Fat-Fuelled Tumours: How Lipid Droplets Drive Colorectal Cancer Aggression

Colorectal cancer remains one of the most formidable health challenges of our time, ranking as the third most common cancer worldwide and carrying the second highest mortality rate of any malignancy. Up to 75 percent of cases are attributable to modifiable lifestyle factors, including smoking, excessive alcohol consumption, high intake of red or processed meat, physical inactivity and diets rich in fat. Among these, obesity stands out as one of the most important preventable risk factors, and it is not merely a matter of cancer initiation. Extensive epidemiological evidence shows that obesity is also associated with colorectal cancer progression, poorer prognosis and higher death rates in patients already diagnosed with the disease. A new study published in the Journal of Cellular and Molecular Medicine now offers a detailed mechanistic explanation for this connection, demonstrating that an abundance of circulating fatty acids can be taken up by colorectal cancer cells, stored in lipid droplets and converted into a driving force for more aggressive tumour behaviour.

The research team, based at Friedrich-Alexander Universität Erlangen-Nürnberg, designed an in vitro model that closely mimics the metabolic environment found in obese patients. In obesity and the metabolic syndrome, hyperlipidemia is a defining feature: free fatty acids released from adipose tissue circulate in the bloodstream, predominantly bound to albumin. To replicate these conditions in the laboratory, the researchers incubated six human colorectal cancer cell lines with oleic acid complexed to bovine serum albumin. The panel included three microsatellite stable lines, HT29, Caco-2 and SW480, and three microsatellite instable lines, SW48, LoVo and HCT116, each with distinct molecular backgrounds and driver mutations. Oleic acid was chosen deliberately, as it represents approximately 80 percent of the circulating monounsaturated fatty acids in human blood, making it a physiologically relevant exposure variable.

The results were striking. Within 48 hours of exposure, the cells accumulated triglycerides in a dose-dependent manner, and oil red O staining revealed the formation of abundant cytosolic lipid droplets. At the same time, the concentration of free fatty acids in the culture supernatant declined over time, confirming that the cancer cells were actively taking up the fatty acids from their surroundings. A key molecular marker of this process was perilipin-2, or PLIN2, a structural protein component of lipid droplets. Both the mRNA and protein levels of PLIN2 rose dose-dependently in the treated cells, and immunofluorescence staining visualised the enhanced formation of lipid droplets in the cytoplasm. Similar findings were observed across all six cell lines, suggesting that this lipid storage response is not restricted to a particular molecular subtype of colorectal cancer and operates independently of microsatellite stability status.

Beneath this visible lipid accumulation, the researchers documented a profound reprogramming of lipid metabolism. When exogenous fatty acids flooded the cells, the expression of enzymes responsible for de novo lipid synthesis declined. ATP citrate lyase, or ACLY, which generates cytosolic acetyl-CoA from citrate to provide building blocks for new fatty acids, showed slightly reduced mRNA expression, and fatty acid synthase, FASN, was downregulated in a dose-dependent manner. Stearoyl-CoA desaturase 1, SCD1, the key enzyme for desaturating saturated fatty acids, was also reduced, fitting with the abundant supply of monounsaturated oleate arriving from outside. In contrast, diacylglycerol-O-acyltransferase 2, DGAT2, a central enzyme of triglyceride synthesis, was increased in HT29 and Caco-2 cells, consistent with the elevated triglyceride levels. The cells, in effect, switched from manufacturing their own fat to importing and storing it.

The study also revealed an upregulation of the machinery for burning fat. Carnitine palmitoyltransferase 1A, CPT1A, the rate-limiting enzyme that shuttles long-chain fatty acids into mitochondria for beta-oxidation, increased dose-dependently at both mRNA and protein levels. Adipose triglyceride lipase, ATGL, which catalyses the first step of intracellular triglyceride hydrolysis, rose in five of the six cell lines, and the lipolytic enzymes HSL and MAGL were also elevated at the mRNA level in HT29 cells. However, functional mitochondrial stress tests painted a more nuanced picture. Oleate treatment produced only slight, statistically non-significant increases in basal respiration, and while the CPT1 inhibitor etomoxir reduced maximal respiration in HT29 cells, Caco-2 cells showed no comparable response. The authors suggest that elevated CPT1A may reflect an enhanced capacity or adaptive readiness for fatty acid oxidation, while most imported fatty acids are actually channelled into storage within lipid droplets rather than immediately combusted.

The most consequential findings concern what this lipid loading does to cancer cell behaviour. Proliferation increased dose-dependently in oleate-stimulated cells, and migratory activity, measured in Boyden chamber assays, was significantly enhanced. At the molecular level, the researchers observed a classic cadherin switch: expression of E-cadherin, the adhesive molecule that stabilises junctions between epithelial cells, was downregulated, while N-cadherin expression rose. This shift is strongly linked to greater migratory and invasive capability, as loss of E-cadherin allows cancer cells to detach from the primary tumour site. The epithelial-mesenchymal transition markers SNAIL and TWIST were also increased in HT29 cells, although these changes were more variable across the other lines. Notably, the proinflammatory cytokine interleukin-8, a marker associated with proliferation, angiogenesis, metastasis and poor outcome in colon carcinoma, increased dose-dependently in four of the six cell lines, hinting that lipid accumulation may fuel inflammatory signalling within the tumour.

To connect these laboratory observations with clinical reality, the team analysed tumour tissue from colorectal cancer patients of normal weight, with body mass index between 20 and 25, and patients with Grade I or II obesity, with BMI between 30 and 40. Obese patients showed a tendency toward higher PLIN2 expression, although the difference did not reach statistical significance in this relatively small cohort. Immunohistochemistry, however, told a clearer story: PLIN2 staining was markedly stronger in tumours from obese patients, and Ki67 staining revealed a higher number of proliferating cells in the tumours of the obese group. In silico analysis of large patient cohorts added a prognostic dimension, showing that high PLIN2 expression correlated with poorer overall and disease-free survival in colorectal carcinoma patients.

Perhaps most intriguing was the significant correlation, observed across 350 human colorectal cancer tissues from The Cancer Genome Atlas, between PLIN2 and CPT1A expression, mirroring the relationship seen in vitro. Patients with high CPT1A expression likewise showed poorer overall and disease-free survival. This association suggests that lipid storage and the capacity for fatty acid oxidation are coordinately regulated in human tumours, consistent with a state of heightened lipid flux. The authors caution that further experiments are needed to establish a causal relationship between the two proteins, and that BMI is only an indirect marker of metabolic status, since it does not directly reflect circulating free fatty acid concentrations. Functional studies and larger, independently validated cohorts incorporating detailed metabolic phenotyping will be required to confirm the clinical relevance of these findings.

The broader implications of this work extend well beyond the culture dish. The study positions exogenous fatty acid uptake as a third route, alongside de novo lipogenesis and lipolysis, by which cancer cells satisfy their high demand for fat, and one that may be particularly important in obesity-associated hyperlipidemia. The findings also resonate with related research across gastrointestinal cancers: recent work in pancreatic ductal adenocarcinoma demonstrated a functional connection between PLIN2 and CPT1A in regulating lipid droplet and mitochondrial interactions, while studies in gastric cancer have linked CPT1A-associated metabolic reprogramming to JAK/STAT3 signalling. Given that CPT1 inhibitors are already being tested for anti-cancer effects, the authors raise the provocative question of whether the efficacy of such strategies, and even of antiangiogenic therapies that induce fatty acid uptake through CD36, might differ between obese and normal-weight patients. If confirmed, the humble lipid droplet, long regarded as a passive fat reservoir, could emerge as both a biomarker and a therapeutic target in the fight against colorectal cancer.

Subject of Research: The role of exogenous fatty acid uptake, lipid droplet formation and PLIN2 expression in promoting the tumorigenic behaviour of colorectal cancer cells

Article Title: Lipid Accumulation Promotes Tumorigenic Behaviour of Colorectal Cancer Cells

Article References: Itzenhäuser, T., Schildt, F. S., Jochem, S., Sommer, J., Stürzl, M., Naschberger, E., Boßerhoff, A. K., & Hellerbrand, C. (2026). Lipid Accumulation Promotes Tumorigenic Behaviour of Colorectal Cancer Cells. Journal of Cellular and Molecular Medicine, 30(19), Article e71393. https://doi.org/10.1111/jcmm.71393

Image Credits: AI Generated

DOI: 10.1111/jcmm.71393

Keywords: colorectal cancer, lipid droplets, fatty acid uptake, obesity, PLIN2, CPT1A, oleic acid, lipid metabolism, beta-oxidation, tumour progression, EMT, interleukin-8