Study Provides Details of Head and Neck Cancer Stem Cells

A 7-year study identified genetic pathways hijacked by cancer stem cells to promote tumor growth.

Key findings paint a detailed picture of head and neck cancer stem cells, providing a target for the development of new therapies.

Published in the Journal of the National Cancer Institute, researchers identified genetic pathways hijacked by cancer stem cells to promote tumor growth, while also visualizing the asymmetric division process.

“We wanted to determine the relationships between key genetic alterations and how head and neck cancer stem cells harness those alterations to drive initiation and growth,” said senior study author Antonia Jimeno, MD, PhD. “I focused on head and neck cancer stem cells because there has been an increase in head and neck cancer incidence of about 50% over the past 10 years in the US and we need to better understand what is at the root of these disease.”

Previously, characterizing cancer stem cells has been a major challenge because of the difficulty in gathering a large enough cell population to study.

“There is a lot of ‘noise’ in cells and you need a lot of them because with only a few cells, it’s impossible to tell which of these genetic differences are meaningful features of cancer stem cells and which are just genetic noise,” said first study author Stephen Keysar, PhD.

In order to address this issue, researched obtained tumor samples from a large amount of head and neck cancer patients. There was a total of 10 patients in all, which was more than any other study prior.

The samples represented both tumors associated with alcohol and tobacco use, and tumors caused by the human papilloma virus (HPV).

“It is important to remember that we were able to make a difference thanks to the generosity of our patients, who enabled us to work with a representative cancer models,” Jimeno said.

Researchers then took the tumors and grew them in mice, a long process consisting of isolating enough cells for genetic studies, and one-by-one transplanting these patient-derived tumor samples onto new mice in order to study how cancer stem cells initiate tumor growth.

The results of the study revealed to researchers that head and neck cancer stem cells are distinct from the rapidly-dividing cells that form the bulk of tumors. Additionally, there is little difference between cancer stem cells in HPV-negative and HPV-positive cancers.

Both are marked by CD44 expression and aldehyde activity, and both use the key pathway PI3K to drive survival, resistance to treatment, and growth. Researchers also discovered that the PI3K pathway deploys a transcription factor called SOX2 in order to activate programs that modulate ‘stemness’ within the cell’s nucleus.

For example, SOX2 was found to control aldehyde activity.

“In normal cells, PI3K is used as a sensor for energy,” Jimeno said. “For a cancer cell to act cancerous, it needs metabolic flexibility — it needs to be able to over-use energy – and so this ‘energy sensory’ is a pathway it wants to hijack. After chemo, PI3K helps the cell shut down and weather the storm. Then when the chemo is gone, PI3K helps cancer stem cells start back up again.”

The PI3K pathway is able to shut down the metabolism of a cancer stem cell, resulting in the cell moving into a dormant state. This process allows the cancer stem cells to evade the chemotherapy.

To remove the ability to evade treatment, researchers eliminated SOX2 in mouse models of head and neck cancer, causing the tumors to become sensitive to the chemotherapies that previously failed; however, when SOX2 was amplified, the tumors became even more resistant to treatment.

“This molecular tread for PI3K to SOX2 to aldehyde was responsible for all the features that define cancer stem cells,” Keysar said. “Since SOX2-expressing cells fully behave like cancer stem cells, we now have a new laboratory tool to study cancer stem cell biology and therapeutics.”

In addition to the findings, the study allowed researchers to witness asymmetric division of cancer stem cells, which had only been partially characterized in head and neck cancer. Researchers were also able to document that when cancer stem cells divide, they don’t divide into 2 of the same.

Instead, 1 cell retains a stem profile, while the other goes a step beyond into differentiation, according to the study. Overall, the 7-year study provided 3 major advances: it characterized head and neck cancer stem cells; documented asymmetric division in head and neck cancer stem cells; and identified the genetic mechanisms that allow the cancer stem cells to grow and resist treatment.

“SOX2 and aldehyde inhibitors are now under exploration, and we’ve also done trials of early PI3K inhibitors here at CU Cancer Center,” Jimeno said.

Authors noted that by identifying these 3 genetic mechanisms of resistance, it could help physicians and researchers overcome it.

“This has been an excellent example of team science,” Roop said. “You have Antonio [Jimeno] — a brilliant young clinician scientist – leading a group that includes basic scientists, pathologists, bio-informaticians, and statisticians, and their expertise can combine to attack a problem in a way that no individual would be able to do on their own. This work will provide the basis for the development of new therapeutic strategies.”