Study identifies new therapeutic target for most common type of pancreatic cancer

Northwestern Medicine researchers have identified a potential therapeutic target for one of the most common types of pancreatic cancer, according to a study published in the journal Developmental Ce.

Our findings demonstrate that the transcription factor ISL2 acts as a tumor suppressor in pancreatic ductal adenocarcinoma (PDA) tumors and that its loss reprograms the transcriptional and metabolic states of PDA cel.

"The status of ISL2 can be a precision medicine approach where we can examine tumors, look at ISL2 levels, and then determine whether those tumors are more dependent on lipid metabolism, or whether we should inhibit this pathway in these types of tumo.

Survival rates for PDA are poor—more than 80 percent of patients are diagnosed in advanced stages of cancer, where the tumor is no longer eligible for surgical remov.

Essentially, PDA tumors contain dense tissue, and cancer cells continually reprogram their DNA transcription and metabolic functions to survive the tumor's harsh microenvironme.

"Currently, we have a good understanding of what drives the initial stages of pancreatic cancer, but after these initial stages, what makes these pancreatic cancer cells so plastic and in different microenvironments," Adli sa.

Using an unbiased genome-wide CRISPR-Cas9 screen, the researchers studied PDA tumor cell lines in mice to identify transcription factors and chromatin regulators that may be involved in PDA cell growth and proliferati.

At the epigenetic level, they found that in primary PDA tumors, the transcription factor ISL2 (ISL2) is silenced through DNA methylati.

The researchers found that increasing ISL2 expression through CRISPR-based epigenetic editing reduced PDA cell proliferati.

"This was a surprising finding because most cancer cells prefer glucose, but recent studies have shown that there are subsets of cancer cells that are actually more dependent on oxidative phosphorylation, and we think ISL2 is a regulator of this dynamic proce.

Advanced molecular analysis of PDA tumor cells in vivo and in vitro also revealed that PDA cells lacking ISL2 may be sensitive to specific inhibitors targeting mitochondrial complex I or oxidative phosphorylation

Taken together, these findings suggest that inhibiting a pathway downstream of ISL2's apparent silencing may be a promising therapeutic target, Adli sa.

"This suggests that ISL2 may spatially regulate this gene expression program to allow pancreatic cancer cells to have this plasticity and survive in this environment," Adli sa.