Lung cancer epithelial
Image Credit: Courtesy of Universities of Manchester
Scientific Frontline: Extended "At a Glance" Summary: Tissue-Specific Aggressiveness in Epithelial Cancers
The Core Concept: The aggressiveness of squamous cell carcinomas (SCC), a common type of epithelial cancer, is determined not solely by the cancer cells themselves, but by the lipid metabolism of fibroblasts within the surrounding tumor microenvironment.
Key Distinction/Mechanism: Fibroblasts in different tissues supply varying types of fats to cancer cells, pushing them toward an invasive epithelial-to-mesenchymal transition. Oral fibroblasts supply sphingomyelins that activate the ceramide/S1P/STAT3 pathway, while lung fibroblasts transfer triglycerides that stimulate cholesterol production; conversely, skin fibroblasts contain significantly fewer fats, resulting in less invasive cutaneous cancers.
Major Frameworks/Components:
- Tumor Microenvironment (TME): The cellular environment, particularly supporting fibroblasts, that dictates cancer progression and behavior.
- Fibroblast Lipid Metabolism: The localized production and transfer of tissue-specific fats (such as sphingomyelins and triglycerides) to nearby cancer cells.
- Epithelial-to-Mesenchymal Transition (EMT): The molecular process triggered by these lipid cues that allows stationary cancer cells to become highly mobile, invasive, and capable of spreading.
- Ceramide/S1P/STAT3 Pathway: A specific chain of molecular events driven by sphingomyelins that fuels cancer cell migration in oral SCC.
Branch of Science: Oncology, Cellular Biology, Biochemistry, Molecular Biology.
Future Application: The development of personalized cancer therapies based on specific tissue biology, including the potential repurposing of existing lipid disorder drugs, such as statins, to block fat production in fibroblasts or disrupt lipid uptake and breakdown by tumors.
Why It Matters: By proving that the anatomical tissue of origin dictates cancer behavior through lipid signaling, this research shifts the paradigm away from treating all SCCs as a single disease. It offers novel, targeted therapeutic strategies to slow or halt metastasis in highly aggressive lung and oral cancers.
A team led by scientists from the Universities of Manchester and Liverpool have revealed why a group of cancers common in older adults exposed to environmental damage behaves so differently depending on where they develop in the body.
The research partially answers a quandary puzzling scientists for decades on why squamous cell carcinomas (SCC) in the mouth, lungs, and skin often look similar under the microscope, but vary dramatically in how aggressively they grow and spread. Squamous cell carcinomas are a type of epithelial cancer.
Co-author Dr Amaya Viros from The University of Manchester says the key to the difference lies not in the cancer cells themselves, but in the fibroblasts—supporting cells in the surrounding tissue—that send powerful biochemical signals shaping how the cancer behaves.
According to the study, fibroblasts from the mouth and lungs have strikingly different patterns of fat metabolism, producing and transferring different types of fats to nearby cancer cells.
The transferred fats act as molecular cues that push SCC cells to become more invasive through a process known as epithelial‑to‑mesenchymal transition, a change that allows cancer cells to move more freely and spread.
In oral cancers, fibroblasts supply cancer cells with sphingomyelins, a type of fat that activates the ceramide/S1P/STAT3 pathway, a chain of molecular events known to drive cancer cell migration and invasion.
In lung cancers, fibroblasts instead transfer another type of fat called triglycerides, which stimulate cholesterol production inside the cancer cells and fuel a highly invasive behaviour associated with poorer patient survival.
By contrast, fibroblasts in the skin contain far fewer fats, and as a result, cutaneous SCC tends to be less invasive than its oral or lung counterparts.
Dr Viros said: “These findings highlight that the tumor microenvironment—particularly the fibroblasts and the fats they produce—plays a decisive role in determining how dangerous a particular SCC will become.
“It suggests several promising therapeutic strategies, including blocking fat production in fibroblasts, preventing cancer cells from taking up these fats, or disrupting the pathways that break them down once inside the tumor. It is encouraging that many drugs that already exist approved for lipid disorders, like statins, can potentially be repurposed to prevent aggressive epithelial cancers”.
Co-author Dr Timothy Budden from the University of Liverpool said: “Targeting these fat‑driven interactions could slow or even halt the spread of oral and lung SCC, offering new hope for patients with these aggressive cancers.
“So, we think this work opens the door to more personalized cancer treatments based on the biology of the tissue where the tumor arises, rather than treating all SCCs as a single disease.”
Funding: Cancer Research UK, the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre (BRC) and The Royal Marsden NHS Foundation Trust and Institute of Cancer Research.
Published in journal: Nature Metabolism
Title: Tissue-specific fibroblast lipid cues impose the rate of epithelial cancer invasion
Authors: Timothy Budden, Noah Palombo, Shilpa Gurung, Martha Gutteridge, Charlotte Russell, Jair Marques, Alex von Kriegsheim, Lyutong An, Catherine Harwood, Luisa Motta, Claus Jorgensen, Carlos López-Garcîa, Caroline Gaudy-Marqueste, Kevin Harrington, Malin Pedersen, Ben O’Leary, Antonio Rullan, and Amaya Virós
Source/Credit: Universities of Manchester
Reference Number: ongy042726_01