CANCER METASTASIS

Identification of important regulators of metastasis in pancreatic cancer

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 Obiettivo del progetto (Objective)

'Pancreatic cancer is one of the leading causes of cancer-associated mortality. One of the primary contributing factors is late diagnosis of the disease, resulting in established metastatic cancer before symptoms emerge. This form of cancer is characterised by a number of well-defined genetic alterations including oncogenic mutation of K-Ras and inactivating mutation of p53, SMAD4 and CDKN2A. Concurrent deregulation of K-ras and these tumor suppressors facilitates uncontrolled proliferation of early stage pancreatic cancer cells and subsequent progression into more advanced adenocarcinomas. However, as many patients present with a metastatic form of pancreatic cancer, treatment of the primary tumor is often insufficient to achieve regression of this disease. Thus, a greater understanding of pancreatic cancer metastasis is needed to identify mechanisms to effectively treat this form of cancer. We wish to perform an in vivo shRNA screen to identify genes that promote or inhibit metastasis of oncogenic K-Ras positive pancreatic cancer cells. We will then investigate the mechanism through which these genes regulate the metastatic process. Finally, we will explore methods to modulate these genes and/or their function for the treatment of pancreatic cancer.'

Introduzione (Teaser)

Cancer ranks amongst the biggest causes of mortality worldwide. There is an ongoing need to understand the underlying mechanisms of cancer onset, progression and metastasis.

Descrizione progetto (Article)

Cancer often arises from activated mutations in oncogenes such as Ras or silenced mutations in tumour-suppressor genes such as p53. Another hallmark of the disease is the ability of cancer cells to migrate from the original site and reach distant organs, a phenomenon known as metastasis. This usually occurs at late stages and is very difficult to treat.

There is an urgent need to identify the genes that are mutated in different cancers, cause abnormalities as well as metastasis. The EU-funded CANCER METASTASIS (Identification of important regulators of metastasis in pancreatic cancer) project worked towards these goals and focused on pancreatic cancer. Given the increased prevalence of pancreatic cancer and its dismal prognosis, insight into the molecular aetiology is required.

Accumulating evidence shows that pancreatic cancer cells present with mutations in K-Ras as well as p53, Cdkn2A and Smad4. However, this information has not been translated into therapeutic interventions.

To address the need for novel therapeutic strategies, the CANCER METASTASIS consortium set out to identify genes implicated in metastasis. They utilised RNAi technology to knock down expression and perform a large genetic screen. Building on previous knowledge on pancreatic cancer, they generated a list of putative target genes.

Scientists went a step further to assess the role of these genes in vivo. They knocked down their expression in pancreatic cancer cells through the use of short hairpin RNA (shRNA) molecules. By comparing the abundance of these molecules before and after metastases formation, researchers identified 18 genes involved in cancer metastasis or growth in lung tissue.

Scientists further demonstrated that five of these genes play a crucial role in pancreatic cancer metastasis in the lung. Although functionally diverse, they all seemed to participate in pancreatic cell communication as well as adaptation in the new environment.

Future research endeavours can further investigate the downstream pathways of these genes to clarify their biological function and identify novel therapeutic targets. These targets could also be applied for the treatment of other forms of metastatic cancer.