Lung cancer is the second leading cancer in the United States and the No. 1 cause of cancer-associated deaths. Despite significant advancements in treatment choices, most lung cancer patients have dismal results, with a five-year survival rate of 21.7% on average.
Moffitt Cancer Center researchers are attempting to better their insights into the molecular mechanisms behind lung cancer to help find novel therapeutic targets for this population of patients.
Elsa R. Flores PhD, Associate Center Director, Basic Science. Image Credit: Moffitt Cancer Center.
The laboratory of Elsa R. Flores PhD, in collaboration with Baylor College of Medicine and MD Anderson Cancer Center, demonstrates how the protein ΔNp63 appears to contribute to disease progression through the regulation of stem cells and crucial aspects known as enhancers, which regulate factors that influence cell identity. The research was published in the journal Nature Communications.
Changes in signaling pathways in stem cells, according to one popular theory of cancer genesis, may contribute to disease development. Stem cells are found in all tissues and can self-renew as well as develop into a variety of cell types. ΔNp63 is a protein that is involved in the control of stem cells and skin malignancies. It is also produced in the lungs, although nothing is known about how this might contribute to the development of lung cancer.
According to Moffitt researchers, ΔNp63 may have comparable activities in the lungs as it does in the skin. To characterize the significance of ΔNp63 in lung cancer formation, researchers conducted a series of laboratory tests employing preclinical mice models of lung adenocarcinoma and squamous cell carcinoma, as well as human cancer cell lines.
They generated animals lacking ΔNp63 in the lungs and found that the mice lacking ΔNp63 grew fewer lung cancers and had fewer stem cells than control mice. These findings show that, like in the skin, ΔNp63 may act as a tumor promoter and govern the self-renewal and differentiation of stem cells in the lungs.
The Flores team then looked into the molecular mechanisms governed by ΔNp63 and determined that the protein controls the enhancer region of genes involved in cell diversification and identity, with BCL9L being one of the crucial genes.
BCL9L facilitates the tumor-promoting activities of Np63 in the lung cancer subtypes adenocarcinoma and squamous cell carcinoma, according to thorough studies. Researchers also discovered that patients with lung adenocarcinoma who had high levels of BCL9L have a worse outlook.
Our findings demonstrate a unifying oncogenic role for ΔNp63 that modulates the enhancer landscape in lung cancer stem cells in both lung adenocarcinoma and squamous cell lung cancer. We will use these findings to develop novel therapeutic approaches to inhibit development of these highly deadly tumor types.”
Elsa. R. Flores, Associate Center Director, Basic Science, Moffitt Cancer Center
Elsa. R. Flores is also a senior member of the Department of molecular oncology.
Napoli, M., et al. (2022) ΔNp63 regulates a common landscape of enhancer associated genes in non-small cell lung cancer. Nature Communications. doi.org/10.1038/s41467-022-28202-1.