Genome Wide Analysis Reveals New Nuclear Hormone Receptor as Therapeutic Target for Aggressive Pancreatic Cancer

Chengzi Guo 22’

Cancer cells in culture illuminated by dark-field amplified contrast at 500x magnification [3].

Pancreatic cancer is known for its notoriously low survival rate. It is one of the most aggressive forms of cancer with a one-year survival rate of 20 percent and a seven-year survival rate of 7 percent. [2]. What makes pancreatic cancer so difficult to treat with traditional methods such as chemotherapy is that the disease is characterized by aggressive remission-resistance relapse. When a patient undergoes chemotherapy initially, most, but not all, of the cancer cells are killed, leaving behind multi-drug resistant cells. Not only are these cells resistant to chemotherapy, they possess stem cell properties that allow them to drive tumor growth and metastasis.

Researchers at the University of California San Diego School of Medicine published a new paper proposing a different approach to treating pancreatic cancer [1]. Their study, published on April 4, 2019 in the journal Cell, uses genome-wide analytical tools to screen for vulnerabilities in the genomes of pancreatic cancer stem cells. Genome-wide analytical tools use a combination of computational and biotechnology techniques to process large amounts of DNA code to look for patterns in the DNA and in protein expression. In particular, researchers looked for particular molecules or proteins that cancer stem cell needed for survival. The screening revealed an unexpected role of immuno-regulatory genes in the maintenance of aggressive pancreatic cancer cells and identified new proteins that can be targeted for cancer treatment.  

Previous work in the field has focused on identifying the most tumorigenic populations within pancreatic can cancers because these cells present the highest risk for disease progression. First author Dr. Nikki Lytle, instead, looked at the molecular signals that sustain such a tumorigenic population. If there are molecular signals that are essential to pancreatic cancer stem cells but not to non-cancerous cells, these signaling pathways provide opportunities for therapeutic targeting and inhibition to slow or halt cancer progression. To do this, Lytle used an integrated genome approach through biotechnology assays such as RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq), along with gene-editing tools such as CRISPR to map the molecular dependencies of pancreatic cancer cells.

The results revealed that a nuclear hormone receptor (retinoic-acid-receptor-related orphan receptor gamma, or RORγ, is especially upregulated in pancreatic cancer cells. RORγ is involved in the immuno-regulatory pathway and plays a role in inflammation and T cell differentiation. When researchers artificially silenced RORγ mRNA in pancreatic cells, cancer growth was significantly reduced and survival rates were improved. Analyzing RORγ expression in patients with pancreatic cancer revealed that RORγ expression is positively correlated with advanced disease progression, suggesting that RORγ can actually be used to predict cancer aggressiveness.

The identification of immuno-regulatory pathways as molecular dependencies in pancreatic cancer offers the potential to use autoimmune drugs to target aggressive cancer growth. Previous research suggests immuno-regulatory signalling is not restricted to pancreatic cancer and may be applicable to other epithelial cancers. As RORγ-targeting drugs are already in phase II of clinical trials for autoimmune diseases, the team has high hopes for RORγ-targeting drugs in treating pancreatic cancer.

Works Cited:

  1. Lytle, N. K., Ferguson, L. P., Rajbhandari, N., Gilroy, K., Fox, R. G., Deshpande, A., … & Noel, P. (2019). A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma. Cell.
  2. University of California – San Diego. (2019, April 4). Genome-wide analysis reveals new strategies to target pancreatic cancer: Researchers discover unexpected role of an immune system receptor; blocking it halts human cancer cell growth and improves survival in animal models. ScienceDaily. Retrieved April 8, 2019 from www.sciencedaily.com/releases/2019/04/190404143639.htm
  3. Fox, C. (1987, November). Cancer Cells. National Cancer Institute.
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