HIPPO PATHWAY IN PEDIATRIC BONE TUMORS

A particular molecular pathway permits stem cells in pediatric bone cancers to grow rapidly and aggressively, according to researchers at NYU Langone Medical Center and its Laura and Isaac Perlmutter Cancer Center. These findings were published by Basu-Roy et al in Nature Communications.

Study Background

In normal cell growth, the Hippo pathway (which controls organ size in animals) works as a dam, regulating cell proliferation. Researchers found that the transcription factor of a DNA binding protein called "sex determining region Y box 2," or Sox2, which normally maintains cell self-renewal, releases the floodgates in the Hippo pathway in osteosarcomas and other cancers. This permits the growth of highly aggressive, tumor-forming stem cells.

“This study is one of the first to identify the mechanisms that underlie how an osteosarcoma cancer stem cell maintains its tumor-initiating properties,” said senior study investigator Claudio Basilico, MD, the Jan T. Vilcek Professor of Molecular Pathogenesis at NYU Langone and a member of its Perlmutter Cancer Center.

Study Details

In the study, the investigators used human and mouse osteosarcomas to pinpoint the molecular mechanisms that inhibit the tumor-suppressive Hippo pathway. The researchers concluded that Sox2 represses the functioning of the Hippo pathway, which, in turn, leads to an increase of the potent growth stimulator Yes-associated protein, known as YAP, permitting cancer cell proliferation.

“Our research is an important step forward in developing novel targeted therapies for these highly aggressive cancers,” said study coinvestigator Alka Mansukhani, PhD, an Associate Professor at NYU Langone and also a member of the Perlmutter Cancer Center. “One possibility is to develop a small molecule that could knock out the Sox2 transcription factor and free the Hippo pathway to reexert tumor suppression.”

Dr. Mansukhani added that the research suggests that drugs such as verteporfin, which interfere with cancer-promoting YAP function, might prove useful in Sox2-dependent tumors.

The study expands on previous work in Dr. Basilico's and Dr. Mansukhani's molecular oncology laboratories at NYU Langone, and on earlier work by Upal Basu-Roy, PhD, MPH, the lead study investigator, who found that Sox2 was an essential transcription factor for the maintenance of osteosarcoma stem cells.

The NYU group has shown that, in addition to playing a role in osteosarcoma, Sox2 operates in other tumors, such as glioblastomas.

Drs. Mansukhani and Basilico are the corresponding authors for the Nature Communications article.

The research was supported by the National Cancer Institute and the New York State Health Department.