Tumor suppression by cell competition through regulation of the Hippo pathway
Open accessAbstract
Homeostatic mechanisms can eliminate abnormal cells to prevent diseases such as cancer. However, the underlying mechanisms of this surveillance are poorly understood. Here we investigated how clones of cells mutant for the neoplastic tumor suppressor gene scribble ( scrib ) are eliminated from Drosophila imaginal discs. When all cells in imaginal discs are mutant for scrib, they hyperactivate the Hippo pathway effector Yorkie (Yki), which drives growth of the discs into large neoplastic masses. Strikingly, when discs also contain normal cells, the scrib − cells do not overproliferate and eventually undergo apoptosis through JNK-dependent mechanisms. However, induction of apoptosis does not explain how scrib − cells are prevented from overproliferating. We report that cell competition between scrib − and wild-type cells prevents hyperproliferation by suppressing Yki activity in scrib − cells. Suppressing Yki activation is critical for scrib − clone elimination by cell competition, and experimental elevation of Yki activity in scrib − cells is sufficient to fuel their neoplastic growth. Thus, cell competition acts as a tumor-suppressing mechanism by regulating the Hippo pathway in scrib − cells.
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Increased JNK or Yki activity has been linked to tumour growth.
“JNK and Yki are known to interact in a context-dependent manner (12-14,32), and increased JNK or Yki activity has been linked to tumour growth (12,33-35).”
From A Tumour-Specific Molecular Network Promotes Tumour Growth in <i>Drosophila</i> by Enforcing a JNK-YKI Feedforward Loop (2023) · cites this paper as [12]
The Discussion reports that increased Yki activity drives hyperproliferation of scrib mutant clones, supporting the Yki part of the claim. For JNK, the Results and Discussion say its activity suppresses Yki and counteracts the growth of those clones, rather than linking increased JNK activity to their tumour growth. (LLM, conf=0.87)
Experimental — accuracy not yet measuredLoss of polarity (scrib) alone is insufficient to induce aggressive growth in somatic clones.
“Loss of polarity ( scrib ) alone is insufficient to induce aggressive growth in somatic clones (Fig. 1, S1) (8,9,12,30)”
From A Tumour-Specific Molecular Network Promotes Tumour Growth in <i>Drosophila</i> by Enforcing a JNK-YKI Feedforward Loop (2023) · cites this paper as [12]
Elimination of scrib- cells by cell competition involves JNK-dependent suppression of Yki activity.
“In contrast, elimination of scrib -cells by cell competition involved JNK-dependent suppression of Yki activity (12,30,36-38).”
From A Tumour-Specific Molecular Network Promotes Tumour Growth in <i>Drosophila</i> by Enforcing a JNK-YKI Feedforward Loop (2023) · cites this paper as [12]
JNK and Yki are known to interact in a context-dependent manner.
“JNK and Yki are known to interact in a context-dependent manner (12-14,32), and increased JNK or Yki activity has been linked to tumour growth (12,33-35).”
From A Tumour-Specific Molecular Network Promotes Tumour Growth in <i>Drosophila</i> by Enforcing a JNK-YKI Feedforward Loop (2023) · cites this paper as [12]
JNK signaling also acts to suppress hyperproliferation of scribble mutant clones.
“JNK signaling also acts to suppress hyperproliferation of scribble mutant clones (Brumby and Richardson, 2003; Igaki et al., 2009; Chen et al., 2012).”
From Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation (2019) · cites this paper as Chen et al., 2012
Elevated expression of Hippo target genes occurs in homozygous scribble mutant discs and in mosaics where scribble mutant clones are neighbored by cells of compromised fitness.
“Elevated expression of Hippo target genes occurs in homozygous scribble mutant discs and in mosaics where scribble mutant clones are neighbored by cells of compromised fitness (Chen et al., 2012; Verghese et al., 2012).”
From Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation (2019) · cites this paper as Chen et al., 2012
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Self-citation
- Authors
- Chen, C.-L., Schroeder, M. C., Kango-Singh, M., Tao, C., & Halder, G.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Baylor College of Medicine (US)
- Department of Biology, Center for Tissue Regeneration and Engineering at Dayton, University of Dayton, Dayton, OH 45469; and
- Department of Biochemistry and Molecular Biology and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-12-21
- Volume
- 109
- Issue
- 2
- Pages
- 484-489
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3258595
- OpenAlex
- W2012163308
- Semantic Scholar
- cd63fc92ed1f004ae92b2afa25f0bd7d3284f47c
- Cited by
- 187
- References
- 33
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 6 · 2023: 9 · 2022: 15 · 2021: 15 · 2020: 11 · 2019: 22 · 2018: 12 · 2017: 9 · 2016: 11 · 2015: 16 · 2014: 16 · 2013: 17 · 2012: 11
- FWCI
- 6.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion, other-oa)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- cell competition, Hippo signaling pathway, Yorkie, Scribble, tumor suppression, imaginal discs, Drosophila, apoptosis, JNK signaling, neoplastic growth, cell proliferation
- MeSH terms
- YAP-Signaling Proteins, Hippo Kinases, Animals, Cells, Cultured, Drosophila, Gene Expression Regulation, Genotype, Membrane Proteins, Nuclear Proteins, Signal Transduction, Trans-Activators, Protein Serine-Threonine Kinases, Tumor Suppressor Proteins, Drosophila Proteins, Intracellular Signaling Peptides and Proteins, Cell Proliferation, Imaginal Discs
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