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Bacteria Detect DNA Shed by Colon Cancer Tumors in Mice

Computer-generated image the gut and gut microbes.
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Engineered bacteria can detect tumor DNA shed by colon cancers into the gastrointestinal (GI) tract in mice, creating the potential for their use as biosensors to detect and respond to disease. The research is published in Science.

Bacteria as biosensors

Some bacterial species can take up DNA from other bacteria in a process called horizontal gene transfer. This allows them to “pickpocket” useful pieces of DNA that aid their survival, like genes conferring resistance to antibiotics. Many bacteria can also take up DNA from their environment, an ability called natural competence.

Previous studies have shown that bacteria can be used in diagnostic and therapeutic applications, including microbes that can respond to gut inflammation or bleeding. However, researchers have been unable to use bacteria to detect specific DNA sequences and mutations outside of cells.

Tumors shed DNA into their surrounding environment, such as the blood, or, for colorectal cancers, into the digestive tract. This is known as cell-free DNA (cfDNA). Such fragments can be detected in the blood and analyzed using a technique called liquid biopsy, shedding light on the genetic characteristics of tumor cells without the need for invasive tissue biopsies.

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In the current study, researchers investigated if they could engineer bacteria that reside in the colon to sense DNA released from colorectal tumors. They developed a new technique called CATCH (cellular assay for targeted CRISPR-discriminated horizontal gene transfer), using it to engineer bacteria using gene-editing CRISPR technology to detect and take up tumor DNA in the colon.

Detection of cancer-associated gene mutations

“There is so much potential to engineer bacteria to prevent colorectal cancer, a tumor that is immersed in a stream of bacteria, that could help, or hinder, its progression,” said Dr. Susan Woods, one of the senior authors of the study and a biomedical scientist at the South Australian Health and Medical Research Institute (SAHMR).

The researchers focused their efforts on a bacterial species called Acinetobacter baylyi that is well known for its horizontal gene transfer abilities and largely non-harmful to humans. They aimed to apply the concept of horizontal gene transfer from tumor DNA into bacteria rather from bacterium to bacterium.

“Knowing that cfDNA can be mobilized as a signal, or an input, we set out to engineer bacteria that would respond to tumor DNA at the time and place of disease detection,” said Dr. Dan Worthley, gastroenterologist and cancer researcher at the Colonoscopy Clinic in Brisbane, Australia and co-senior author of the study.

A. baylyi bacteria were modified using CATCH to detect DNA from a gene called KRAS, which is commonly mutated in colorectal cancers, giving them the ability to discriminate the normal gene from the mutated gene. This way, only the bacteria that took up mutated KRAS would survive to signal or respond to the disease.

The engineered bacteria were tested in lab-grown colorectal cancer cells and organoids as well as mouse models, with the successful tumor DNA-detecting bacteria acquiring antibiotic resistance.

“It was incredible when I saw the bacteria that had taken up the tumor DNA under the microscope. The mice with tumors grew green bacterial colonies that had acquired the ability to grow on antibiotic plates,” said study co-author Dr. Josephine Wright, senior research fellow in the Gut Cancer Group at SAHMR.

Developing the technique further

Despite the success of this technique in lab models, the researchers note that the “technology is not yet ready for clinical application.” Further optimization and refinement are required to develop it into a suitable biosensor for clinical care.

“As we started on this project four years ago, we weren’t even sure if using bacteria as a sensor for mammalian DNA was even possible,” said Jeff Hasty, a professor in the UC San Diego School of Biological Sciences and Jacobs School of Engineering. “The detection of gastrointestinal cancers and precancerous lesions is an attractive clinical opportunity to apply this invention.”

“There’s a future where nobody need die of colorectal cancer,” added Worthley. “We hope that this work will be useful to bioengineers, scientists and, in the future, clinicians, in pursuit of this goal.”

Reference: Cooper RM, Wright JA, Ng JQ, et al. Engineered bacteria detect tumor DNA. Science. 2023. doi: 10.1126/science.adf3974

This article is a rework of a press release issued by the University of California, San Diego. Material has been edited for length and content.