RNA-Regulated Mechanism Validated as a Target in GI Tract Cancers

15
Mar

Jonathan Brody 2

Investigators from the Sidney Kimmel Cancer Center at Jefferson, Thomas Jefferson University, and Drexel University have uncovered a critical regulatory mechanism involved in pancreatic and colorectal cancer progression. The study results were recently published in Molecular Cancer Research.

The researchers investigated the role of the RNA-binding protein HuR (also known as ELAVL1) in gastrointestinal (GI) tract cancers, specifically pancreatic ductal adenocarcinoma, the third leading cause of cancer-related deaths in the United States, and colorectal cancer, the third most common cancer. By screening a publicly available database, the researchers were able to determine that HuR expression levels were elevated in pancreatic and colorectal tumor samples as compared to normal, non-cancerous pancreas and colon tissues.

Following up on this observation with functional studies, the team used state-of-the-art gene targeting technology called CRISPR to delete the HuR gene in pancreatic and colorectal tumor cell lines derived initially from patients, and then tested the ability of these altered human cells to give rise to tumors when grafted into mice. This approach, known as “xenografting,” enables the behavior of human-derived cells to be assessed in an appropriate mammalian pre-clinical model. Surprisingly, the HuR-deficient pancreatic cancer cells were unable to initiate growth in mice as compared to the identical pancreatic cancer cells that had an intact HuR gene. Although not as dramatic, the HuR-deficient colorectal cells had a significant decrease in growth in mice. Together, these findings provided strong evidence that the HuR gene and its activity are required for growth and progression of some types of gastrointestinal tumors.

“From a basic science perspective, our results underscore the importance of a powerful but overlooked mechanism involving a fast and productive way GI cancers regulate gene expression,” said senior study author Jonathan Brody, PhD, co-director of the Jefferson Pancreas, Biliary and Related Cancer Center. ”We have demonstrated that this pathway and its component protein HuR are critical for some pancreatic cancers to initiate growth in this experimental model. These genetically engineered cell lines are particularly exciting in that they offer us a new tool with which to decipher the critical downstream targets and pathways regulated by HuR. These targets may be exciting new ‘druggable’ targets in GI cancers.”

As a first step in this direction, the investigators used their new model to identify mRNAs that were bound by the HuR RNA-binding protein and which were functionally required for transformation of a two-dimensional cell culture into three-dimensional cell organoids, a process that recapitulates key features of tumorigenesis. Further analysis revealed that HuR may indirectly regulate aspects of the oncogene KRAS and a subset of pro-oncogenic genes, raising the intriguing possibility that enhanced HuR expression supports a pro-oncogenic gene network in GI cancers.

Brody noted that this concept raises exciting clinical and translational applications. “This work highlights and validates the idea that HuR appears to be an important target in pancreatic and colorectal cancers,” he said. “If we can successfully target it either genetically or using small molecular inhibitors, we could perhaps inhibit the growth of pancreatic tumors in patients. We are currently exploring all of these approaches, and we are also interested in targeting HuR in combination with existing therapies to see if we can enhance patient outcomes.”

In addition to these clinical applications, the investigators continue to analyze the molecular function of HuR in carcinogenesis, with new experiments underway to evaluate the distinct roles HuR might play in the initial formation of precursor cancer cells, along with the survival and progression of more advanced invasive tumors.