PTENLKB1

Implication of energy sensing pathways in prostate cancer biology

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 Obiettivo del progetto (Objective)

'Prostate cancer is among the most prevalent forms of cancer in men and the fifth cause of dead from cancer in men worldwide. Therefore, the understanding of prostate cancer biology is a key step in the development of new effective therapeutic approaches. In this line, the use of genetically engineered mouse models has been critical in the understanding of the genetic cues that regulate the process of prostate epithelial cell transformation. We have previously characterized the tumor suppressive function of the tumor suppressor PTEN in different stages of prostate cancer, from precancerous lesions to invasive cancer and metastasis. Importantly, we have shown that early and acute loss of PTEN elicits senescence response that functions as a brake for the progression of prostate cancer. Notably, prostate cancer has been demonstrated to be exquisitely sensitive to metabolic changes and to cancer genes altering metabolic homeostasis. In this proposal we aim to ascertain the role of energy sensing pathways in prostate cancer progression, with special emphasis in the crosstalk between the master energy-sensing kinase LKB1 and the tumor suppressor PTEN. Using genetically modified mice and cells, as well as pharmacological agents, we will study i) the contribution of LKB1-loss to the biological features elicited by loss of PTEN, especially the activation of the cellular senescence response, ii) the role of LKB1 signaling in the development of invasive lesions and the onset of metastasis, and iii) the therapeutic relevance of the crosstalk between PTEN and LKB1 in the prostate epithelium. In turn, this proposal aims to contribute to the development of more accurate mouse models of prostate cancer progression as well as to the discovery of potential therapeutic approaches directed to modulate LKB1 signaling in prostate cancer.'

Introduzione (Teaser)

Understanding prostate cancer biology is a key step in the development of new effective therapeutic approaches. The use of genetically engineered mouse models is critical for understanding the process of prostate epithelial cell transformation.

Descrizione progetto (Article)

Scientific evidence revealed that cancer cells exhibit aberrant cellular metabolism (less efficient anaerobic use of glucose in the presence of oxygen). After intensive research, we now have a better understanding about how cancer cells undergo metabolic switch or reprogramming.

Prostate cancer cells, in particular, are exquisitely sensitive to metabolic changes and to cancer genes altering metabolic homeostasis. The EU-funded 'Implication of energy sensing pathways in prostate cancer biology' (PTENLKB1) proposal aims to investigate the role of energy sensing pathways in prostate cancer progression.

Liver kinase B1 (LKB1) is a protein that acts as a metabolic tumour suppressor. This protein regulates adenosine monophosphate-activated protein kinase (AMPK), the central energy sensor in the cell. AMPK activation turns on the cascade in tumour suppressive program. This project is based on the premise that LKB1 functionally interacts with proteins like the phosphatase and tensin homolog (PTEN) to suppress prostate cancer.

During the first two years, the project focused on a multidisciplinary approach involving use of cell systems, cancer mouse models and human specimens. Findings demonstrated that despite the reported lack of LKB1 mutations in prostate cancer, its expression is altered in prostate cancer biopsies. This observation reinforces the hypothesis about its tumour suppressive activity.

Genetic manipulations restored LKB1 function in cells with deficiencies in the pathway. In addition, data-mining studies identified potential compounds to increase therapeutic efficacy in the cells with compromised LKB1 function. Finally, the appropriate genetic background mouse model where LKB1 can be deleted in a tissue-specific manner was established.

Project activities should facilitate the development of better mouse models of prostate cancer progression and the discovery of novel therapeutic approaches for treating prostate cancer.