PTENLKB1 · Implication of energy sensing pathways in prostate cancer biology
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2012-01-02 → 2016-01-01
- Финансиране от ЕС
- 100 000 €
- Участници
- 1
- Схема
- MC-IRG
Линиите свързват координатора с партньорите.
Накратко на български
Протеинът LKB1 и неговата роля в метаболизма на клетките при рак на простатата се анализират чрез клетъчни модели и човешки биопсии. Разбирането на този механизъм помага за откриването на нови начини за терапия при пациенти с рецидивиращо заболяване.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
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.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
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.
Оригинален текст от CORDIS (на английски).
Участници
- ASOCIACION CENTRO DE INVESTIGACION COOPERATIVA EN BIOCIENCIAS · DERIO VIZCAYAКоординаторИспания
Връзки
Данни: CORDIS, © Европейски съюз