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Pancreatic Cancer Subtype With Poor Outcomes Shows Low Methylation, High Interferon Signature

NEW YORK – Researchers in Germany have uncovered two subtypes of pancreatic cancer, one of which is more aggressive but could also be susceptible to a targeted therapy.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a five-year survival rate of about 9 percent. To examine the mutational landscape of the disease, which accounts for most cases of pancreatic cancer, researchers from the German Cancer Research Center (DFKZ) teased out pancreatic epithelial cells from PDAC tumors and normal pancreatic tissue.

As they reported in the journal Cancer Discovery on Thursday, the researchers found that the tumor cells they isolated from patients separated into two groups based on their methylation patterns. Tumors with low methylation also expressed a different gene signature than tumors with higher methylation levels, marked by the activation of an interferon signature as well as poor patient outcome. This low-methylation, high-interferon pattern indicated that these tumors might be vulnerable to treatment with therapies that block interferon signaling, suggesting a potential targeted therapy. 

"Based on the methylation patterns of the tumor genomes, we were able to define two completely different subtypes of adenocarcinomas, which differ in the course of carcinogenesis and in their aggressiveness," first author Elisa Espinet from DFKZ and the Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM) said in a statement.

The researchers used a FACS-based approach to isolate epithelial cells from pancreatic tumors and normal adjacent tissue of seven patients with untreated PDAC tumors for whole-genome bisulfite sequencing and RNA sequencing. While more than 56,000 DNA regions were differentially methylated in PDAC versus normal cells, the tumor samples themselves also separated into two clusters based on their methylation patterns.

Transcriptomic data further highlighted 320 genes that were differentially expressed between the two methylation-based clusters (MC1 and MC2), and a gene set enrichment analysis noted that MC2 samples were enriched for IFN-ɑ and IFN-γ response signatures.

To differentiate between the groups, the researchers developed a 47-gene signature based on the genes enriched in MC2 involved in the IFN-ɑ and IFN-γ responses. This gene signature is highly expressed in a subset of PDAC patients, the researchers noted, adding that IFNsignhigh patients have significantly worse overall outcomes. 

When the researchers explored the differences in methylation between MC1 and MC2 samples, they found that MC2 cells had significantly lower levels of methylation at sites surrounding repetitive repeat elements, SINES, and LTR/ERVs. Based on their transcriptomic data, they further found increased expression of LTR/ERV and LINE-derived transcripts, as well as a dsRNA response and high IFN signaling. They validated their findings in samples from a further 11 PDAC patients.

The results suggest that the changes in methylation trigger a viral mimicry response in which the tumor provokes inflammatory reactions that further stimulate cancer growth. 

But the findings also suggest that inhibiting IFN signaling could disrupt tumor growth. In a mouse model, the researchers found that treatment with the approved JAK/STAT inhibitor ruxolitinib reduced the expression of interferon-related genes and impaired the tumor growth of IFNsignhigh but not IFNsignlow cells.

This, the researchers added, establishes a proof-of-concept that tailored inhibition of IFN signaling might benefit patients with MC2 PDAC. "By blocking the interferon signaling pathways at various sites, we were able to significantly slow down cancer growth in mice to which human pancreatic cancer cells had been transferred," senior author Andreas Trumpp from DKFZ and HI-STEM said in a statement. "However, the regulation of these signals is highly complex. We are now looking for ways to not only slow down the tumor cells, but actually eliminate them."

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