Lung cancer is the second most commonly diagnosed cancer and is the leading cause of cancer death worldwide, with an estimated 1.8 million deaths in 2020 (2). Mutations in the TP53 tumor suppressor gene occur in 50% of lung adenocarcinoma and associate with a poor prognosis.
“However, mechanisms of p53-mediated lung cancer suppression remain a mystery. We sought to establish how p53 restrains the development of lung adenocarcinoma and how these tumor suppression programs might be implicated in governing pulmonary hemeostasis,” says José A. Seoane, Principal Investigator of the Vall d’Hebron Institute of Oncology’s (VHIO) Cancer Computational Biology group and a co-author of this present study (1) led by first author Alyssa Kaiser, Postdoctoral Research Fellow, the Division of Radiation and Cancer Biology at the Stanford University School of Medicine (CA, USA).
Tumor suppressor genes including TP53 are implicated in various biological processes such as cell division, regulation of gene expression, cell-cycle control, and programmed cell death. Alterations and mutations in these genes can cause cells to become malignant and multiply out of control, leading to the development of tumors.
The investigators, led by corresponding author Laura D. Attardi, Professor of Radiation Oncology and of Genetics at the Stanford University School of Medicine, have shed preclinical light on the mechanisms of p53-mediated lung adenocarcinoma, in which p53 governs the differentiation of pulmonary alveolar type 1 (AT1) cells. Their findings, published in Nature (1), also suggest that tumor suppression reflects a fundamental role of p53 in orchestrating tissue repair after cell damage.
p53 as a super-suppressor of lung cancer initiation and progression
“In engineered mouse models, the researchers observed that mice with just one or without mutations in p53 had fewer and smaller tumors versus those bearing a total p53 loss. In mice with mutant p53 proteins, findings showed that epigenetic changes were produced by chromatin modification that altered the identity of normal lung cells, driving differentiation into AT1 cells”.
“We subsequently analyzed genomic data to evaluate if the same thing observed in mice and cell lines could be seen in human lung tumor samples, mainly in adenocarcinoma, with and without p53 mutations. We confirmed that samples with mutations in p53 also presented gene expression signatures associated with significantly reduced AT1 cell character,” adds Seoane.
Collectively, results of this study illuminate mechanisms of p53-mediated adenocarcinoma suppression, in which p53 governs AT1 differentiation, and suggest that promoting AT1 differentiation may mimic critical functions of p53 and provide a promising new treatment avenue for patients with lung adenocarcinoma.
“Considering the poor outcomes associated with p53 mutation in lung adenocarcinoma, our findings point to the promise of differentiation therapy for this patient population. This strategy is already showing success in the treatment of other tumor types, particularly in acute promyeloid leukemia,” concludes José A. Seoane.
VHIO’s Cancer Computational Biology Group, directed by José A. Seoane, is supported by funding received from the “la Caixa” Foundation.
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