- Alfonso Cayota, MD, PhD (Head)
- Julia Sanguinetti (Msc Student)
- Juan Pablo Tosar (Doctoral Student)
- Braulio Bonilla (MSc Student)
- Fabiana Gambaro (Undergraduate Student)
In the last years, our main focus of research has been centered on the biology of small RNAs in the regulation of gene expression with especial emphasis in extracellular small RNAs and their role in cell-to-cell communication in human cancer. Our work is also intended to identify and validate small RNAs in different extracellular fractions as new biomarkers in human cancer.
“THE SECRETED RNAome”: AN UNEXPECTED PATHWAY OF INTERCELLULAR COMMUNICATION AND NEW SOURCE OF BIOMARKERS IN CANCER”
Cell-free DNA/RNA are normally secreted from a variety of normal and diseased cells to the extracellular media either through membrane-bound vesicles or included in ribonucleoprotein complexes. Studies over the past few years showed that these structures contain bioactive molecules, lipids, nucleic acids and proteins, which like hormones can influence normal homeostasis and many aspects of cancer progression including tumor development, invasion and metastasis.
Circulating mRNAs and microRNAs are detectable in the serum and plasma of healthy individuals and cancer patients. It is known that RNA released into the circulation is surprisingly stable in spite of the high levels of RNases in the blood. High stability and resistance to degradation is achieved through its packaging into either membrane-bound structures (i.e. exosomes, ectosomes and apoptotic blebs) or circulating ribonucleoprotein complexes.
Cancer is currently the second leading cause of death worldwide. Despite the advances in cancer therapeutic approaches during the last decades, the morbidity and mortality rates still remain high. The earliest possible diagnosis and treatment is still the best approach to improve survival. The National Cancer Institute of USA estimates that premature deaths, which may have been avoided through screening, range from 3% to 35% (www.cancer.gov). Screening for cancer is usually attempted whenever worrying symptoms arise, having as a result the diagnosis of cancer as a latest age disease. The current methods for diagnosis of the disease are usually invasive and expensive whereas the existing biological markers are not definitive and lack high sensitivity and specificity. At present, growing scientific efforts in human cancer are aimed to find and develop new, sensitive, non-invasive and inexpensive biomarkers to identify high risk individuals, detect cancer at an early stage, to predict outcome, to monitor treatment and to screen for disease recurrence. Detection of extracellular or cell-free nucleic acids (DNA or RNA) in blood or body fluids has been recently suggested as surrogates for non-invasive and cost effective biomarkers in human cancer.
Our present work is aimed to analyze in depth the total repertoire of RNA transcripts and small RNAs secreted by tumor cells to the extracellular media and their contribution to different fractions of circulating species in normal plasma as well as in cancer patients. Methodological and conceptual results issues from this study should be useful to establish new working hypothesis in the near future and to better understand their diagnostic and predictive value in human cancer and possibly other human diseases.
Thus, vesicular and non-vesicular horizontal transfer of small RNAs could emerge as a relatively wide-spread process that may complement intercellular communication by other mechanisms. One of the most intriguing questions in this regard is how, and to what extent, is this process involved in various forms of cellular pathology. Of particular interest is the role of MVs in cancer whose exploration may both afford new avenues in cancer biology and inspire new therapeutic and diagnostic approaches in biomedicine.
“CIRCULATING SMALL RNAs AS POTENTIAL BIOMARKERS IN HUMAN LUNG CANCER”
Despite advances in diagnosis, treatment and prevention of human cancer in last years, the incidence and mortality rates remain extremely high. For this reason, cancer represents today the second leading cause of death in adults.
Lung cancer is the more frequent cancer in men and the fourth place in frequency in women and the cancer with the higher rate of mortality (rates per 100.000 of 29.2 and 10.9 in men and women respectively). Thus, lung cancer accounts for 24.3% y 7.3% of deaths by cancer in men and women respectively.
This high mortality rate of lung cancer is mainly explained by the absence of specific symptoms and signs in the initial stages which explains the high frequency of diagnosis in advanced stages of the disease. Thus advanced lung cancer (IIIa or IIIb) is associated to a poor survival and partial responses to therapy with mortality rates at 3 and 5 years of 35% and 15% respectively.
In contrast to other cancer types there is no at present biomarkers with enough sensibility to detect lung cancer at early stages when therapeutics inducing long lasting survival or disease remission are highly effectives.
This project is aimed to analyze the potential differential expression of small RNAs in tumor tissues from advanced lung cancer when compared to normal lung tissues.
Advances in this field should contribute to identify novel pathways and potential therapeutic targets in lung cancer. Additionally, correlation between tissue and plasma small RNA could have the potential to identify circulating specific small RNAs that could be used as novel biomarkers.
- “ARNs extracelulares y cáncer: caracterización e implicancias en la modulación recíproca entre células malignas y no malignas” Juan Pablo Tosar ANII Amount Granted USD 13.000. 2013-2015
- “Desarrollo de un servicio de genotipificación de biomarcadores de respuesta al tratamiento con bevacizumab en pacientes con cáncer colorrectal metastásico. Alfonso Cayota. Alianzas – ANII (Casmu-Ipmont) Amount Granted USD 80.000.
- Tosar JP, Rovira C, Naya H, Cayota A. Mining of public sequencing databases supports a non-dietary origin for putative foreign miRNAs: Underestimated effects of contamination in NGS (2014) RNA, 20 (6), pp. 754-757. – IF: 5.377
- Garcia-Silva MR, das Neves RF, Cabrera-Cabrera F, Sanguinetti J, Medeiros LC, Robello C, Naya H, Fernandez-Calero T, Souto-Padron T, de Souza W, Cayota A. Extracellular vesicles shed by Trypanosoma cruzi are linked to small RNA pathways, life cycle regulation, and susceptibility to infection of mammalian cells. Parasitol Res. 2014 Jan;113(1):285-304. doi: 10.1007/s00436-013-3655-1. Epub 2013 Nov 17. PubMed PMID: 24241124. – IF: 2.327
- Garcia-Silva MR, Sanguinetti J, Cabrera-Cabrera F, Franzén O, Cayota A. A particular set of small non-coding RNAs is bound to the distinctive Argonaute protein of Trypanosoma cruzi: Insights from RNA-interference deficient organisms (2014) Gene, 538 (2), pp. 379-384. – IF: 2.082
- Garcia-Silva MR, Cabrera-Cabrera F, Cura Das Neves RF, Souto-Padrón T, De Souza W, Cayota A. Gene expression changes induced by Trypanosoma cruzi shed Microvesicles in mammalian host cells: Relevance of tRNA-derived halves (2014) BioMed Research International, 2014, art. no. 305239. – IF: —