Understanding How Lung Squamous Cell Carcinoma Begins Can Lead to Discoveries of Targeted Therapies

Trudy Oliver, PhD, an assistant professor of oncological sciences at the University of Utah and Huntsman Cancer Institute (HCI) investigator, recalls a very exciting day in the Oliver Lab: “Everyone was screaming and running around high-fiving each other. Just to see this tumor blob in a lung.”

What caused all the excitement, and what does it have to do with mice and lungs? Squamous cell carcinoma (SCC) is the second most common type of lung cancer, with only 15% of patients surviving five years past diagnosis. Little is known about how it arises, preventing the development of targeted therapies to fight the disease if standard chemotherapy regimens are ineffective.

That is, until now. In 2014, Oliver and a group of HCI investigators published findings online in Cell Reports that the misregulation of two genes, Sox2 and Lkb1, drives squamous cell lung cancer in mice. The discovery will help uncover new treatment strategies and provide a mouse model in which to test them.

Genetic Mutations and the Onset of Cancer

Tumors are groups of cells that grow out of control due to genetic mutations. Only some mutations, however, actually make cells cancerous. The trick for developing targeted therapies is to distinguish the mutated genes that drive cancerous cell division.

mouse models of cancer

About Mouse Cancer Models
Mouse cancer models provide exceptional insight into the biology of human cancers and their genetics. A major reason mice are used in cancer research is the similarity of mouse and human genetics. The mouse was the first mammal whose genome was sequenced when the human genome sequence was almost completed. This greatly increased the value of mouse models for research on cancer and many other human disorders. Learn more about mouse models for cancer research from the National Cancer Institute.

Oliver’s team zeroed in on “drivers” of squamous cell lung cancer (SCC) by poring through documented gene abnormalities found in human SCCs. Sox2 was designated a prime candidate based on its overexpression in 60 to 90% of SCCs and on its 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 to 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.

Mouse Model for Squamous Cell Lung Cancer

“A pathologist looking under the microscope at our tumors would not know they're from the mouse,” says 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.”

Not many mouse models develop lung SCC and those that did developed multiple tumor types, but Oliver’s Sox2/Lkb1 model generates SCC exclusively. Combined with the fact that the Sox2/Lkb1 model was created based on patient data, it provides a relevant model in which to test new targeted therapies that may one day help humans.

“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,” says Anandaroop Mukhopadhyay, PhD, HCI scientist and a lead author on the paper.

Model Allows for More Answers, Development of Targeted Therapies

While no known drugs directly target either Sox2 or Lkb1, some existing therapies interfere with biochemical pathways thought to be activated by these genes. What’s more, the scientists found these pathways, Jak-Stat and mTOR, were activated in tumors in the new mouse model. These findings suggest that drugs blocking these pathways, STAT3 and mTOR inhibitors, are good candidates for testing 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 explains. “That gives us direction for testing the efficacy of drugs aimed at these pathways. Now that we have a model it just unleashes so many questions that we can ask to gain a better understanding of the disease.”

Oliver points out two primary questions:

“One, what lung cell type do these genetic changes, Sox2 and Lkb1 loss, arise in that lead to the development of SCC? We can start to really understand what the cell of origin is for this tumor, and the earliest changes that promote cancer. The second thing that we can ask is what therapies work. We can use the mouse model to test novel therapies, novel combinations of therapies, and we can do this in a way that would be impossible to do in humans. This is the most exciting thing we’ve done.”