A groundbreaking study published in Cell Reports sheds light on a critical driver of tumor progression and drug resistance in pancreatic cancer. Researchers at the University of California, San Diego, have identified the STAT3 protein as a master regulator of gene expression that enables cancer cells to become more aggressive and evade therapy.
STAT3 has long been recognized for its role in promoting gene expression linked to cancer initiation, tumor progression, and resistance to treatment. However, the key downstream targets responsible for these effects remained poorly understood until now.
Using a genomic screening approach, the researchers exposed pancreatic ductal adenocarcinoma cells to two conditions that activate STAT3: hypoxia and inflammation. They then mapped where active STAT3 bound across the genome using chromatin immunoprecipitation followed by sequencing (ChIP-seq).
The result was the identification of a set of 18 genes, 10 of which were consistently upregulated in both stress and inflammatory conditions. These genes, known as the “stress-up signature,” appear to be uniquely predictive of cancer progression, drug resistance, and overall tumor aggressiveness.
According to the researchers, this genetic signature is inducible, meaning some cancers already express these genes at high levels, while others can be pushed into doing so through chronic inflammation or stress. This discovery opens up a window of opportunity to intervene.
The study also shows that this pathway is reversible, and the drug ruxolitinib, currently used to treat inflammatory diseases, can block the activation of STAT3. This makes it a potential candidate to treat patients with cancers that rely on this pathway for survival and resistance.
The researchers validate their findings by analyzing single-cell sequencing data from tumor samples from patients who had and hadn’t received treatment. They found that patients whose tumors expressed the stress-up genes, particularly integrin beta 3, showed dramatically higher expression levels.
Cheresh believes that understanding the role of STAT3 in cancer progression can help identify patients at risk of aggressive disease and tailor treatments to their specific needs. The study provides a foundation for precision oncology strategies tailored to the tumor’s evolutionary state, which could potentially lead to new therapies for some intractable cancers.
Source: https://www.insideprecisionmedicine.com/topics/oncology/stat3-pathway-a-key-driver-of-tumor-aggression-and-drug-resistance-in-pancreatic-cancer