Gatekeeper Gene Linked with Aggressive Lung Cancers

Lung cancer, conceptual image
Lung cancer, computer illustration showing malignant tumour in the lung.

A study of the molecular mechanisms behind lung cancer found that the protein ΔNp63 contributes to disease development in two aggressive lung cancer types: lung adenocarcinoma and lung squamous cell carcinoma. In a paper published in Nature Communications, In a paper published in Nature Communications, researchers from the Department of Molecular Oncology at the H. Lee Moffitt Cancer Center found that the protein controls stem cells and crucial elements known as enhancers involved in the regulation of cell identity.

Known to be oncogenic in other tumor types, one of the properties of the ΔNp63 protein is inhibitor of the tumor suppressor p53, an important pathway for tumors. “This study provided us with novel insights on lung tumors that have an inactive p53 pathway,” says first author Marco Napoli, PhD, research scientist in the laboratory of Elsa R. Flores, Ph.D. Researchers at Moffitt had previously investigated ΔNp63 in other tumor types – namely breast cancer and squamous cell carcinoma of the skin – discovering its importance for the stem cell potential of respective tissues.

To learn more about the protein’s role in lung cancer, Moffitt researchers mined data from the Tumor Cancer Genome Atlas (TCGA) looking for the gene signatures regulated by ΔNp63 delta and the clinical features of lung adenocarcinoma and lung squamous cell carcinoma.

“What we found is that the the genes that are regulated by this transcription factor, ΔNp63, correlate with poorer overall survival and higher-grade staging of these tumor types,” Napoli explains. To learn more about its role in these tumors, they studied its function in vivo using mouse models deficient in ΔNp63  to characterize the protein’s role.

“We observed that mice that did not have this protein had fewer tumors and the tumors were of a lower grade compared to the wildtype mouse that still expressed this oncogene,” he says. “Losing this protein counteracts tumor formation and progression.”

Because the team knew ΔNp63  was an important regulator of skin stem cells in the skin, they studied if that was the case in lung stem cells of lung. “Indeed, we found that if we deleted this gene, the stem cells of the lung did not work properly;  they were losing their regeneration potential, their capability to divide and differentiate into the different cell types of the lung,” says Napoli.

The study included two of the most aggressive and deadly types of lung cancer:  lung adenocarcinoma and lung squamous cell carcinoma. Both arise from mutations in specific stem cells. In the case of lung squamous cell carcinomas these stem cells are called basal cells. In lung adenocarcinoma, the stem cells are called AT2 (alveolar Type 2). “What we found is that if we deleted ΔNp63 from these two stem cell types, there was an alteration in expression of cell identity genes, which govern the features of these stem cells,” says Napoli. When overexpressed, some of these cell identity genes promote lung cancer. Specifically, the team found that one of these cell identity genes, BCL9L, is in common to basal cells and AT2 cells.

BCL9L has been associated in colon adenocarcinoma, hepatocellular adenocarcinoma, and pancreatic cancers which Napoli emphasizes are all aggressive and deadly cancer  types like lung cancer.

“In this paper, we are the first to find that BCL9L to be an oncogene that can promote both lung adenocarcinoma and lung squamous cell carcinoma,” Napoli explains. The researchers also discovered that lung adenocarcinoma patients who have high levels of BCL9L have a poorer prognosis. “This suggests the possibility that targeting ΔNp63 or BCL9L could provide alternative therapeutic ways to treat these lung cancer types.”

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