The complete genetic characterization of tumours is important to understand cancer development, to encourage the discovery of new drugs and to improve the selection of patients that may benefit from a given targeted cancer therapy. Our group is interested in the use of the latest high-throughput sequencing technologies to create profiles and catalogues of the recurrently altered genes in cancer. We are also deeply interested in understanding the mechanisms by which the abnormal function of these genes contributes to cancer development. Ultimately, our purpose is to define combinations of pathways according to the gene alteration profiles and the key molecule/s (Achilles’ heel/s) that need to be blocked to effectively reduce or abolish proliferation and inhibit invasion/metastasis. We hope that our work can help to improve the clinical management of cancer patients and to design novel therapeutic strategies.
For the last fifteen years, our group has provided information relevant to the understanding of lung cancer biology. We have discovered novel tumour suppressor genes and have contributed to the characterization of the molecular abnormalities of lung cancer.
My laboratory has been a pioneer in identifying genetic inactivation of BRG1 (the ATPase of the SWI/SNF complex) (Medina et al. 2010), now recognized as important tumour suppressor gene. In addition, we reported that SWI/SNF orchestrates the response to retinoid acid, glucocorticoids and histone deacetylase inhibitors, involving downregulation of MYC (Romero et al, 2012 & 2017).
Additionally, we unveiled inactivating mutations at the MYC-partner, MAX, in small cell lung cancer (Romero et al. 2014) and mutations in the polarity-related gene and PARD3 (Bonastre et al. 2015). In collaboration with European researchers, we observed the presence of recurrent mutations and of intragenic deletions at these genes, affecting 8-10% of the lung cancers. We also confirmed the ability of MAX and PARD3 to suppress cell growth and we have performed functional studies on the molecular effects associated with the inactivation of these genes.
More recently, and also with the contribution of various collaborators (at the European and Spanish level) we have performed whole exome and RNA sequencing of patient derived xenographs (PDX) and of patient derived cancer cells (PDCs) (Pereira et al. 2017; Pros et al. submitted). One of the genes found to be altered, was B2M, which codes for the small subunit of the HLA-class I complex, involved in immunosurveillance. We characterized these alterations, as well as others related to the response to interferon gamma, and proposed them as markers for predicting response to the current drugs based on inhibitors of PD-1 and PD-L1 (Pereira et al. 2017; Saigi et al. 2018 &2019).
Lines of Research
Derived from all our previous work, we have three important ongoing lines of research in the laboratory:
- Determination of genetic profiles in cancer. We are interested in pursuing the use of exome and RNA sequencing to discover novel genes altered in lung cancer and the description of genetic profiles. We also undertake functional and mechanistic analysis for the dissection of pathways.
- Study of the abnormalities at MYC/MAX/MGA and BRG1-(SWI/SNF) related pathways. Using high throughput technologies, including chromatin immunoprecipitation sequencing (ChIP-seq) and immunoprecipitation–mass Spectrometry (IP-MS), we aim to understand the functional connection between these pathways and how their abnormal function contributes to tumour development.Additionally, we are interested in identifying molecular vulnerabilities that can be used therapeutically.
- Identification of markers that predict response to tyrosine kinase inhibitors (TKIs) and to immunocheckpoint inhibitors. Study of the mechanisms that underlie acquired resistance to tyrosine kinase inhibitors and to immunocheckpoint inhibitors in lung cancer.