In In The News by Barbara Jacoby

From: UC Davis Comprehensive Cancer Center

Protein blocks dangerous epithelial-to-mesenchymal transition

Researchers at UC Davis have shown that the protein LRIG1 reduces breast cancer invasion and could potentially help control metastasis. Using aggressive basal-like breast cancer cell lines, the scientists found that restoring LRIG1 expression reduced these cells’ growth and invasiveness.

The findings provide strong evidence that LRIG1 could be exploited therapeutically to block metastasis. The research was published online today in the journal Oncogene.

“The loss of LRIG1 has been linked to poor clinical outcomes in a number of cancers,” said Colleen Sweeney, senior author, professor and director of the Breast Cancer Research Program at the UC Davis Comprehensive Cancer Center. “On the other hand, patients whose breast cancers have retained LRIG1 expression demonstrate longer metastasis-free survival. Now, for the first time, we have shown in the lab that LRIG1 has metastasis-suppressing properties.”

The study was led by Nucharee Yokdang, a UC Davis post-doctoral fellow. Also first author on the paper, Yokdang has a long-standing interest in developing novel strategies to combat breast cancer metastasis.

Mesenchymal cells are critical to early development, migrating throughout the body to form organs and other structures. However, cancer hijacks this process, converting stationary epithelial cells into nomadic mesenchymal ones. This transformation gives cancer cells the ability to move around the body and invade healthy tissues, making them much more dangerous.

“As cancer cells become more mesenchymal, they become more invasive, aggressive and metastatic — all the things we don’t want them to do,” Sweeney said.

To determine whether LRIG1 could block this process, Sweeney’s team studied human mammary epithelial cells specifically engineered to undergo the epithelial-to-mesenchymal transition (EMT). LRIG1 depletion sped up the transition, while induced expression of LRIG1 opposed it, serving as an endogenous “barrier” to EMT. The team achieved equally promising results when studying aggressive triple-negative, basal-like breast cancer cells. When they restored LRIG1, these cells lost their ability to migrate and invade.

“We really knocked them back to a much less aggressive form,” Sweeney said. “LRIG1 made them revert to a more normal phenotype.”

In addition, LRIG1 suppressed markers associated with tumor-initiating cells, also known as cancer stem cells, indicating the protein could knock down these dangerous cells.

“Most scientists believe it’s the tumor-initiating cells that underlie metastasis, recurrence and treatment resistance,”  Sweeney said. “There have been ongoing efforts to target this population.”

While these efforts indicate LRIG1 has great potential as a cancer treatment, there is still much work to be done. Breast cancer cells have shown the ability to down-regulate the protein, escaping LRIG1’s therapeutic effects. The Sweeney research team is continuing to refine their approach, developing smaller versions of the tumor suppressor that could better target breast and other cancers.

“If we make a soluble form of the protein, while preserving its ability to suppress metastasis, it would be much easier to deliver,” Sweeney said. “We could take away cancer’s most deadly feature, and it could then be treated as a chronic, not a life-threatening, disease.”

In addition to Sweeney and Yokdang, other UC Davis researchers on the study included: J Hatakeyama, JH Wald, C Simion, JD Tellez, DZ Chang, MM Swamynathan, M Chen, WJ Murphy and KL Carraway III.

This research was funded by the NIH (CA118384, CA166412 and CA108459), NCI (NCI P30CA093373) and a Lawrence Livermore National Labs UC Davis Fitzpatrick Research Fellowship. Yokdang is supported by the NIH Training Program in Oncogenic Signals and Chromosome Biology, NIH-2 T32 CA108459-09 and the NCI Cancer Center Support Grant.