Servizio Comunitario di Informazione in materia di Ricerca e Sviluppo - CORDIS

Final Report Summary - PTENLKB1 (Implication of energy sensing pathways in prostate cancer biology)

Prostate cancer is among the most prevalent type of neoplasm in developed societies. Albeit being effectively treated, a subset of patients exhibit recurrence of the disease that can progress to metastatic disease, a main factor in the mortality of this type of cancer. A century ago, Otto Warburg performed seminal experiments to demonstrate that cancer cells exhibit an aberrant cellular metabolism (less efficient anaerobic use of glucose in the presence of oxygen), which was termed the Warburg effect. In recent years there has been a renaissance of the concept initiated by Warburg and, as a result of the intensive research that has been carried out, we now understand better how cancer cells undergo metabolic switch or reprogramming. Cancer genes (oncogenes and tumour suppressors) maintain metabolic homeostasis when functional, and alterations in these genes result in the metabolic switch.
Among the metabolic tumour suppressors of increasing interest we have the master kinase LKB1. This protein regulates the central energy sensor in the cell, AMPK, which in turn elicits upon activation a tumour suppressive program. LKB1 has been widely studied in a large array of cancer, in which mutations have been found. This research project was initiated with the hypothesis of the tumour suppressive activity of LKB1 in prostate cancer, and the aim of corroborating this fact and defining a mechanism of action and a therapeutic avenue emanating from it.
We have carried out a multidisciplinary approach through the use of cellular systems, cancer mouse models and human specimens. Our results reveal that LKB1 protein expression is altered in a significant fraction of prostate cancer biopsies, which in turn reinforces the notion of its hypothetical tumour suppressive activity.
We have evaluated in vitro the expression levels of LKB1 pathway component and identified target cell lines that would serve to test the hypothesis of the tumour suppressive potential of LKB1. Genetic manipulation has allowed us to restore LKB1 function in cells with deficiencies in the pathway. This system has revealed an exquisite regulation of cell fate by LKB1, and the potential of AMPK activating drugs to more efficiently alter the homeostasis of LKB1 deficient cells. We have characterized the molecular mechanism underlying the activity of LKB1 in prostate cancer. Importantly, we have integrated mouse genetics and in vitro assays in order to characterize the histological features of LKB1-loss driven cancers. These results have in turn resulted in: 1) the comprehension of the molecular complexity of prostate cancer, 2) the characterisation of novel molecular signalling stemming from LKB1 and 3) the identification of LKB1-deficient cancers-directed therapies.

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