A new tool to confront lung cancer

June 19, 2014
sox2/lkb1 lung tumors have characteristic squamous cell histology. Credit: Anand Mukhopadhyay, Ph.D.

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.

Published online in Cell Reports on June 19, Huntsman Cancer Institute investigators report that misregulation of two genes, sox2 and lkb1, drives squamous cell 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.

This is a microCT reconstruction of sox2/lkb1 mouse lung with tumor in blue. Credit: Anand Mukhopadhyay, Ph.D.

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."

Explore further: Molecular mechanisms regulating tumour initiation and cancer stem cells functions in skin squamous cell carcinoma

More information: 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. www.cell.com/cell-reports/abst … -1247%2814%2900430-6

Related Stories

Molecular mechanisms regulating tumour initiation and cancer stem cells functions in skin squamous cell carcinoma

June 10, 2014
Squamous cell carcinoma (SCC) represents the second most frequent skin cancer with more than half million new patients affected every year in the world. Cancer stem cells (CSCs) are a population of cancer cells that have ...

Researchers develop process to help personalize treatment for lung cancer patients

June 3, 2014
Moffitt Cancer Center researchers, in collaboration with the Lung Cancer Mutation Consortium, have developed a process to analyze mutated genes in lung adenocarcinoma to help better select personalized treatment options for ...

Testing for mutations identified in squamous cell lung cancer tumors helps personalize treatment

May 17, 2012
Screening lung cancer tumor samples for cancer-causing, or "driver," genetic mutations can help physicians tailor patients' treatments to target those specific mutations. While scientists have identified cancer-causing mutations ...

New view of tumors' evolution

March 13, 2014
Cancer cells undergo extensive genetic alterations as they grow and spread through the body. Some of these mutations, known as "drivers," help spur cells to grow out of control, while others ("passengers") are merely along ...

New study aims to rapidly test lung cancer drugs

June 16, 2014
A bold new way to test cancer drugs started Monday. Like a medical version of speed dating, doctors will sort through multiple experimental drugs and match patients to the one most likely to succeed based on each person's ...

Recommended for you

New therapeutic approach for difficult-to-treat subtype of ovarian cancer identified

July 24, 2017
A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Anti-cancer chemotherapeutic agent inhibits glioblastoma growth and radiation resistance

July 24, 2017
Glioblastoma is a primary brain tumor with dismal survival rates, even after treatment with surgery, chemotherapy and radiation. A small subpopulation of tumor cells—glioma stem cells—is responsible for glioblastoma's ...

Immune cells the missing ingredient in new bladder cancer treatment

July 24, 2017
New research offers a possible explanation for why a new type of cancer treatment hasn't been working as expected against bladder cancer.

No dye: Cancer patients' gray hair darkened on immune drugs

July 21, 2017
Cancer patients' gray hair unexpectedly turned youthfully dark while taking novel drugs, and it has doctors scratching their heads.

Shooting the achilles heel of nervous system cancers

July 20, 2017
Virtually all cancer treatments used today also damage normal cells, causing the toxic side effects associated with cancer treatment. A cooperative research team led by researchers at Dartmouth's Norris Cotton Cancer Center ...

Immune-cell numbers predict response to combination immunotherapy in melanoma

July 20, 2017
Whether a melanoma patient will better respond to a single immunotherapy drug or two in combination depends on the abundance of certain white blood cells within their tumors, according to a new study conducted by UC San Francisco ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.