Translational Lung Cancer Biology - Carlos Lopez-Garcia

Carlos completed his PhD at the University of Murcia (Spain) in 2007, where he investigated the role of polyamine metabolism in prenatal development. Later that year, he joined the laboratory of Doug Winton at the CRUK Cambridge Institute with a postdoctoral fellowship awarded by the regional government of Murcia (Spain) to investigate stem cell dynamics in the intestinal epithelium. In 2011, Carlos joined the laboratory of Professor Charles Swanton at the London Research Institute (later The Francis Crick Institute) where he investigated new drivers of chromosomal instability in colorectal cancer and identified BCL9L as novel driver of aneuploidy tolerance

In 2019, Carlos joined the CRUK Manchester Institute as Senior Research Associate in the Cancer Biomarker Centre, led by Professor Caroline Dive. He became an Institute Fellow in 2021 with a project grant funded by the NC3Rs to develop new human models of lung squamous cell carcinoma.

Introduction

Lung cancer is a cancer type characterised by multiple histological subtypes (such as small cell and non-small cell lung cancer), which can also be subdivided into molecular subtypes with different prognoses, driver genes and dysregulated pathways. This heterogeneity is especially prominent in lung squamous cell carcinoma (LUSC), the second most frequent type of non-small lung cancer after lung adenocarcinoma, and one of the most aggressive forms of lung cancer. Multiple driver genes and pathways have been involved in LUSC progression, including inactivation of TP53 and CDKN2A tumour suppressors and somatic alterations in components of multiple oncogenic pathways (Figure 1A).

team photo
Figure 1. A: Tumour suppressors and oncogenic pathways involved in LUSC development. The individual and combined roles of those alterations in driving LUSC is mostly unknown.

These alterations, which arise in a defined order during LUSC evolution (Figure 1B), occur in subsets of patients with no clear correlation with molecular subtypes or trends towards co-occurrence or mutual exclusivity. The poor understanding of this inter-patient heterogeneity hinders the development of therapeutic approaches to treat LUSC, which is currently without targeted therapies. Additionally, this lack of therapies to treat LUSC patients emphasises the importance of early detection and the identification of methods to detect preinvasive LUSC stages to prevent deaths by LUSC.

team photo
Figure 1. B: Recurrent evolutionary history of LUSC observed in patients. OS: Oxidative stress; SD: Squamous differentiation.

In our laboratory, we intend to disentangle the biological meaning of this heterogeneity, using a multiangle approach to explore the individual and cooperative role of major LUSC drivers in the transformation of the homeostatic bronchial epithelium into preinvasive stages and ultimately invasive. In addition, we are investigating the therapeutic potential of targeting genes located in focal chromosomal amplifications and deletions that have been frequently observed in subsets of LUSC patients. Understanding the biological meaning of this LUSC evolution and inter-patient heterogeneity is necessary to design new personalised therapeutic strategies and to gain a better knowledge about the mechanisms that drive LUSC progression.

Selected Publications


Gronroos E, López-García C. (2018)
Tolerance of Chromosomal Instability in Cancer: Mechanisms and Therapeutic Opportunities.
Cancer Research 78(23):6529-6535. PubMed abstract (PMID: 30420473)

López-García C, Sansregret L, Domingo E, McGranahan N, Hobor S, Birkbak NJ, Horswell S, Grönroos E, Favero F, Rowan AJ, Matthews N, Begum S, Phillimore B, Burrell R, Oukrif D, Spencer-Dene B, Kovac M, Stamp G, Stewart A, Danielsen H, Novelli M, Tomlinson I, Swanton C. (2017)
BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer.
Cancer Cell 31(1):79-93. PubMed abstract (PMID: 28073006)

Sansregret L, Patterson JO, Dewhurst S, López-García C, Koch A, McGranahan N, Chao WCH, Barry DJ, Rowan A, Instrell R, Horswell S, Way M, Howell M, Singleton MR, Medema RH, Nurse P, Petronczki M, Swanton C. (2017)
APC/C Dysfunction Limits Excessive Cancer Chromosomal Instability.
Cancer Discovery 7(2):218-233. PubMed abstract (PMID: 28069571)

Cremades A, Del Rio-Garcia J, Lambertos A, López-Garcia C, Peñafiel R. (2016)
Tissue-specific regulation of potassium homeostasis by high doses of cationic amino acids.
Springerplus 5:616. PubMed abstract (PMID: 27330882)

López-Garcia C, Ramos-Molina B, Lambertos A, López-Contreras AJ, Cremades A, Peñafiel R. (2013)
Antizyme inhibitor 2 hypomorphic mice. New patterns of expression in pancreas and adrenal glands suggest a role in secretory processes.
PLoS One 8(7):e69188. PubMed abstract (PMID: 23874910)

Lopez-Garcia C, Klein AM, Simons BD, Winton DJ. (2010)
Intestinal stem cell replacement follows a pattern of neutral drift.
Science 330(6005):822-5. PubMed abstract (PMID: 20929733)

Graduate Student
Julia Ogden

Related Items

Related Items random header image


Translational Lung Cancer Biology - Projects



Related Links



Download our Annual Report

Annual report download image