Dr Carla Martins
Modelling Tumour Development and Therapy
Schematic representation of research strategy
The main aim of our programme is to define the molecular and functional alterations that enable lung tumour progression from benign stages to high-grade adenocarcinoma. While our immediate goal is to improve the targeting of tumours harbouring particular sets of mutations, our ultimate goal is to identify broader and targetable signatures associated with benign and advanced disease. We are currently focused on the evolution of lung tumours expressing mutant versions of Kras and p53.
Despite being two of the most frequent mutations in human lung adenocarcinoma, how each of these key alterations contributes to malignant progression remains unclear. To address these key questions our lab uses a multidisciplinary approach that combines the generation of genetically modified tumour models that closely
recapitulate the evolution of the human disease to “omics” approaches, microscopy and in-vivo imaging.
Our Main Research Themes Are:Role and prognostic implications of Kras locus alterations on lung tumour progression
We previously identified Kras allelic imbalance as a frequent alteration associated with advanced murine lung tumours and these genetic changes are also frequently encountered in human lung cancer. Using a multidisciplinary approach we aim to establish the prognostic and therapeutic implications of these alterations.
Impact of p53 mutations on lung cancer progression and therapy
p53 mutations affect almost half of all human cancers and are among the few mutational events associated with lung cancer malignant progression. The oncogenic and therapeutic impact of these mutations in lung cancer remains largely unknown. Using mouse models that closely recapitulate the human disease we aim to define the oncogenic effect of p53 mutations on lung cancer progression and therapy.
Molecular and functional requirements of lung cancer evolution
Using unbiased genetic, transcriptional and metabolic approaches we aim to dissect the mechanistic drivers of lung tumour evolution in order to identify targetable signatures associated with benign and advanced disease.
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Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Kerr E, Guade E, Turrell F, Frezza C, Martins CP. Nature. 2016. 24 Feb. doi:10.1038/nature16967. [Epub ahead of print].
From tumor prevention to therapy: Empowering p53 to fight back. Frezza C, Martins CP. Drug Resist Updat. 2012 Oct;15(5-6):258-67. doi: 10.1016/j.drup.2012.10.001.
Validation of MdmX as a therapeutic target for re-activating p53 in tumors. Garcia D, Warr MR, Martins CP, Brown Swigart L, Passegué E, Evan GI. Genes & Development.Genes Dev. 2011 Aug 15;25(16):1746-57. doi: 10.1101/gad.16722111.
Selective activation of p53-mediated tumour suppression in high-grade tumours.Junttila MR, Karnezis AN, Garcia D, Madriles F, Kortlever RM, Rostker F, Brown Swigart L, Pham DM, Seo Y, Evan GI, Martins CP. Nature. 2010 Nov 25;468(7323):567-71.
Modeling the therapeutic efficacy of p53 restoration in tumors. Martins CP, Brown-Swigart L, Evan GI. Cell. 2006 Dec 29;127(7):1323-34.