Published online in Cell Reports on June 19, Huntsman Cancer Institute investigators report that misregulation of two genes, sox2 and lkb1, drives squamous cell lung cancer in mice. The discovery uncovers new treatment strategies, and provides a clinically relevant mouse model in which to test them.
This is the most exciting thing weve done, said senior author Trudy Oliver, Ph.D., an assistant professor of oncological sciences at the University of Utah and Huntsman Cancer Institute investigator. Now that we have a model it unleashes so many questions we can ask to gain a better understanding of the disease.
By definition, tumors are groups of cells that are out of control. As a result, they acquire mutations, only some of which drive properties – such as excess growth and motility - that make cells cancerous. The trick for developing targeted therapies is to distinguish the driver from passenger mutations that are merely along for the ride.
Call it guilt by association, but Olivers team honed in on drivers of squamous cell carcinoma (SCC) of the lung by poring through documented gene abnormalities found in human SCCs. Sox2 was designated a prime candidate based on its overexpression in 60-90% of SCCs, and a frequent early appearance during tumor formation, suggesting it could be an initiator of cancer. Tumor suppressor genes were also candidates, including Lkb1, which is mutated in 5-19% of SCCs.
While disruption of either gene alone failed to trigger cancer, combining overexpression of sox2 in the lung with loss of lkb1 led to frequent development of lung SCC in mice.
A pathologist looking under the microscope at our tumors would not know its from the mouse, said Oliver. They visually look like human tumors, and then when we stain them for biomarkers of the human disease, our mouse tumors light up for those markers.
This is a microCT reconstruction of sox2/lkb1 mouse lung with tumor in blue.
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Unlike most previously existing lung SCC mouse models that develop multiple tumor types, the sox2/lkb1 model generates SCC exclusively. Combine this with the fact that it was created based on patient data makes the model clinically relevant, and well poised for testing novel targeted therapies.
Beyond lung cancer, findings from this model may have important clinical implications for other squamous or Sox2-driven malignancies such as small cell lung cancer, and brain, esophageal, and oral cancers, said Anandaroop Mukhopadhyay, Ph.D., Huntsman Cancer Institute scientist and lead author on the paper.
While there are no known drugs that directly target either Sox2 or Lkb1,
there are existing therapies that interfere with biochemical pathways that are thought to be activated by these genes. Whats more, the scientists found that these pathways, Jak-Stat and mTOR, were activated in tumors in the new mouse model. These findings suggest that the drugs that block these pathways, STAT3 and mTOR inhibitors, are good candidates for working as lung SCC targeted therapies.
These are pathways that had not been previously explored for the treatment of squamous tumors because we didnt realize they were important, Oliver explained. That gives us direction for testing the efficacy of drugs aimed at these pathways.
Listen to an interview with Trudy Oliver about creation of the sox2/lkb1 mouse model on The Scope Radio
Mukhopadhyay, K.C. Berrett, U. Kc, P.M. Clair, S.M. Pop, S.R. Carr, B.L. Witt, T.G. Oliver (2014) Sox2 cooperates with Lkb1 loss in a mouse model of squamous cell lung cancer. Cell Reports published online ahead of print, June 19, 2014
This work was supported by DoD USAMRAA W81XWH-12-1-0211, The V Foundation for Cancer Research, Huntsman Cancer Foundation., and Damon Runyon Cancer Research Foundation
About Huntsman Cancer Institute at the University of Utah:
Huntsman Cancer Institute (HCI) is one of the worlds top academic research and cancer treatment centers. HCI manages the Utah Population Database - the largest genetic database in the world, with more than 16 million records linked to genealogies, health records, and vital statistics. Using this data, HCI researchers have identified cancer-causing genes, including the genes responsible for melanoma, colon and breast cancer, and paraganglioma. HCI is a member of the National Comprehensive Cancer Network (a 25-member alliance of the worlds leading cancer centers) and is a National Cancer Institute-Designated Cancer Center. HCI treats patients with all forms of cancer and operates several high-risk clinics that focus on melanoma and breast, colon, and pancreas cancers. The HCI Cancer Learning Center for patient and public education contains one of the nations largest collections of cancer-related publications. The institute is named after Jon M. Huntsman, Sr., a Utah philanthropist, industrialist, and cancer survivor.
Information Source: EurekAlert!