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Rac1b: potential pancreatic cancer drug target
Three proteins, namely matrix metalloproteinase-3 (MMP3), Rac1b and KRAS work together to drive progression and tumourigenesis in pancreatic cancer. This pathway provides a therapeutic target for this notoriously difficult to treat cancer. These are the main findings of a new study in the journal Molecular Cancer Research from researchers in the Mayo Clinic and Unikliniken Marburg Und Giessen.

Pancreatic cancer features genetic alterations in a cancer-associated oncogene called KRAS. Tumours are also supported by their microenvironment which is characterised by influx of immune cells. Cells that surround the tumour make matrix metalloproteinases such as MMP3. These are enzymes that break cell adhesions and in the cancer context allow tumour cells to move away from the tumour to other sites, a process known as metastasis. The RAC1 protein superfamily of proteins are important in regulation of cell growth and cell movement. Some forms of these proteins, such as Rac1b, had been previously implicated in other cancers but not in pancreatic cancer.

In the current study, the research team wanted to establish what drives the expression of MMP3 in pancreatic cancer. They used several strategies, including examination of a cohort of pancreatic cancer tissue biopsy samples, transgenic mouse models and in vitro studies of cultured pancreatic cancer cells.

The biopsy samples revealed that both MMP3 and Rac1b are expressed in pancreatic cancer cells. Their expression was correlated and the location of the Rac1b in the cells was associated with the patient’s prognosis. The transgenic mouse models studies showed that co-expressing MMP3 with activated KRAS in pancreatic cells stimulated development of the tumour microenvironment. Finally, using pancreatic cancer cells in culture and exposing them to recombinant MMP3 directly stimulated Rac1b expression and also increased the invasiveness of the cells and their expression of cancer-associated genes.

The results suggest that Rac1b is associated with the aggressiveness of pancreatic cancer and may provide a drug target for pancreatic cancer, especially in patients who do not respond well to other therapies. Dr Derek Radisky, senior investigator on the study, further explains the significance of the findings: "The implication from our research is that Rac1b is activating unique pathways in pancreatic tumours that make this cancer aggressive. If we can therapeutically target that pathway, we may be able to have an impact on this very difficult-to-treat disease."

However, targeting Rac1b directly would be difficult as it is involved in many normal biological processes. Thus, the research team are now undertaking some scientific detective work to identify targets among the cancer-causing pathways activated by Rac1b. Dr Radisky concludes: "Pancreatic cancer is not uniformly aggressive — some patients have a relatively better outcome. This work allows us to hone in on those patients who don't do as well, and who would most benefit from more targeted therapies.”


Mehner, C., Miller, E., Khauv, D., Nassar, A., Oberg, A.L., Bamlet, W.R., Zhang, L., Waldmann, J., Radisky, E.S., Crawford, H.C. and Radisky, D.C. (2014). Tumor Cell-derived MMP-3 Orchestrates Rac1b and Tissue Alterations that Promote Pancreatic Adenocarcinoma. Molecular Cancer Research (21 May 2014). doi: 10.1158/1541-7786.MCR-13-055

Press release: Mayo Clinic
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