Shining a (laser) light on the ancestry of cancers


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Fluorescence colonoscopy shows some tumors are all red or green (left, right) or a mix (middle). Credit: Chris Zahm and Rich Halberg in PLoS ONE

In any research field, shifting a paradigm is never easy. If you’re going to try, it never hurts to continuously improve your techniques and evolve your models. And, use lasers.

Rich Halberg, associate professor of medicine at the UW Carbone Cancer Center, has spent over a decade challenging the tenet of cancer biology that tumors arise from one rogue cell gone bad.

“If I show you the textbooks, every single one says that tumors are monoclonal, that they arose from one cell,” Halberg says. “We’ve shown that in many cases, these tumors are multi-ancestral; that a single founder recruits its neighbors to become part of the tumors.”

In a study published in the journal PLoS ONE, Halberg and colleagues developed a new mouse model of colorectal cancer that not only confirmed their previous findings – that roughly half of colon tumors arise from more than one cell – but it also allows them to answer questions about how multi-ancestral tumors form, how they are maintained and how to treat them in a clinical setting.

As in a previous colorectal cancer mouse model used by Halberg, these mice are genetically predisposed to developing approximately a dozen colon polyps (which include pre-cancerous lesions and cancers) by six months of age. However, beginning early in development, these new mice either express a green fluorescent protein or a red one in their colon cells. By performing what amounts to a fluorescent colonoscopy, the researchers could observe the fluorescence pattern of whole polyps.

“These mice allowed us to see the cell lineages of colon tumors in the mouse without first doing microscopy,” says Chris Zahm, a former graduate student in the Halberg lab and lead author of the study.

Adds Halberg, “In about half the polyps, we saw, for example, discrete regions of green cells within a red region, indicating there may be up to four or five green cells recruited to a red founder.”

The use of fluorescent proteins also allowed the researchers to recreate a three-dimensional image of intact tumor structure – once they developed a custom-built microscope that could perform the task. That’s how co-author Joe Szulczewski, a UW LOCI (Laboratory for Optical and Computational Instrumentation) graduate student got involved.

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3-D microscopy image of an intact colon polyp. Credit: Chris Zahm and Rich Halberg in PLoS ONE

“Joe basically built the microscope and discovered that we could image both red and green fluorescence at the same time using a powerful laser, which allowed us to image deeper into tissue than had been done before.” says Zahm. “This paper is the first successful imaging of the full depth of an intact intestinal tumor.”

Halberg says the other advantage of the new mice is that they can visualize the fluorescent tumors and then perform further studies on the cells.

“Our previous mouse model eliminated any further molecular analyses because we had to kill the cells to visualize tumor lineages,” Halberg says. “We can now use living cells, which we need because we’re interested in the origins of cancer and we want to identify the signals that allow these founder cells to ‘talk’ to and recruit other cells.”

Multi-ancestry is not unique to colorectal cancer, and over 20 other cancer types have been shown to also arise from multiple founders. Halberg is collaborating with other researchers on campus to study the multi-ancestor origins of liver and prostate cancer, as well.