To creep into distant parts of the body, some cancer cells have developed a knack for shapeshifting – morphing on command to squeeze into the body’s nooks and crannies. Now, scientists at the Johns Hopkins Kimmel Cancer Center have identified the gene target that confers this ability to prostate cancer cells.
Metastasis is, arguably, the most dangerous part of cancer. This is the ability of cancer to spread from the primary site to secondary organs. Indeed, about 90 percent of cancer-related deaths are attributed to metastatic events, which severely impede the effectiveness of anticancer therapies.
In studying prostate cancer cells, researchers noticed a unique pattern for a gene known as AIM1 ( also known as “absent in melanoma 1”). This gene seemed to be deleted in more prostate cancers (about 40 percent) that have spread. Furthermore, compared to prostate cancer that’s localized, the level of AIM1 expression is about two- to four times lower in metastatic prostate cancer. The observations suggest that cancer migration is somehow tied to reduced levels of AIM1.
“Our experiments show that loss of AIM1 proteins gives prostate cancer cells the ability to change shape, migrate and invade. These abilities could allow prostate cancer cells to spread to different tissues in an animal and presumably a person,” says Michael Haffne, a former postdoctoral fellow at the Johns Hopkins Kimmel Cancer Center, and the study’s lead author. “It’s not the whole story of what is going on in the spread of prostate cancer, but it appears to be a significant part of it in some cases.”
Closer analysis of AIM1’s presence in tumor cells revealed differences in the protein’s location within the cell types. For example, in normal prostate cells, AIM1 was found to accompany another protein, beta-actin, on the outside periphery of the cell. By contrast, in prostate cancer cells, AIM1 did not accompany beta-actin, and was not at the cells’ outer borders.
“It appears that when AIM1 protein levels drop, or when it’s abnormally spread throughout the cell instead of confined to the outer border, the prostate cancer cells’ scaffolding becomes more malleable and capable of invading other tissues,” says Vasan Yegnasubramanian, an associate professor at the Kimmel Cancer Center and a member of the research team, and the study’s senior author.
The team hypothesized that AIM1 helps cells maintain rigidity and structural integrity. In the absence of the AIM1 protein, the cancer cells are free to morph into different shapes. This malleability may be why these cells can migrate to distant parts of the body.
The team was able to confirm their suspicions in quantitative single-cell analyses, and in mouse studies. In mice implanted with prostate cancer cells lacking AIM1, the cancer spread up to 100 times higher than those implanted with cells with normal AIM1 levels. They observed that although AIM1 allowed cancer cells to spread, they did not colonize at distant parts of the body. This suggests players, other than AIM1, are involved.
“AIM1 may help prostate cancer cells disseminate throughout the body, but something else may be helping them form full-blown metastatic tumors when they get there,” says Yegnasubramanian.
The team hopes further investigations will reveal more tricks that cancer cells use to metastasize. Knowing these tricks could translate into drug targets that will prevent or reverse metastasis.