Disrupting cancer cell-fat cell interactions prevents metastasis in ovarian cancers

spreading cancer cells

Advanced cancers spread from their site of origin, a process known as metastasis. In ovarian cancer, fat cells adjacent to cancer cells reprogram the glucose metabolic pathway through hypoxia-inducible factor (HIF) 1α to promote metastasis, according to a study published in the September 2023 issue of Nature Metabolism.

Researchers at the University of Chicago Medicine Comprehensive Cancer Center set out to understand how abdominal cancers spread and how cancer cells rely on/deploy energy sources like sugar and fat to survive.

“We are specifically interested in metastatic ovarian cancers, as patients come in with heavily metastatic disease, and there is no therapeutic means to target metastatic diseases,” said first author Abir Mukherjee, PhD, Pathways to Independence Instructor of Obstetrics and Gynecology at UChicago Medicine. “Targeting cancer cells in adipose tissue may be beneficial to these patients.”

Interaction between cancer cells and adipocytes

A large fat pad called the omentum is the primary metastatic site for cancers in the abdomen cavity. These include gastric, colorectal and ovarian cancers.

As tumors grow, the new cancer cells utilize glucose as a chief carbon source to synthesize various cellular structures. For example, lipids, a fat required for the synthesis of cell membranes, is primarily drawn from metabolized glucose.

“We are interested in understanding the interaction between cancer cells and fat cells (adipocytes) and how glucose is utilized in the fat-rich microenvironment as in the case of metastasis to the omentum,” said Mukherjee.

Understanding how tumor cells interact with their environment will allow us to find better, more efficient treatments for cancer.

Senior author Ernst Lengyel, MD, PhD, Professor and Chair of Obstetrics and Gynecology at UChicago Medicine, has published studies demonstrating how ovarian cancer cells utilize lipids from neighboring adipocytes. Lengyel’s ovarian cancer research lab has ongoing interest in understanding how cancer cells process excess lipids, which are toxic to cells.

He and his colleagues are also interested in how cancer cells adapt in a fat-rich microenvironment.

Cancer cells reprogram glucose metabolism

When cancer cells from ovarian cancer patients were grown along with adipocytes, researchers noticed an increased rate of glucose metabolism, or glycolysis, in ovarian cancer cells. These cells accumulated a large amount of triglycerides and phospholipids in the form of lipid droplets.

This was not the case when the cancer cells were grown without adipocytes. The question: What is the source of these triglycerides and phospholipids?

To solve the puzzle, researchers conducted a carbon tracing experiment where cancer cells were fed with glucose labeled with a non-radioactive heavy isotope. They found that the carbons in the glucose were redirected to make triglycerides and phospholipids.

When the researchers imaged the tumor samples from the omentum, they saw phospholipids in the cancer cells adjacent to the adipocytes.

“These findings were interesting for us because this reprogramming was not very well-studied and we tried to figure out the functional consequence of this altered use of glucose,” said Mukherjee.

The researcher found that HIF-1α gene inhibition resulted in reduced phospholipid and triglyceride accumulation in ovarian cancer cells grown with adipocytes. HIF-1α inhibition restricted cancer spread in mouse models of metastatic ovarian cancer.

“Understanding how tumor cells interact with their environment will allow us to find better, more efficient treatments for cancer,” Lengyel said.

Adipocytes reprogram cancer cell metabolism by diverting glucose towards glycerol-3-phosphate thereby promoting metastasis” was supported by an R35 National Cancer Institute Outstanding Investigator Award to Lengyel, and the Ann and Sol Schreiber Award from the Ovarian Cancer Research Alliance and the Department of Defense OCRP Pilot Award to Mukherjee.

Additional authors include Malu Zandbergen, BASc, Chun-Yi Chiang, MS, Medine Tasdemir, BS, and Brandon Faubert, PhD, from the University of Chicago; Divya Bezwada, PhD, Hieu Vu, PhD, and Ralph DeBerardinis, MD, PhD, from the University of Texas Southwestern Medical Center; Francesco Greco, PhD, MSc, and Liam A. McDonnell, PhD, MChem, from Sant’Anna School of Advanced Studies in Italy; Tong Shen, PhD, Dmitry Grapov, PhD, Michael La Frano, PhD, John W. Newman, PhD, and Oliver Fiehn, PhD, from the University of California, Davis; Johannes Fahrmann, PhD, from The University of Texas MD Anderson Cancer Center; and Luigi Nezi, PhD, MMB, from the European Institute of Oncology in Italy.

Medical oncologist Sonali Smith, MD, and lymphoma patient Clayton Harris

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