Orozco, Betsy Valdez, Matthew P Salomon, Chikako Matsuba, Maria Solivellas-Pieras, Andrés F Bedoya-López, Borja Sesé, Anja Mezger, Mattias Ormestad, Fernando Unzueta, Siri H Strand, Alexander D Boiko, E Shelley Hwang, Javier Cortés, Maggie L DiNome, Manel Esteller, Mathieu Lupien, Diego M Marzese
BMC Molecular Cancer. 2023. PMID: 38017545 PMCID: PMC10683115 DOI: 10.1186/s12943-023-01906-8
3‐D chromatin conformation, accessibility, and gene expression profiling of triple‐negative breast cancer
Pere Llinàs‐Arias, Miquel Ensenyat‐Méndez, Javier I. J. Orozco, Sandra Íñiguez‐Muñoz, Betsy Valdez, Chuan Wang, Anja Mezger, Eunkyoung Choi, Yan Zhou Tran, Liqun Yao, Franziska Bonath, Remi‐André Olsen, Mattias Ormestad, Manel Esteller, Mathieu Lupien and Diego M. Marzese
BMC Genomic Data. 2023;24:61.
Epigenetic Profiles of Triple-Negative Breast Cancer of African American and White Females.
Ensenyat-Mendez M, Solivellas-Pieras M, Llinàs-Arias P, Íñiguez-Muñoz S, Baker JL, Marzese DM, DiNome ML.
JAMA Netw Open. 2023 Oct 2;6(10):e2335821. doi: 10.1001/jamanetworkopen.2023.35821. PMID: 37796506
Ensenyat-Mendez M, Orozco JIJ, Llinàs-Arias P, Íñiguez-Muñoz S, Baker JL, Salomon MP, Martí M, DiNome ML, Cortés J, Marzese DM.
Commun Med (Lond). 2023 Jul 10;3(1):93. doi: 10.1038/s43856-023-00311-y.
PMID: 37430006
Multiplatform Analysis of Intratumoral PTEN Heterogeneity in Melanoma.
Chagani S, De Macedo MP, Carapeto F, Wang F, Marzese DM, Wani K, Haydu LE, Peng W, Ong GT, Warren SE, Beechem JM, Hoon DSB, Mills GB, Tetzlaff MT, Lazar AJ, Kwong LN, Davies MA.
J Invest Dermatol. 2023 Mar 4:S0022-202X(23)00164-1. doi: 10.1016/j.jid.2023.01.034.
PMID: 36871660
We are grateful to the following funding entities
for supporting our research:
