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Updated: Nov 23, 2025
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Targeting the mutant p53 secretome
Kartik Sehgal1,2, David A Barbie1,2
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Abstract:
While p53 is the most highly mutated and perhaps best studied tumor suppressor protein related to cancer, it remains refractory to targeted therapeutic strategies. In this issue of the JCI, Tan and colleagues investigated the mechanistic basis of the mutant p53 secretome in preclinical models of lung adenocarcinoma. The authors uncovered miR-34a as a regulator of a conventional protein secretion axis, which is mediated by three proteins: the Golgi reassembly and stacking protein 55 kDa (GRASP55), basic leucine zipper nuclear factor 1, and myosin IIA. Inhibition of GRASP55 in TP53-deficient lung adenocarcinoma suppressed protumorigenic secretion of osteopontin/secreted phosphoprotein 1 and insulin-like growth factor binding protein 2 and reduced tumor growth and metastases in mice as well as in patient-derived xenografts. These results provide a therapeutic opportunity to target downstream effects of p53 loss.
Insights
Researchers identified a novel therapeutic target for lung adenocarcinoma by uncovering how mutant p53 proteins are secreted. Inhibiting GRASP55 suppressed tumor growth and metastasis, offering a new strategy against p53-deficient cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- The tumor suppressor protein p53 is frequently mutated in cancer and remains a therapeutic challenge.
- Understanding the mechanisms of mutant p53's role in cancer progression is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the mechanistic basis of the mutant p53 secretome in preclinical models of lung adenocarcinoma.
- To identify novel therapeutic targets for TP53-deficient lung cancers.
Main Methods:
- Investigated the role of microRNA-34a (miR-34a) in regulating protein secretion.
- Examined the involvement of Golgi reassembly and stacking protein 55 kDa (GRASP55), basic leucine zipper nuclear factor 1, and myosin IIA in the secretion pathway.
- Assessed the effects of GRASP55 inhibition in TP53-deficient lung adenocarcinoma models.
Main Results:
- Discovered miR-34a as a regulator of a conventional protein secretion axis involving GRASP55, NF-Y, and myosin IIA.
- Inhibition of GRASP55 suppressed the secretion of osteopontin and IGFBP2, which promote tumor growth.
- Reduced tumor growth and metastasis in mice and patient-derived xenografts upon GRASP55 inhibition.
Conclusions:
- The study reveals a novel secretion pathway regulated by miR-34a and involving GRASP55, crucial for mutant p53-driven lung adenocarcinoma.
- Targeting GRASP55 presents a promising therapeutic strategy to counteract the protumorigenic effects of p53 loss in lung cancer.
