Transcriptional Networks in Lung Cancer

Cancer is one of the most pernicious diseases in the developed world and the main obstacle to a cancer cure is chemoresistance. Over the last decade, a growing number of non-coding transcripts (ncRNAs) have been found to have a pivotal role in gene regulation and cell biology. The most well-known ncRNAs are microRNAs (miRNAs), single stranded RNAs of 19–25 nt in length, that negatively regulate gene expression by translational inhibition or degradation of the mRNA targets. MiRNAs are differentially expressed in almost all types of human cancers versus the normal tissue counterpart and are key players in cancer onset and progression, functioning as tumour promoters (TP) or tumour suppressors (TS). Recent data demonstrate that selective modulation of miRNA activity can improve the response to chemotherapy. We investigate the molecular mechanisms, involving non-coding RNAs, determinants in lung cancer development and in de novo or acquired chemoresistance, which ultimately represents the main cause of cancer-related deaths.

The application of miRNAs to cancer therapeutics and diagnostics is emerging as an important field of gene therapy. Thus far both miRNA replacement and miRNA inhibition strategies have been successfully used to restore normal gene networks in vitro and in vivo, evidencing the huge potential of microRNAs in the fight against cancer. Combining in vitro and in vivo models we aim to develop miRNA-based therapeutics as a new strategy to overcome chemoresistance in lung cancer.

Our group also focuses on the dissection of the role of microRNAs in the tumour microenvironment. The communication between the tumour cells and the surrounding cells, the microenvironment, helps drive the process of tumour progression. Exosomes function as mediators of intercellular communication and contain multiple functional molecules including microRNAs. Using several approaches, including molecular biology, mouse models and next generation sequencing, we inquire how microRNAs released from cancer cells, as a result of external stimuli, affect the surrounding stroma and tumour growth.

Figure 1. MicroRNA dysregulation in cancer