Liposuction and cosmetic procedures may not typically be linked with cancer discussions, yet they have inspired a groundbreaking method to combat the disease by utilizing engineered fat cells to starve tumors of their nutrients. At UC San Francisco, researchers employed the advanced CRISPR gene-editing technique to convert standard white fat cells into ‘beige’ fat cells that eagerly expend calories as heat.
Researchers transformed traditional energy-storing white fat cells into calorie-burning ‘beige’ fat. These cells, once implanted, competed with tumors for essential resources, effectively reducing five different cancer types in laboratory tests.
Liposuction and cosmetic surgery might not usually be associated with cancer.
However, they have served as inspiration for an innovative cancer treatment involving engineered fat cells designed to starve tumors.
Researchers at UC San Francisco harnessed the power of CRISPR gene-editing technology to convert regular white fat cells into ‘beige’ fat cells, which are known for their ability to burn calories for heat production.
Subsequently, these altered cells were injected near tumors, akin to how plastic surgeons use fat from one body area to enhance another. The beige fat cells absorbed available nutrients, leading to the starvation and eventual death of most tumor cells. Remarkably, this method proved effective even when the fat cells were placed far from the tumors in mice.
Utilizing familiar medical procedures paves the way for this approach to become a viable form of cellular therapy sooner rather than later.
“We regularly remove fat using liposuction and reinject it in plastic surgeries,” explained Dr. Nadav Ahituv, the director of the UCSF Institute for Human Genetics and a professor in the Department of Bioengineering and Therapeutic Sciences. He is the senior author of a study published on February 4 in Nature Biotechnology.
“These fat cells can be easily modified in a lab setting and safely reintroduced into the body, making them a compelling option for cellular therapies, including for cancer.”
Beige fat cells outperform cancer cells in nutrient competition
During their research, Ahituv and his post-doc Hai Nguyen, PhD, recognized previous studies indicating that cold exposure could inhibit cancer growth in mice.
In one notable study, cold therapy even seemed to assist a patient with non-Hodgkin lymphoma, as scientists concluded that thyroid cells activated by the cold were starving the cancerous cells by utilizing nutrients to generate heat.
However, cold therapy is not a feasible option for cancer patients with delicate health statuses.
Consequently, Ahituv and Nguyen explored the potential of engineered beige fat, hypothesizing that they could stimulate enough calorie burning, even without cold exposure, to inhibit tumor growth.
Nguyen, the lead author of the study, utilized CRISPR to activate genes dormant in white fat cells but active in brown fat cells, seeking to identify those that would transform white fat into the most calorie-hungry beige fat cells.
They discovered that a gene known as UCP1 was particularly effective.
Nguyen then cultured UCP1 beige fat cells alongside cancer cells in a specially designed ‘trans-well’ setup. The cancer cells resided below while the fat cells were housed in an upper compartment, separated yet sharing the same nutrient source.
The results were astonishing.
“In our initial trans-well test, very few cancer cells survived. Initially, we thought we had made a mistake – we were convinced it was an error,” Ahituv recalled. “But after repeating the experiment multiple times, we consistently observed the same outcome.”
The beige fat cells effectively suppressed two varieties of breast cancer cells, in addition to colon, pancreatic, and prostate cancer cells.
Despite these results, researchers were unsure if the implanted beige fat cells would demonstrate similar efficacy in more realistic scenarios.
Fat cell therapy shows promise against various cancers in the lab
To validate their theory, the team utilized fat organoids, compact cell clusters grown in a lab, to see if they could outcompete tumor cells when implanted near tumors in mice.
This technique proved successful against breast cancer alongside pancreatic and prostate cancer. The cancer cells perished as the beige fat cells consumed all the nutrients.
The beige fat cells were so effective that they inhibited both pancreatic and breast tumors in genetically predisposed mice, even when placed far from the cancerous cells.
To explore their effectiveness with human tissue, Ahituv and Nguyen collaborated with Dr. Jennifer Rosenbluth, a breast cancer expert at UCSF. Rosenbluth had compiled a library of breast cancer surgeries that included both fat and cancer cells.
“Since breast tissue contains a substantial amount of fat, we could extract fat from the same patient, modify it, and conduct a single trans-well experiment using that patient’s own breast cancer cells,” explained Ahituv.
These same-patient beige fat cells successfully outperformed breast cancer cells in both petri dishes and when implanted into mouse models.
Considering that different cancers have distinct nutrient preferences, the researchers tailored fat cells specifically to consume certain nutrients. For instance, particular pancreatic cancer types rely on uridine when glucose levels are low.
They engineered fat cells to specifically target uridine and efficiently surpassed these pancreatic cancer cells, indicating that fat cells can be customized to suit any cancer’s dietary needs.
A novel method for living cell therapy
Ahituv highlights several advantages of using fat cells for living cell therapies.
These cells are easily harvested from patients, grow well in laboratory conditions, can be genetically modified to perform various tasks, and tend to stay localized when reintroduced into the body, minimizing potential issues with the immune system.
This is evidenced by extensive advancements in the field of plastic surgery over the years.
“Fat cells have minimal interaction with their environment, reducing the risk of cells dispersing throughout the body and causing complications,” stated Ahituv.
Moreover, fat cells can be engineered to emit signals or undertake more intricate biological functions.
Their capability to combat cancer even when they are not immediately adjacent to tumors could be particularly valuable for addressing difficult-to-treat cancers like glioblastoma, which targets the brain, or a range of other diseases.
“We believe these cells could be engineered to detect glucose levels in the bloodstream and release insulin to address diabetes, or to absorb excess iron in conditions like hemochromatosis,” Ahituv added. “The possibilities for these fat cells are vast.”
