A colorectal cancer cell lacking the Ku protein complex (red) sits inside an enlarged cancer cell with the same deficiency (green).
Nurten Saydam

Some cells in a tumor feed off others to help them survive and possibly metastasize, according to a report published March 29 in Frontiers in Cell and Developmental Biology. The authors say this occurs when a DNA repair protein complex is disabled in cancer cells, a deficiency that kills the cells unless they invade neighboring tumor cells and gather cytoplasmic material. They report that this is the first evidence, to their knowledge, that cancer cells can become parasitic in the absence of a critical gene.

“Despite the interesting and thought-provoking results, the study is still a proof of concept. More experiments are needed to verify this finding,” Jawad Fares, a neuro-oncology fellow at the Northwestern Feinberg School of Medicine, writes in an email to The Scientist.

Okay Saydam and Nurten Saydam, molecular biologists at the University of Minnesota, sought to learn how cancerous cells adapt to the loss of the Ku protein complex, which helps DNA repair itself and is critical to cell survival. They used a colorectal cancer cell line engineered with this deficiency, which gradually knocked out the Ku70 protein, resulting in depletion of both parts of the Ku complex, Ku70 and Ku86. They then studied the movement of these Ku-deficient cancer cells under a microscope and compared their activity to parental cancer cells with their Ku protein intact.

After 10 days without the Ku complex, around 80 percent of the cancer cells had died. Those that survived grew larger and generated strikingly elongated membranes. Some Ku-deficient cells ended up fully within adjacent colorectal cancer cells that also lacked Ku, although the exact rate of absorption was unquantified. Live cell imaging for 48 hours showed that the surviving cancer cells were able to enter these hosts and exit intact. The Saydams plan to conduct other experiments to see if similar results occur when other DNA repair proteins besides Ku are absent.

“The deficiency of Ku created a specific cell type with an ability to attack the neighboring cells, inhabit the neighboring cells and exit from the neighboring cells,” says Nurten Saydam in an email to The Scientist.

Watch a Ku70-deficient colorectal cancer cell (green, followed by the yellow arrow) exit one cell, then enter two others in sequence. Scale bar 25 µm
O. Saydam, N. Saydam, "Deficiency of Ku induces host cell exploitation in human cancer cells," Front Cell Dev Biol, 9:651818. doi:10.3389/fcell.2021.651818, 2021.

“I really think the cooption of a host cell, leading to these strange structures that they found, was exciting and not something that I’ve seen under the microscope, probably because we haven’t looked at these DNA-damaging mutations,” says Daniele Gilkes, a cancer biologist at the Johns Hopkins School of Medicine.

Gilkes notes that all the cells in this study were cancerous, making it impossible to glean the interaction between different cell types. “I’d be interested in knowing if the Ku70-depleted cells could affect adjacent normal cells, because I would kind of see that more as coopting your host.”

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The researchers also studied so-called DAOY cells, which in humans can lead to medulloblastoma, a cancerous brain tumor that begins in the cerebellum. They report that these cells lack both Ku70 and Ku86 in their nucleus, where they would be in a normally functioning cell, but instead had these proteins in the cytoplasm. This mislocation of the Ku proteins in the DAOY cells resulted in protruding membranes and cellular invasions similar to those seen in the genetically engineered colorectal cancer cells.

“Parasites go into the cell. They hide there. And then when everything is all over, they can come out and grow much better,” says Nurten Saydam in a phone interview. Her hypothesis is that the parasitic behaviors she observed allow for cancerous cells to adapt to genetic stresses in their microenvironment and ultimately metastasize.

Gilkes cautions that the time scale in the study was too short to ascertain if protein deficiencies in cancer cells will lead to metastasis. One possible way to verify this, Gilkes suggests, would be to build a mouse cancer model missing the Ku proteins and then look for damage to the animals’ organs over time.

“The Ku70 depletion doesn’t necessarily lead to metastasis, [but] it could lead to tumor progression,” Gilkes says. “The connection to metastasis is the next step.”

O. Saydam, N. Saydam, “Deficiency of Ku induces host cell exploitation in human cancer cells,” Front Cell Dev Biol, doi:10.3389/fcell.2021.651818, 2021.