Cancer Cells and Lipolysis: How Breast Cancer Steals Energy From Fat Cells

A paper published in Nature Communications shows a direct “communication line” between tumor cells and neighboring fat cells in the breast. The researchers found that gap junctions are formed between breast cancer cells and adipocytes, through which the messenger molecule cAMP passes from tumor cells into fat. This turns on lipolysis in nearby fat tissue, releasing fatty acids - fuel for the tumor. The key “connector” is the protein connexin-31 (Cx31, gene GJB3 ): when its level in triple-negative cancer (TNBC) is increased, the connection is stronger, lipolysis is more active and tumors grow more aggressively; when Cx31 is reduced, growth is inhibited. The authors demonstrate this using patient material, xenograft and co-culture models, and mice.

Background of the study

Breast cancer does not grow in a vacuum, but in a “block” of immune cells, fibroblasts, and especially adipose tissue. In recent years, it has become clear that adipocytes near the tumor (cancer-associated adipocytes) are not just decoration: they activate lipolysis, release free fatty acids, and thus feed cancer cells, enhancing their proliferation, migration, and resistance to stress. This metabolic traffic has been demonstrated both in co-cultures and in vivo, and reviews emphasize that the more fatty the microenvironment, the higher the chances that the tumor will switch to “fat fuel.”

In triple-negative breast cancer (TNBC), this lipid dependence is especially pronounced. Many studies link the aggressiveness of TNBC with increased oxidative utilization of fatty acids (FAO), and in the high MYC subtype, this is almost a “signature” of metabolism: fatty acids enter the mitochondria, feed the respiratory chain and support oncogenic signals (up to the activation of Src). Hence the interest in drugs that hit FAO, and in general - in breaking the “fat supply line” in the tumor microenvironment.

On the other side of the "wire" is the biochemistry of the fat cell. The classic scheme is as follows: the growth of cAMP in the adipocyte turns on PKA, which phosphorylates hormone-sensitive lipase (HSL) and associated proteins of the fat droplet (for example, perilipin), which triggers the breakdown of triglycerides. This cAMP→PKA→HSL/ATGL circuit is the central switch of lipolysis, well described in the physiology of adipose tissue. If there is a "consumer" nearby - an active tumor, free fatty acids almost immediately go to its needs.

A key missing piece of the puzzle is how exactly the tumor sends the “burn fat” command to neighboring adipocytes. One candidate is gap junctions: channels made of connexins through which cells directly exchange small molecules, including cAMP. In oncology, connexins behave in different ways - from a protective role to supporting invasion - and depend on the isoform and tissue context (Cx43, Cx26, Cx31, etc.). Therefore, the idea of a “wired” metabolic connection between cancer and fat has come to the fore: if a signal can be transmitted through gap junctions that turns on lipolysis right next to the tumor, this will explain the sustained fuel flow and open up new therapeutic targets (selective modulation of connexins, disruption of the “cancer↔fat” channel).

How was this tested?

The scientists first "looked at reality": they measured the tissue composition of 46 patients using the three-component mammographic technique (3CB) and compared the lipidity of normal tissue at different distances from the tumor (concentric "rings" within 0-6 mm). The closer to the tumor, the less lipids and smaller adipocytes - classic signs of included lipolysis. These observations were reinforced by protein and transcriptomic data: markers of cAMP-dependent lipolysis (phosphorylated HSL, etc.) are increased in the adipose tissue adjacent to the tumor.

The team then showed that the cancers indeed connect to adipocytes via functional gap junctions: in a dye-transfer assay between cells, the signal passed through, and the gap junction inhibitor carbenoxolone markedly reduced this transfer and caused cAMP to accumulate in the tumor cells, a sign that cAMP normally “leaks” through the channels into its neighbors. In coculture with primary adipocytes, a fluorescent analogue of cAMP passed from the tumor cells into fat, and this flow was attenuated when Cx31 was partially “switched off.” In response, the adipocytes turned on cAMP-dependent genes (such as UCP1), indicating activation of the pathway that leads to lipolysis.

Finally, in mouse models of TNBC, partial reduction of Cx31 levels in implanted tumor cells delayed tumor emergence and endpoint; markers of lipolysis fell in adjacent adipose tissue. A remarkable control: if lipolysis was pharmacologically triggered in such mice (the β3-adrenergic receptor agonist CL316243), the tumor onset delay disappeared – as if the cancer were being “fed” bypassing the blocked contacts. This is a strong causal thread between gap junctions → cAMP in fat → lipolysis → tumor growth.

The main thing is in one place

• Direct contact "cancer↔fat". Tumor cells form gap junctions with adipocytes, through which they transmit cAMP.
• Lipolysis near the tumor. In the adipose tissue adjacent to the tumor, lipolysis markers are elevated in patients and models, and adipocytes are smaller and poorer in lipids.
• The culprit is Cx31 (GJB3). Elevated Cx31 is associated with TNBC aggressiveness and increased lipolysis around it; decreased Cx31 slows tumor growth in vivo.
• MYC-high TNBC are more vulnerable. TNBC lines with high MYC levels are more sensitive to gap junction blockade, which highlights the metabolic dependence of such tumors.
• Functional verification: Artificially turning on lipolysis in mice compensates for the loss of Cx31 - that is, lipid flow from fat actually feeds the tumor.

Why is this important?

Breast tumors almost always grow in a “sea” of fat. It has long been known that TNBC readily “burns” on fatty acid oxidation; the question remained: how does cancer systemically connect to a fuel source? The new work adds the missing piece: not only “long-range chemistry” (cytokines/hormones), but also “near-range communication” via gap junctions. This changes the view of the tumor microenvironment and opens up new therapeutic points - from Cx31/gap junction inhibitors to disrupting the lipid “bridge” on the fat side.

A little deeper into the mechanics

Gap junctions are nanochannels between neighboring cells, assembled from connexins (in this case, Cx31). They let through small signaling molecules, including cAMP. When cancer "throws" cAMP into an adipocyte, the latter receives the signal as a command to "burn fat": hormone-sensitive lipase (HSL) and other enzymes are activated, triglycerides are broken down into free fatty acids, which are immediately taken up and oxidized by the tumor. The result is not just a neighborhood, but a metabolic symbiosis.

What this might mean for treatment - ideas that come to mind

• Block the communication "wire".
  • development of selective Cx31 inhibitors or modulators of gap junctions in tumors;
  • local strategies to avoid “switching off” beneficial contacts in healthy tissues.
• Shut off the fuel.
  • target lipolysis in adjacent fat (beta-adrenergic axis),
  • target fatty acid oxidation in tumors (FAO inhibitors), especially in MYC-high TNBC.
• Diagnosis and stratification.
  • assessment of GJB3 /Cx31 expression in tumor;
  • visualization of the lipid gradient around the tumor (3CB/dual-energy mammography) as a marker of active fuel "pumping".

Important limitations

This is mostly preclinical work: there is no confirmation in the form of randomized clinical trials of Cx31 targets yet. Carbenoxolone is a pan-gap junction inhibitor and is not suitable as a precise clinical tool; selectivity must be sought. Associations (lipid gradients, markers) have been shown in patient tissues, and causal relationships have been proven in models; tolerability of interventions in real oncology requires a separate pathway. Finally, several families of connexins are expressed in tumors, and Cx31 is probably one of several players.

What will science do next?

• Mapping connexins in cancer: Deciphering the contribution of other GJB families to the tumor “fat connectome.”
• Targets and tools: Design selective Cx31 blockers and test them in combination with FAO inhibitors/chemotherapy in MYC-high TNBC.
• Clinic "next door". Check if there are similar "cancer↔fat" contacts in other tumors growing near fat depots (ovaries, stomach, omentum).

Research source: Williams J. et al. Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis. Nature Communications, August 20, 2025. https://doi.org/10.1038/s41467-025-62486-3