Listen to an interview with Dr. Trudy Oliver about her lung cancer work on The Scope Radio
Only 15% of patients with squamous cell lung cancer – the second most common lung cancer – survive five years past diagnosis. Little is understood about how the deadly disease arises, preventing development of targeted therapies that could serve as a second line of defense once standard chemotherapy regimens fail.
microCT reconstruction of SCC tumor in mouse lung
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 we’ve 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 Oliver’s 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 it’s 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.”
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. What’s 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 didn’t 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 world’s 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 world's 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 nation's largest collections of cancer-related publications. The institute is named after Jon M. Huntsman, Sr., a Utah philanthropist, industrialist, and cancer survivor.
Director, Public Affairs , Huntsman Cancer Institute
Linda Aagard | Eurek Alert!
'Neuron-reading' nanowires could accelerate development of drugs for neurological diseases
12.04.2017 | University of California - San Diego
PET radiotracer design for monitoring targeted immunotherapy
10.04.2017 | Society of Nuclear Medicine
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
Two researchers at Heidelberg University have developed a model system that enables a better understanding of the processes in a quantum-physical experiment...
Glaciers might seem rather inhospitable environments. However, they are home to a diverse and vibrant microbial community. It’s becoming increasingly clear that they play a bigger role in the carbon cycle than previously thought.
A new study, now published in the journal Nature Geoscience, shows how microbial communities in melting glaciers contribute to the Earth’s carbon cycle, a...
20.04.2017 | Event News
18.04.2017 | Event News
03.04.2017 | Event News
21.04.2017 | Physics and Astronomy
21.04.2017 | Health and Medicine
21.04.2017 | Physics and Astronomy