TGFB1-induced autophagy affects the pattern of pancreatic cancer progression in distinct ways depending on SMAD4 status
Open accessAbstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies. Given that macroautophagy/autophagy activation is prevalent in PDAC, the dual roles of autophagy could be involved in PDAC heterogeneity. In this work, we demonstrated that TGFB1 induced autophagic flux through SMAD4-dependent or SMAD4-independent pathways based on a distinct genetic context. In SMAD4-positive PDAC cells, TGFB1-induced autophagy promoted proliferation and inhibited migration by decreasing the nuclear translocation of SMAD4. Conversely, TGFB1-induced autophagy inhibited proliferation and promoted migration in SMAD4-negative cells through the regulation of MAPK/ERK activation. TGFB1 expression also positively correlated with LC3B expression in PDAC specimens. A high level of LC3B was associated with unfavorable overall survival (OS) and disease-free survival (DFS) in SMAD4-negative PDAC patients, although LC3B could not predict OS and DFS for the 110 PDAC patients. Thus, TGFB1-induced autophagy contributed to the different patterns of PDAC progression. This knowledge can aid in improving our understanding of the molecular classification of PDAC and might guide the development of therapeutic strategies for PDAC, especially for SMAD4-negative PDAC.Abbreviations CDH1: cadherin 1; CDH2: cadherin 2; CI: combination index; CQ: chloroquine; DFS: disease-free survival; EMT: epithelial-to-mesenchymal transition; ERK: extracellular signal-regulated protein kinase; GFP: green fluorescent protein; IHC: immunohistochemistry; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPK: mitogen-activated protein kinase; OS: overall survival; PBS: phosphate-buffered saline; PDAC: pancreatic ductal adenocarcinoma; RAP: rapamycin; RFP: red fluorescent protein; RT: room temperature; shRNA: short-hairpin RNA; SQSTM1: sequestosome 1; TCGA: The Cancer Genome Atlas; TEM: transmission electron microscopy; TGFB1: transforming growth factor beta 1; TMA: tissue microarray
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TGFB1-induced autophagy is more pronounced in SMAD4-negative cells.
“TGFB1-induced autophagy was more pronounced in SMAD4-negative cells.”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [69]
LC3B expression correlates with poor prognosis in SMAD4-negative PDAC patients.
“LC3B expression correlated with poor prognosis in SMAD4-negative PDAC patients, suggesting its potential as a prognostic marker [69].”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [69]
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Guidelines for the use and interpretation of assays for monitoring autophagy
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“Therefore, the patterns of disease progression are not solely affected by SMAD4 status, and controversy remains in the prognostic value of SMAD4 status, especially in resected PDAC [22,25].”
BackgroundSMAD4 Expression Predicts Local Spread and Treatment Failure in Resected Pancreatic Cancer
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Dai, E., Han, L., Liu, J., Xie, Y., Kroemer, G., Klionsky, D. J., Zeh, H. J., Kang, R., Wang, J., & Tang, D. (2020) · Autophagy · doi:10.1080/15548627.2020.1714209 · Cited by 613 · see citing works
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Self-citationSignificance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer
Stefanoudakis, D., Frountzas, M., Schizas, D., Michalopoulos, N. V., Drakaki, A., & Toutouzas, K. G. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46040177 · Cited by 110 · see citing works
- Authors
- Liang, C., Xu, J., Meng, Q., Zhang, B., Liu, J., Hua, J., Zhang, Y., Shi, S., & Yu, X.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- Corresponding author
- Shi, Si
- Yu, Xianjun
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2019-06-17
- Volume
- 16
- Issue
- 3
- Pages
- 486-500
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- PMC
- PMC6999639
- OpenAlex
- W2949637147
- Cited by
- 106
- References
- 4
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 14 · 2023: 17 · 2022: 31 · 2021: 24 · 2020: 8 · 2019: 1
- FWCI
- 5.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Autophagy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81502031)
- National Science Foundation for Distinguished Young Scholars of China (81625016)
- Shanghai Sailing Program (17YF1402500)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- pancreatic ductal adenocarcinoma, TGF-β1, SMAD4, autophagic flux, ERK signaling, cell proliferation, cell migration, LC3B, tumor progression, prognostic factors, tumor heterogeneity
- MeSH terms
- Sequestosome-1 Protein, Adenocarcinoma, Autophagy, Cell Nucleus, Female, Humans, Male, Microtubule-Associated Proteins, Middle Aged, Pancreatic Neoplasms, Prognosis, Disease Progression, MAP Kinase Signaling System, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Smad4 Protein, Transforming Growth Factor beta1
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