Uncovering a protein’s key role in the spread of ovarian cancer
A protein beacon on the surface of runaway ovarian cancer cells guides them to a sanctuary organ where they take hold and spread.
MD Anderson researchers discovered that these circulating tumor cells (CTCs) rely specifically on the HER3 protein to home in on the omentum, a sheath of fatty tissue that covers and supports abdominal organs.
“This completely new way of thinking about ovarian cancer metastasis provides new potential avenues to predict and prevent recurrence or spread,” says Anil Sood, M.D., professor of Gynecologic Oncology and Reproductive Medicine and Cancer Biology.
HER3, the human epidermal growth factor receptor 3, is a sibling to the more famous HER2, active in 20 to 25% of breast cancer cases and a target for the drug trastuzumab, or Herceptin. HER3’s heavy presence on ovarian CTCs makes it both a potential indicator of metastasis and a new target for therapy.
Sood, the study’s senior author, first author Sunila Pradeep, Ph.D., an instructor in Gynecologic Oncology and Reproductive Medicine, and colleagues reported their findings in the journal Cancer Cell.
Anil Sood and his research team have discovered that certain ovarian cancer cells rely on a protein called HER3 to home in on the omentum, a sheath of fatty tissue that covers and supports abdominal organs. From there the cells spread.
The team used mouse model experiments to show that CTCs spread to the omentum, and more than 95% of those cells heavily expressed HER3. They also found that the protein that activates HER3 by fitting into it like a key in a lock was also heavily present in omental metastases.
This activating protein, called NRG1, was found to be more prominently expressed in and around the omentum than on neighboring organs.
“The NRG1 ligand expressed in the omentum attracts the HER3-positive CTCs,” Sood says.
Blocking HER3 might increase survival
In tumor samples from 11 ovarian cancer patients, 90% of cells were HER3-positive. Tumor cells found in the omental blood vessels of five patients also had strong HER3 expression.
In a cohort of 217 advanced-stage patients, lower HER3 expression correlated with improved overall survival of almost five years, compared with just over three years for high-HER3 tumors. Researchers found HER3 expression to be significantly higher in stage III and IV tumors compared with stage I and II tumors.
Sood notes the team’s findings could lead to use of HER3-positive cells as a biomarker for recurrence in patients or for occurrence in women at high risk for developing ovarian cancer. Maintenance anti-HER3 therapy after treatment could prevent or delay recurrence.
Drugs are being developed to block HER3. Its similarity to HER2 might make it vulnerable to drugs that hit that target. Clinical trials are underway for pertuzumab, an antibody that blocks HER2, to explore if it might thwart both proteins in ovarian and breast cancers.