Lung squamous cell cancers comprise up to 30% of all lung cancers and are responsible for about 70,000 new cases and approximately 40,000 deaths each year in the United States. Lung squamous carcinoma (LUSC) is a highly metastatic disease with a poor prognosis. Now, researchers at UNC Lineberger Comprehensive Cancer Center, have discovered a potential new target to attack lung squamous cell cancer, known as CDR1as.

Chad V. Pecot, MD. [UNC Lineberger Comprehensive Cancer Center]

Their findings, “A circle RNA regulatory axis promotes lung squamous metastasis via CDR1-mediated regulation of Golgi trafficking,” is published in the journal Cancer Research and led by Chad V. Pecot, MD, an associate professor at the UNC School of Medicine.

LUSC is one type of non-small cell lung cancer (NSCLC). It begins in the squamous cells—thin, flat cells that look like fish scales when seen under a microscope. They line the inside of the airways in the lungs. LUSC occurs when abnormal lung cells multiply out of control and form a tumor. Eventually, tumor cells can metastasize to other parts of the body.

“LUSC is a highly metastatic disease with a poor prognosis. Using an integrated screening approach, we found that miR-671-5p reduces LUSC metastasis by inhibiting a circular RNA (circRNA), CDR1as,” noted the researchers.

Circular RNA is a type of single-stranded RNA which, unlike linear RNA, forms a covalently closed continuous loop. A large number of researchers have demonstrated that circRNAs are correlated with the pathogenesis of various human diseases, including nervous system disorders, cardiovascular disorders, Alzheimer’s disease, diabetes, cancer, and more. In particular, circRNAs have been reported to play critical roles in cancer growth, metastasis, and resistance to therapy.

The researchers found that one of the keys to how CDR1as works was through an unstudied protein called CDR1. The researchers collaborated with others to uncover details about CDR1 and arrived at Golgi trafficking.

The Golgi apparatus is often referred to as a cellular “post office” for its ability to package proteins into vesicles for transportation to other sites within or outside the cell. Unfortunately, in cancer cells, Golgi bodies must reposition themselves so that cells can metastasize or spread. The researchers tested whether altering Golgi trafficking could affect what happened in the cell.

“We found that CDR1as plays a large role in driving metastasis in lung squamous cancer,” said Pecot. “However, because nothing was really known about CDR1, the protein regulated by CDR1as, our journey was just beginning. We eventually determined that CDR1 in part operates by increasing Golgi trafficking, which we found to be critical to its role in helping cancer spread.”

Moving forward, the researchers will continue to study CDR1as and CDR1. Pecot views them both as enticing drug targets because they are usually not turned on in the rest of the body. So blocking them would be destructive to cancer cells but should not affect or cause much toxicity to the rest of the body.

“Cancer is revealing, at a rapid pace, that it has many more vulnerabilities than we previously believed, including the one we’ve elucidated, which undoubtedly means better treatment options ahead,” explained Pecot. “I’m very hopeful, based on our work and much of what is being done in the field of drug development, that many new medicines are on the horizon.”

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