Interrogating the genome to reverse chemoresistance

HudsonAlpha scientists discover a gene that could reverse chemoresistance in pancreatic cancer 

In the United States, cancer is the second leading cause of death, behind heart disease. When it comes to cancer treatment and survival, two significant challenges can arise: metastasis and chemoresistance. Metastasis is the process by which cancer cells spread from the primary tumor to other parts of the body. This can happen through the bloodstream or the lymphatic system, making it harder to treat and control the disease. 

Chemoresistance is the ability of cancer cells to become resistant to chemotherapy drugs, making them less effective in fighting the disease. This resistance can occur due to various factors, such as genetic mutations within the cancer cells or protective mechanisms that prevent the drugs from effectively targeting the cancerous growth. Both chemoresistance and metastasis pose considerable hurdles in cancer treatment, highlighting the need for ongoing research and innovative approaches to improve patient outcomes. 

Investigating a deadly type of cancer 

One type of cancer plagued by chemoresistance and metastatic complications is pancreatic cancer. About half of the patients diagnosed with pancreatic cancer already have cancer spread beyond the area of the pancreas. Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers, with a five-year survival rate of only 11 percent, due to the lack of early diagnostic markers for PDAC to catch the disease early and its high rate of treatment resistance. 

HudsonAlpha Institute for Biotechnology Faculty Investigator Sara Cooper, PhD, and her lab focus on identifying novel targets to prevent cancer chemoresistance, especially in pancreatic cancer. They recently published results in BMC Cancer from a promising study led by senior scientist Emily Gordon, PhD, identifying several potential targets for reversing chemoresistance in PDAC. 

Sara Cooper, PhD
Sara Cooper, PhD
Emily Gordon, PhD

In 2016, Cooper and colleagues at HudsonAlpha identified genes whose expression positively or negatively correlated with PDAC patient survival. High expression of a gene called ANGPTL4 was linked with poor patient survival and, when knocked down in cell lines, increased their sensitivity to a common pancreatic cancer treatment. ANGPTL4 has a defined role in cardiovascular disease and lipid metabolism, but its role in cancer is unclear. 

“This work builds upon an earlier finding that highlighted ANGPTL4 as a possible drug target,” says Dr. Cooper. “We are considering ANGPTL4 as a possible drug target based on its link to patient outcomes and the evidence that inhibition can improve response to treatment.”

ANGPTL4 is a potential target for reversing chemoresistance 

The team sought to dive further into ANGPTL4’s function to understand possible mechanisms contributing to patient survival. Through a series of cell-based experiments, the scientists found that overexpression of ANGPTL4 leads to chemotherapy resistance in PDAC. The overexpression also increased the migratory potential of the cells, a factor that plays a role in metastasis. 

ANGPTL4 is not alone in its ability to influence patient survival. The expression of several genes downstream of ANGPTL4 was altered by its overexpression. The genes were linked to epithelial to mesenchymal transition, a phenomenon that allows cancer cells to detach from the main tumor site and move to other parts of the body. Overexpression of genes downstream of ANGPTL4 also predicts patient outcomes, providing more potential targets to study. 

Using CRISPR to knock down factors downstream of ANGPTL4 in cell lines, the scientists showed that the chemoresistance could be reversed. It also reduced the migratory potential of cells. This means that targeting ANGPTL4 or its downstream partners with a drug could be a potential solution to reverse chemoresistance in PDAC. 

The data from this study suggest that ANGPTL4 and its downstream pathway are potential therapeutic targets for the reversal of treatment resistance in pancreatic cancer. 

“These data help us understand the function of ANGPTL4 in pancreatic cancer and provide evidence to support advancing ANGPTL4 and its targets as potential drug targets and aid in developing much-needed treatments for pancreatic cancer,” says Dr. Cooper. 

This research was funded in part by NIH grant UL1TR003096, NIH grant R43CA232844 in collaboration with CFD Research, and support from the State of Alabama.

Manuscript citation: Gordon, E.R., Wright, C.A., James, M. et al. Transcriptomic and functional analysis of ANGPTL4 overexpression in pancreatic cancer nominates targets that reverse chemoresistance. BMC Cancer 23, 524 (2023).

Byline: Sarah Sharman, PhD