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Dartmouth research links genetic mutation and melanoma progression.

Dartmouth researchers have found that the genetic mutation BRAFV600E , frequently found in metastatic melanoma, not only secretes a protein that promotes the growth of melanoma tumour cells, but can also modify the network of normal cells around the tumour to support the disease’s progression. Targeting this mutation with Vemurafenib reduces this interaction, and suggests possible new treatment options for melanoma therapy. They report on their findings in British Journal of Cancer.

This work supports the importance of the tumour cells ‘talking’ with the normal cells present in the tumour microenvironment.  Targeting the tumour cells with specific therapy to reduce the secreted proteins can reduce the aggressive behavior of the tumour and inhibit disease progression.

Melanoma, the most lethal form of skin cancer, is responsible for more than 80 percent of all skin cancer deaths and spreads readily to the lymph nodes and other organs. While early stage melanoma is curable, the later vertical growth phase (VGP) is frequently metastatic, with median survival times of less than nine months. Melanoma that progresses to this stage is often associated with the gene mutation BRAFV600E, which is found in about 50 percent of melanomas. This BRAF mutation activates certain enzyme pathways that are involved in many cell processes.

Using genetically engineered melanoma cell lines and xenograft mouse models, the researchers found that BRAFV600E melanoma cells expressed higher levels of several cytokines (proteins that act on the immune system and can be used to help the body fight cancer) and Matrix Metalloproteinase-1 (MMP-1; MMPs are associated with various processes including tissue repair and metastasis). Their study also suggests a mechanistic link between BRAFV600E and MMP-1 that modifies the network of normal cells surrounding melanoma tumours, making these normal cells more supportive of tumour growth and development. Vemurafenib, a therapeutic drug that specifically targets the BRAFV600E mutation, is able to reduce the expression of several proteins essential for activating this interaction.

The data shows that Vemurafenib is able to reduce the expression of several proteins that are essential for activating the tumour microenvironment (TME), a next step would be to ask whether Vemurafenib normalizes the TME, or keeps it from becoming activated.  If so, the team would now like to investigate if a window of time is created where the TME can be targeted, normalised, enhancing the patient’s therapeutic response.

Source:  Dartmouth-Hitchcock Medical Center 

 

2008 International Science and Engineering Visualization Challenge Winners.  3D Imaging of Mammalian Cells with Ion-Abrasion Scanning Electron Microscopy was awarded an Honorable Mention in Illustration. It shows a melanoma tumour cell, using a new approach for imaging mammalian cells at nanometer resolution. Donald Bliss and Sriram Subramaniam, US National Library of Medicine, made the image.
2008 International Science and Engineering Visualization Challenge Winners. 3D Imaging of Mammalian Cells with Ion-Abrasion Scanning Electron Microscopy was awarded an Honorable Mention in Illustration. It shows a melanoma tumour cell, using a new approach for imaging mammalian cells at nanometer resolution. Donald Bliss and Sriram Subramaniam, US National Library of Medicine, made the image.

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