Tuesday, February 19, 2013
I would like to apologize for the lack of updates these past few weeks: I've been busy at work drafting/gathering my research results for publication, taking a science writing course through Johns Hopkins, and preparing for the wedding (April 6th!)- in other words, it's been hectic. I haven't forgotten about you, readers, and I am going to make every effort to update more frequently in the future. Thanks for your patience!
Wednesday, February 6, 2013
In the previous entry I wrote about cancer cell metastasis, and researchers’ attempt to understand the mechanics behind cancer cell migration. Understanding why and how cancer cells metastasize can be approached from several angles, however, and just as important as determining the ‘how’ is figuring out the ‘why’. If less than 1% of cancer cells have the ability to metastasize, what makes these cells so different from their peers?
|An invasive cancer cell makes its way into a pore. Image credit: Cornell University Chronicle Online|
Previously, researchers have addressed this question by identifying molecular signatures of metastatic cancer cells. To do this, scientists can compare which genes are turned ‘on’ or ‘off’ within a cell using RNA expression as a readout for gene activity. When a gene is active, the DNA sequence of that gene is translated into RNA, a close relative of DNA. While genomic DNA remains esconced within the nucleus of the cell, RNA is often shuttled outside of the nucleus and throughout the cell. Some RNA sequences contain the instructions for making a protein, and they are read by the cell’s protein production machinery to direct the formation of a new protein.
Another class of RNA, appropriately referred to as ‘noncoding RNA’, does not code for a new protein. But don’t be fooled: just because they don’t encode a protein doesn’t mean that they aren’t equally important. Noncoding RNAs carry out a number of different tasks within the cell, and are essentially to regulating the myriad processes occurring within the cell.
Certain noncoding RNAs have been identified as molecular markers of cancer cells, as their activity correlates with cancer progression. MALAT1 is one such example: it has been linked to various types of lung cancer, and usually serves as a predictor for a cell’s ability to metastasize. Increased levels of MALAT1 usually means bad news for lung cancer patients: the more MALAT1 cancer cells express, the more likely it is that they will metastasize and disease progression will subsequently take a turn for the worse. MALAT1 promotes metastasis by regulating genes involved in cell motility; however, until now it has not been clear how this regulation occurs.
The first possibility was that MALAT1 encouraged alternate splicing of RNA transcripts. When RNA is translated from DNA, the original sequence usually does not remain intact. Instead, it is cut, or ‘spliced’, and pasted back together in various combinations. Different combinations may produce different RNA transcripts and subsequently proteins with very different functions. It has also been hypothesized that MALAT1 may activate metastasis by turning on cell motility genes.
In a paper recently published in Cancer Research, a team of scientists led by Sven Diedrichs reported finding the latter hypothesis to be true: that MALAT1 induced the activation of genes associated with metastasis, and suppressed genes inhibiting metastasis. They found no support for the alternative splicing hypothesis.
They obtained these results by inserting sequences into the MALAT1 genome region marking MALAT1 transcripts for degradation, effectively eliminating all MALAT1 RNA from the cell. The effects of loss of MALAT1 in lung cancer cell cultures were compared to cells in which MALAT1 had not been lost. The variation between alternative splicing forms in both was insignificant, but the activity of several genes associated with metastasis was inversely correlated in the ‘normal’ and knockout cells. The ability of MALAT1 knockout cells to invade surrounding tissue was also significantly reduced when compared to cells retaining MALAT1.
To determine the effect of loss of MALAT1 in vivo, or in a living organism, the researchers then injected cancer cells with and without MALAT1 into mice. The cells with intact MALAT1 formed a greater number of tumors in the lungs of the injected mice than the cells without it, indicating that the metastatic ability of the tumors which developed from MALAT1 knockout cells was impaired.
Finally, the researchers wondered whether it would be possible to therapeutically suppress MALAT1 and, in doing so, inhibit cancer cell metastasis. They collaborated with
pharmaceuticals to create strands of RNA which complemented MALAT1 RNA, and
routinely injected these strands into mice which had also been injected with
human cancer cells. They anticipated that the complementary RNA would bind and
effectively silence MALAT1 transcripts in the cell. After five weeks they found
that the mice which had been given this treatment had fewer and smaller tumor
nodules when compared to mice that had not received the same treatment. These
results confirmed their initial findings, and are a promising platform for