ID1 Mediates Escape from TGFβ Tumor Suppression in Pancreatic Cancer
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Abstract
TGFβ is an important tumor suppressor in pancreatic ductal adenocarcinoma (PDA), yet inactivation of TGFβ pathway components occurs in only half of PDA cases. TGFβ cooperates with oncogenic RAS signaling to trigger epithelial-to-mesenchymal transition (EMT) in premalignant pancreatic epithelial progenitors, which is coupled to apoptosis owing to an imbalance of SOX4 and KLF5 transcription factors. We report that PDAs that develop with the TGFβ pathway intact avert this apoptotic effect via ID1. ID1 family members are expressed in PDA progenitor cells and encode components of a set of core transcriptional regulators shared by PDAs. PDA progression selects against TGFβ-mediated repression of ID1. The sustained expression of ID1 uncouples EMT from apoptosis in PDA progenitors. AKT signaling and mechanisms linked to low-frequency genetic events converge on ID1 to preserve its expression in PDA. Our results identify ID1 as a crucial node and potential therapeutic target in PDA. Significance: Half of PDAs escape TGFβ-induced tumor suppression without inactivating the TGFβ pathway. We report that ID1 expression is selected for in PDAs and that ID1 uncouples TGFβ-induced EMT from apoptosis. ID1 thus emerges as a crucial regulatory node and a target of interest in PDA. This article is highlighted in the In This Issue feature, p. 1
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The regulatory consequences of Sp/Klf motif enrichment are in genes associated with modulation of reactive oxygen species and metabolism such as SOD1, ID1, and NDUFV2.
“In doing so, we find that the regulatory consequences of Sp/Klf motif enrichment are in genes associated with modulation of reactive oxygen species and metabolism such as SOD144, ID145, and NDUFV246.”
From Occult polyclonality of preclinical pancreatic cancer models drives in vitro evolution (2022) · cites this paper as [45]
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TGF-β signaling in health and disease
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“ID1 was also shown to mediate the escape of pancreatic cancer from TGFβ tumor suppression.(81) TGFβ can increase the expression of B-cell lymphoma 2 (BCL2)-interacting mediator of cell death (BIM), BCL2-modifying factor (BMF), FAS and death-associated protein kinase (DAPK) genes and decrease the expression of BCL2 and…”
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Self-citationOccult polyclonality of preclinical pancreatic cancer models drives in vitro evolution
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- Authors
- Huang, Y.-H., Hu, J., Chen, F., Lecomte, N., Basnet, H., David, C. J., Witkin, M. D., Allen, P. J., Leach, S. D., Hollmann, T. J., Iacobuzio-Donahue, C. A., & Massagué, J.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- 4The David M. Rubinstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
- Corresponding author
- Massagué, Joan
- ORCID
- Venue
- Cancer Discovery
- Published
- 2020-01-01
- Volume
- 10
- Issue
- 1
- Pages
- 142-157
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC6954299
- OpenAlex
- W2977756441
- Cited by
- 78
- References
- 53
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 5 · 2023: 15 · 2022: 18 · 2021: 10 · 2020: 15
- FWCI
- 3.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NCI (R01-CA34610, R35-CA220508, F30-CA203238)
- MSKCC (P30-CA008748)
- Medical Scientist (T32-GM007739)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- Id1, TGF-beta signaling, pancreatic ductal adenocarcinoma, epithelial-mesenchymal transition, apoptosis, SOX4, KLF5, Akt signaling, therapeutic target
- MeSH terms
- Animals, Female, Humans, Mice, Nude, Pancreatic Neoplasms, Tumor Cells, Cultured, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Transforming Growth Factor beta, Apoptosis, Carcinoma, Pancreatic Ductal, Xenograft Model Antitumor Assays, Cell Proliferation, Mice, Inhibitor of Differentiation Protein 1, Epithelial-Mesenchymal Transition
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