SPOCK1 and TWIST2 have been identified as regulators of brain metastases in patients with lung cancer, according to researchers at the Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada. They published their findings in the journal Acta Neuropathologica.
In cancer patients, brain metastases are a leading cause of death, as well as being the most common brain tumor in adults.
“Brain metastases are a secondary brain tumor, which means they are caused by cancer cells that escape from primary tumors like lung, breast, or melanoma, and travel to the brain,” said lead author Mohini Singh, PhD candidate, biochemistry, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.
“We set out to find which genes can regulate the cells that initiate brain metastases, which we've termed brain metastasis initiating cells or BMICs. In other words, what are the genes that are sending the signal to these lung BMICs to leave the lung tumor, go into the blood stream, invade the blood-brain barrier and form a tumor in the brain,” added Singh. “If you can identify the genes that cause metastases, then you can determine a predictive model and you can work towards blocking those genes with possible treatments.”
For this study, these researchers used samples from patients with lung cancer who had brain metastases. They incubated these samples to enrich for BMICs, and then injected this into the lungs, hearts, and brains of mice, and studied the ensuing development of brain metastases.
With in vitro and in vivo RNA interference screens of these BMIC models, Singh and colleagues identified SPOCK1 and TWIST2 as essential BMIC regulators. They found that SPOCK1 is a novel regulator of BMIC self-renewal that acts to modulate tumor initiation and metastasis from the lung to the brain. A prospective cohort of primary lung cancer specimens demonstrated that SPOCK1 was overexpressed only in patients who ultimately developed brain metastases.
“If you look at a set of lung cancer patients, like we did in the paper, who develop brain metastases, they all have those two genes in their primary lung cancer,” said research supervisor Sheila Singh, MD, PhD, associate professor, Michael G. DeGroote School of Medicine; scientist, Stem Cell and Cancer Research Institute, McMaster University; and neurosurgeon, McMaster Children’s Hospital. “Patients who don’t get brain metastases don’t have these genes in their primary lung cancer.”
Via protein-protein interaction network mapping between SPOCK1 and TWIST2, they identified pathway interactors with significant prognostic value in lung cancer patients. Among these, expression of INHBA, which is a TGF-beta ligand that mutates in lung adenocarcinoma, was reduced in BMICs with SPOCK1 knockdown.
The research was funded by the Department of Surgery at McMaster University, the Ontario Institute for Cancer Research Cancer Stem Cell Program, a Canadian Cancer Society Research Institute Innovation Grant, the Brain Canada Foundation, and the Boris Family Fund for Brain Metastasis Research.