RAGE receptor identified as key driver of age-related metastasis

Researchers at Georgetown Lombardi Comprehensive Cancer Center have identified a biological mechanism that may explain why older people with breast cancer often experience poorer outcomes, with scientists pointing to a receptor linked to inflammation and the spread of tumours.

The study focused on Receptors for Advanced Glycation End-products (RAGE), a cell surface receptor known to amplify inflammatory signalling. Researchers found that the receptor becomes increasingly active as breast cancer progresses and appears to play a major role in age-related cancer metastasis.

The findings, suggest that ageing itself may actively alter the body in ways that help tumours spread.

Ageing linked to increased metastasis

“Our study addresses a major gap by showing that ageing dramatically increases breast cancer metastasis and that this effect depends on RAGE, a receptor on the surface of cells that fuels inflammation,” said Dr Barry Hudson, Associate Professor of Oncology at Georgetown Lombardi and corresponding author of the study.

“Most laboratory studies rely on young mice which has limited our understanding of how ageing itself alters the host environment, including immune function and chronic inflammatory states that, in turn, influence cancer behavior.”

A key element of the research emerged unexpectedly during the COVID pandemic. Reduced laboratory activity meant some mouse colonies aged longer than originally planned, creating a rare opportunity for scientists to compare tumour behaviour in older and younger animals.

Using three different mouse models of triple-negative breast cancer, one of the most aggressive forms of the disease, researchers found that older mice developed significantly more lung metastases than younger mice, despite both groups showing similar primary tumour growth.

When researchers genetically removed RAGE from the mice, the age-related increase in metastasis was almost completely eliminated.

Inflammation found to drive tumour spread

The study found that ageing increased levels of inflammatory molecules known to activate RAGE, including the proteins S100 and HMGB1. These proteins were identified in both primary tumours and metastatic sites and appeared to make it easier for cancer cells to invade surrounding tissue and spread to other organs.

“These findings show that ageing doesn’t just increase cancer risk – it actively changes the body in ways that help tumours spread,” Hudson said. “RAGE appears to be a key mediator of these harmful age-related pathways.”

Researchers also analysed breast cancer data from more than 1,000 patients and found that higher expression of AGER, the gene responsible for encoding RAGE, along with related inflammatory gene signatures, was linked to poorer patient outcomes.

Drug already under investigation

RAGE is already being explored as a therapeutic target in several age-related diseases and researchers believe it may also be key to limiting cancer metastasis.

Earlier work by the Georgetown team showed that the RAGE inhibitor TTP488, also known as azeliragon, could suppress breast cancer metastasis in preclinical studies. In the latest research, scientists found that the drug reduced tumour cell invasiveness triggered by blood serum taken from older mice.

A clinical study is now under way at Georgetown Lombardi evaluating TTP488 in breast cancer patients undergoing chemotherapy, with researchers focusing on both safety and cognitive outcomes. The drug has already demonstrated a favourable safety profile in people.

“This study highlights the importance of the host environment in cancer. While cancer is often viewed as driven primarily by mutations intrinsic to tumour cells, systemic factors such as ageing and inflammation play a critical role in shaping how cancers behave,” Hudson said. “Most deaths due to cancer occur because tumours spread to other organs, so understanding these influences may help identify new strategies to limit metastasis.”