Epithelial-to-Mesenchymal Transition Rewires the Molecular Path to PI3K-Dependent Proliferation
Published version of a preprint
Abstract
Tumors showing evidence of epithelial-to-mesenchymal transition (EMT) have been associated with metastasis, drug resistance, and poor prognosis. Heterogeneity along the EMT spectrum is observed between and within tumors. To develop effective therapeutics, a mechanistic understanding of how EMT affects the molecular requirements for proliferation is needed. We found that although cells use phosphoinositide 3-kinase (PI3K) for proliferation in both the epithelial and mesenchymal states, EMT rewires the mechanism of PI3K pathway activation. In epithelial cells, autocrine ERBB3 activation maintains PI3K signaling, whereas after EMT, downregulation of ERBB3 disrupts autocrine signaling to PI3K. Loss of ERBB3 leads to reduced serum-independent proliferation after EMT that can be rescued through reactivation of PI3K by enhanced signaling from p110α, ERBB3 reexpression, or growth factor stimulation. In vivo, we demonstrate that PIK3CA expression is upregulated in mesenchymal tumors with low levels of ERBB3. This study defines how ERBB3 downregulation after EMT affects PI3K-dependent proliferation. Significance: This study describes a mechanism through which EMT transition alters the proliferative potential of cells by modulating ERBB3 expression. Furthermore, it demonstrates the potential for multiple molecular routes to drive proliferation in different cell states, illustrating how changes in EMT status can rewire signaling upstream of cell proliferation. Cancer Discov; 4(2); 186–199. ©2013 AACR. See related commentary by Niederst and Benes, p. 149 This article is highlighted in the In This Issue feature, p. 131
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High feedback activation of the FGFR/AXL signaling pathway was found in mesenchymal cells.
“High feedback activation of the FGFR/AXL signaling pathway was found in mesenchymal cells.”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [138]
Inhibition of the FGFR signaling pathway reduces ERK and mTOR activation, whereas AXL inhibition attenuates the activation of PI3K pathway.
“Inhibition of the FGFR signaling pathway reduces ERK and mTOR activation, whereas AXL inhibition attenuates the activation of PI3K pathway [43, 136–139].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [138]
Oncogenic KRAS signaling involves PI3K-AKT-mTOR via interaction with the catalytic subunits of PI3K.
“Oncogenic KRAS signaling also involves PI3K-AKT-mTOR, via the interaction with the catalytic subunits of PI3K (78–80).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [79]
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- Authors
- Salt, M. B., Bandyopadhyay, S., & McCormick, F.
- Affiliations
- University of California, San Francisco (US)
- Venue
- Cancer Discovery
- Published
- 2014-02-01
- Volume
- 4
- Issue
- 2
- Pages
- 186-199
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2068769869
- Cited by
- 124
- References
- 39
- Citations by year
- 2025: 4 · 2024: 27 · 2023: 11 · 2022: 7 · 2021: 13 · 2020: 11 · 2019: 11 · 2018: 4 · 2017: 8 · 2016: 9 · 2015: 12 · 2014: 6 · 2013: 1
- FWCI
- 4.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Association for Cancer Research
- Gladstone Institutes
- University of California, San Francisco
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- epithelial-mesenchymal transition, PI3K signaling, cell proliferation, HER3, PIK3CA, p110α, autocrine signaling, tumor heterogeneity, mesenchymal tumors
- MeSH terms
- Humans, Lung Neoplasms, Signal Transduction, Gene Expression Regulation, Neoplastic, Cluster Analysis, Phosphatidylinositol 3-Kinases, Autocrine Communication, Gene Expression Profiling, Receptor, ErbB-3, Intercellular Signaling Peptides and Proteins, Cell Line, Tumor, Cell Proliferation, Proto-Oncogene Proteins c-akt, Gene Knockdown Techniques, Epithelial-Mesenchymal Transition, ErbB Receptors
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