CRISPR-Engineered Fat Cells Show Promise in Preclinical Cancer Models

Cancer is rarely discussed alongside liposuction or plastic surgery. However, a groundbreaking approach to cancer treatment is drawing inspiration from these procedures by using engineered fat cells to starve tumors of essential nutrients.

Researchers at the University of California, San Francisco (UCSF) leveraged the gene-editing tool CRISPR to convert ordinary white fat cells into "beige" fat cells, known for their ability to burn calories to generate heat. They then implanted these modified fat cells near tumors, much like plastic surgeons transfer fat from one area of the body to another for cosmetic enhancement. The engineered fat cells absorbed key nutrients, effectively starving tumor cells. Remarkably, the therapy worked even when the fat cells were implanted far from the tumors in mice.

This innovative approach could accelerate the adoption of fat-cell-based therapies, as fat cells are routinely extracted and reinjected in medical procedures. "These fat cells can be easily manipulated in the lab and safely placed back into the body, making them an attractive platform for cellular therapy, including for cancer," said Nadav Ahituv, PhD, study senior author and professor at UCSF. The study was published in Nature Biotechnology.

Cold Therapy Sparks a New Idea

Ahituv and his then-postdoctoral researcher, Hai Nguyen, PhD, were inspired by studies showing that exposure to cold could suppress cancer in mice. One case even suggested cold therapy might have helped a patient with non-Hodgkin lymphoma. Scientists believe this effect occurs because cold activates brown fat cells, which burn nutrients to produce heat, depriving cancer cells of sustenance.

However, cold therapy isn't a viable option for many cancer patients due to their fragile health. This led Ahituv and Nguyen to explore whether beige fat could be engineered to burn calories and starve tumors without requiring cold exposure.

Nguyen used CRISPR to activate genes typically dormant in white fat but active in brown fat, searching for those that could transform white fat into highly active beige fat. The key candidate was a gene called UCP1. Nguyen then grew UCP1-engineered beige fat cells in a petri dish alongside cancer cells, separated by a barrier that forced them to share nutrients without direct contact. The results were astonishing.

"In our very first experiment, almost no cancer cells survived. We thought we had made a mistake," Ahituv recalled. "But after repeating it multiple times, we kept seeing the same effect."

The engineered beige fat cells proved effective against multiple cancer types, including breast, colon, pancreatic, and prostate cancers.

Cancer is No Match for Hungry Fat

Encouraged by their initial findings, the researchers tested whether beige fat cells could work in a more realistic setting. Using fat organoids—clusters of cells grown in a dish—they implanted the engineered fat cells near tumors in mice. The approach successfully suppressed breast, pancreatic, and prostate cancer cells as the fat cells outcompeted the tumors for nutrients.

In genetically engineered mice predisposed to developing pancreatic and breast cancer, the beige fat cells significantly slowed tumor growth, even when implanted far from the tumor site.

To test the therapy in human tissue, the team collaborated with UCSF breast cancer specialist Jennifer Rosenbluth, MD, PhD. Rosenbluth provided mastectomy samples containing both fat and cancer cells. The researchers modified fat cells from the same patient and tested them against their own breast cancer cells in a trans-well experiment.

"Because the breast naturally contains a lot of fat, we could take fat from the same patient, modify it, and test it against their own cancer cells," Ahituv explained. The results were promising both in petri dishes and when implanted in mouse models.

Recognizing that different cancers have distinct nutritional dependencies, the team also engineered fat cells to target specific nutrients. For example, some pancreatic cancers rely on uridine when glucose is scarce. By programming the fat cells to consume uridine, they outcompeted the cancer cells, demonstrating that fat cells could be tailored to target various cancer types.

A New Approach to Living Cell Therapy

Ahituv highlighted several advantages of using fat cells for living cell therapies. They are easy to extract from patients, thrive in laboratory conditions, and can be genetically modified to perform specific functions. Once reintroduced into the body, they stay localized to the implantation site and interact well with the immune system—a conclusion supported by decades of plastic surgery experience.

"With fat cells, there is minimal concern about them migrating elsewhere in the body and causing problems," Ahituv noted.

Beyond cancer treatment, fat cells could be programmed for other medical applications. "We believe these cells could be designed to sense glucose and release insulin for diabetes, or absorb excess iron in conditions like hemochromatosis. The possibilities are vast," Ahituv said.

This innovative approach opens new doors for cellular therapy, offering a promising strategy not just for cancer but potentially for a range of metabolic and genetic diseases.