Gene Signature Could Serve as Early Warning System for Aggressive Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal forms of cancer, with early detection remaining a major challenge. Precancerous cells must overcome significant stress and inflammation to progress into malignant tumors, and these conditions also contribute to resistance against treatments. Prior studies have established that inflammation and cellular stress activate a protein called STAT3 in pancreatic cells, which promotes tumor development and resistance. However, the specific mechanisms through which STAT3 contributes to these processes were unclear. In a new study, researchers have discovered how STAT3 activates genes that help cancer cells adapt to stress and inflammation, providing a clearer picture of tumor progression and offering a potential early warning system for PDAC.

Researchers at the UC San Diego School of Medicine (La Jolla, CA, USA) identified that STAT3, when activated by inflammatory proteins and low oxygen levels, turns on a gene called Integrin β3 (ITGB3) in both human and mouse pancreatic cells. This gene was found to significantly promote the initiation and progression of PDAC tumors. The study also revealed that chemotherapy-induced stress activated STAT3, further increasing ITGB3 expression in pancreatic cancer cells. Moreover, STAT3 was shown to regulate a set of ten genes, including ITGB3, forming a genetic profile the researchers named the “STRESS” signature. This gene signature was better at predicting both the potential of precancerous cells to become cancerous and the aggressiveness of resulting tumors than any previously known markers.

Image: Pancreas cells (left) showing early stages of malignant cancer in brown and same cells stained blue (right) indicate they are Integrin β3 (ITGB3) positive (Photo courtesy of UC San Diego Health Sciences)

The findings, published in Cell Reports, demonstrated that blocking the STAT3 pathway that controls ITGB3 delayed the initiation of pancreatic tumors. The STRESS gene signature showed high predictive value in identifying cells likely to develop into PDAC and determining how aggressive the cancer could become. Researchers believe these insights could lead to precision medicine approaches, such as early screening tools to detect precancerous cells and strategies to predict which patients might respond well to conventional treatments. The team now plans to explore molecules that block the activation of ITGB3 by inflammation, not only in pancreatic cancer but also in other cancers affecting surface tissues, such as lung, breast, and skin cancers.

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UC San Diego School of Medicine