An Ectopic Network of Transcription Factors Regulated by Hippo Signaling Drives Growth and Invasion of a Malignant Tumor Model
Open accessAbstract
Cancer cells have abnormal gene expression profiles; however, to what degree these are chaotic or driven by structured gene regulatory networks is often not known. Here we studied a model of Ras-driven invasive tumorigenesis in Drosophila epithelial tissues and combined in vivo genetics with next-generation sequencing and computational modeling to decipher the regulatory logic of tumor cells. Surprisingly, we discovered that the bulk of the tumor-specific gene expression is controlled by an ectopic network of a few transcription factors that are overexpressed and/or hyperactivated in tumor cells. These factors are Stat, AP-1, the bHLH proteins Myc and AP-4, the nuclear hormone receptor Ftz-f1, the nuclear receptor coactivator Taiman/SRC3, and Mef2. Notably, many of these transcription factors also are hyperactivated in human tumors. Bioinformatic analysis predicted that these factors directly regulate the majority of the tumor-specific gene expression, that they are interconnected by extensive cross-regulation, and that they show a high degree of co-regulation of target genes. Indeed, the factors of this network were required in multiple epithelia for tumor growth and invasiveness, and knockdown of several factors caused a reversion of the tumor-specific expression profile but had no observable effect on normal tissues. We further found that the Hippo pathway effector Yorkie was strongly activated in tumor cells and initiated cellular reprogramming by activating several transcription factors of this network. Thus, modeling regulatory networks identified an ectopic and ordered network of master regulators that control a large part of tumor cell-specific gene expression.
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Previously ectopic upregulation of a network of transcription factors (Upd, JAK-STAT, AP-1, Myc, Ftz, Ets, Irbp18, Xrp1, Slow border, and Vrille) promotes growth and invasiveness of RasV12,scrib- tumours.
“Previously ectopic upregulation of a network of transcription factors e.g., Upd, JAK-STAT, AP-1, Myc, Ftz, Ets, Irbp18, Xrp1, Slow border, and Vrille were reported to promote the growth and invasiveness of the Ras V12 ,scrib -tumours (53-57).”
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 [54]
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ResultLoss of ferritin in developing wing cells: Apoptosis and ferroptosis coincide
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“Furthermore, while Ras is active, Yorkie induces a coordinated network of pro-proliferative transcription factors that sustain tumor formation [13].”
BackgroundDeregulation and Therapeutic Potential of the Hippo Pathway in Cancer
Lin, K. C., Park, H. W., & Guan, K. (2017) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030617-050202 · Cited by 20 · see citing works
“…have highlighted the role of YAP/TAZ in driving oncogenesis by promoting transcriptional programs necessary for tumor growth and progression (Atkins et al. 2016, Verfaillie et al. 2015, Zanconato et al. 2015), and because all signals ultimately regulate the nuclear localization of YAP/TAZ,…”
BackgroundExploring MYC relevance to cancer biology from the perspective of cell competition
Paglia, S., Sollazzo, M., Giacomo, S. D., Strocchi, S., & Grifoni, D. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.05.009 · Cited by 19 · see citing works
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Rox8 promotes microRNA-dependent yki messenger RNA decay
Guo, X., Sun, Y., Azad, T., van Rensburg, H. J. J., Luo, J., Yang, S., Liu, P., Lv, Z., Zhan, M., Lu, L., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2013449117 · Cited by 18 · see citing works
“While impaired Hippo pathway is required for the overgrowth (23), JNK signaling is necessary for the invasion (9).”
BackgroundMethodMetabolic reprogramming in cancer: mechanistic insights from Drosophila
Wong, K. K. L., & Verheyen, E. M. (2021) · Disease Models & Mechanisms · doi:10.1242/dmm.048934 · Cited by 19 · see citing works
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“While several advances have since been made in identifying genetic factors that regulate tumorigenesis in the wing- disc tumor model (Atkins et al., 2016; Dillard et al., 2021; Doggett et al., 2015; Logeay et al., 2022), our understanding of the mechanisms driving neoplastic remodeling of the”
BackgroundTorres, J., Monti, R., Moore, A. L., Seimiya, M., Jiang, Y., Beerenwinkel, N., Beisel, C., Beira, J. V., & Paro, R. (2018) · eLife · doi:10.7554/elife.32697 · Cited by 17 · see citing works
“The datasets used for comparison were retrieved from the following references: (Graveley et al., 2011; Gan et al., 2010; Jüschke et al., 2013; Potier et al., 2014; Berger et al., 2012; Naval-Sánchez et al., 2013; Czech et al., 2013; Atkins et al., 2016).”
BackgroundMethodNuclear receptors connect progenitor transcription factors to cell cycle control
Neto, M., Naval-Sánchez, M., Potier, D., Pereira, P. S., Geerts, D., Aerts, S., & Casares, F. (2017) · Scientific Reports · doi:10.1038/s41598-017-04936-7 · Cited by 16 · see citing works
Self-citationAuthor Correction: Genetically engineered cerebral organoids model brain tumor formation
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A Model for the Hippo Pathway in the Drosophila Wing Disc
Gou, J., Lin, L., & Othmer, H. G. (2018) · Biophysical Journal · doi:10.1016/j.bpj.2018.07.002 · Cited by 14 · see citing works
CEBPG promotes acute myeloid leukemia progression by enhancing EIF4EBP1
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“Knockdown of CEBPG suppressed tumor growth [25].”
Logeay, R., Géminard, C., Lassus, P., Rodríguez-Vázquez, M., Kantar, D., Héron‐Milhavet, L., Fischer, B., Bray, S. J., Colinge, J., & Djiane, A. (2022) · Development · doi:10.1242/dev.200110 · Cited by 12 · see citing works
Gray, M., Turnbull, A., Meehan, J., Martínez-Pérez, C., Kay, C., Pang, L. Y., & Argyle, D. J. (2020) · Frontiers in Veterinary Science · doi:10.3389/fvets.2020.00439 · Cited by 12 · see citing works
“This pathway regulates cellular proliferation and apoptosis and has multiple family members that act as tumor suppressors (73).”
BackgroundDecoding transcriptional states in cancer
Wouters, J., Atak, Z. K., & Aerts, S. (2017) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2017.01.003 · Cited by 13 · see citing works
Self-citationRounding up the Usual Suspects: Assessing Yorkie, AP-1, and Stat Coactivation in Tumorigenesis
Hamaratoǧlu, F., & Atkins, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21134580 · Cited by 11 · see citing works
“In Drosophila tumors, the b-Zip transcription factors Jra, Kay, Atf-3, Pdp1, and Irbp18 have been implicated as potential effectors [41,43,44,50,93,94].”
BackgroundMethodInfluentialSelf-citationWingless signaling regulates winner/loser status in Minute cell competition
Akai, N., Igaki, T., & Ohsawa, S. (2018) · Genes to Cells · doi:10.1111/gtc.12568 · Cited by 12 · see citing works
Yorkie-Cactus (IκBα)-JNK axis promotes tumor growth and progression in Drosophila
Snigdha, K., Singh, A., & Kango-Singh, M. (2021) · Oncogene · doi:10.1038/s41388-021-01831-4 · Cited by 11 · see citing works
“Oncogenic cooperation can induce Yki and JNK activity in a context-dependent manner [42, 43].”
BackgroundWang, Z., Xia, X., Li, J., & Igaki, T. (2022) · eLife · doi:10.7554/elife.77340 · Cited by 11 · see citing works
Drug-Resistant Breast Cancer: Dwelling the Hippo Pathway to Manage the Treatment
Kaur, S., Najm, M. Z., Khan, M. A., Akhter, N., Shingatgeri, V., Sikenis, M., Sadaf, S., & Aloliqi, A. A. (2021) · Breast Cancer Targets and Therapy · doi:10.2147/bctt.s343329 · Cited by 11 · see citing works
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New regulators ofDrosophilaeye development identified from temporal transcriptome changes
Quiquand, M., Rimesso, G., Qiao, N., Suo, S., Zhao, C., Slattery, M. G., White, K. P., Han, J. J., & Baker, N. E. (2021) · Genetics · doi:10.1093/genetics/iyab007 · Cited by 10 · see citing works
Fortezza, M. L., Grigolon, G., Cosolo, A., Pindyurin, A. V., Breimann, L., Blum, H., van Steensel, B., & Classen, A.-K. (2018) · Epigenetics & Chromatin · doi:10.1186/s13072-018-0196-y · Cited by 10 · see citing works
“4b′, Additional file 5: Table S2) and align with the stressdependent activation of chinmo, Atf3, Ets21C, Ilp8, upd3 and SOCS36E associated with high JNK and JAK/ STAT activity during wound healing, regeneration and tumorigenesis [38, 44, 54–57].”
BackgroundInfluentialdTcf/Pangolin suppresses growth and tumor formation in Drosophila
Song, S., Andrējeva, D., Freitas, F. C. D. P., Cohen, S. M., & Herranz, H. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1816981116 · Cited by 7 · see citing works
“The ability to induce growth and tumorigenesis is not unique to the wing epithelium and Ftz-f1 can also induce growth in the eye imaginal disk of the fly (84), and is up-regulated and required for neoplasia in Drosophila Rasscrib tumors induced in the eye epithelium (71, 72).”
BackgroundKülshammer, E., Kilinc, M., Csordás, G., Bresser, T., Nolte, H., & Uhlířová, M. (2022) · FEBS Journal · doi:10.1111/febs.16408 · Cited by 7 · see citing works
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Mitchell, K. A., Vissers, J. H. A., Pojer, J. M., Brooks, E., Hilmi, A. J. S., Papenfuss, A. T., Schröder, J., & Harvey, K. F. (2024) · Current Biology · doi:10.1016/j.cub.2024.07.060 · Cited by 6 · see citing works
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miR-137 targets Myc to regulate growth during eye development
Padma, R., Subramanian, M., Chimata, A. V., Rai, A., Yogi, S., Sangeeth, A., Kango‐Singh, M., & Singh, A. (2025) · Development · doi:10.1242/dev.204373 · Cited by 5 · see citing works
“Myc is upregulated in tumor models (Atkins et al., 2016; Proberand Edgar, 2002).”
Hippo signaling promotes Ets21c-dependent apical cell extrusion in the Drosophila wing disc
Ai, X., Wang, D., Zhang, J., & Shen, J. (2020) · Development · doi:10.1242/dev.190124 · Cited by 5 · see citing works
Church, S. J., Pulianmackal, A. J., Dixon, J. A., Loftus, L. V., Amend, S. R., Pienta, K. J., Cackowski, F. C., & Buttitta, L. (2025) · Disease Models & Mechanisms · doi:10.1242/dmm.052001 · Cited by 4 · see citing works
“4C) (Atkins et al., 2016; Kulshammer et al., 2015) and wound healing gene expression profiles (Khan et al., 2017) (Table S5).”
Evidence for a nuclear role for Drosophila Dlg as a regulator of the NURF complex
Sharp, K. A., Khoury, M. J., Wirtz-Peitz, F., & Bilder, D. H. (2021) · Molecular Biology of the Cell · doi:10.1091/mbc.e21-04-0187 · Cited by 4 · see citing works
“Figure 5: NURF RNAi rescues Yki target gene expression in dlg tumors A-C. ex-LacZ expression (α-β-gal) in control wing discs (A) was unaffected by either E(bx) (B) or iswi (C) RNAi.”
BackgroundInfluentialXu, Q., Gao, B., Liu, X., Zhang, X., Wu, L., Xing, D., Ma, L., & Liu, J. (2022) · PubMed Central · Cited by 4 · see citing works
An Evolutionary Perspective on Hox Binding Site Preferences in Two Different Tissues
Folkendt, L., Lohmann, I., & Domsch, K. (2021) · Journal of Developmental Biology · doi:10.3390/jdb9040057 · Cited by 4 · see citing works
Jin, L., Feng, X., & Luo, D. (2022) · Tropical Journal of Pharmaceutical Research · doi:10.4314/tjpr.v20i5.7 · Cited by 3 · see citing works
“Some scholars believe that the biological behaviors of malignant tumors are the result of multiple factors and intergenic interactions [1].”
BackgroundBlockade of Crk eliminates Yki/YAP-activated tumors via JNK-mediated apoptosis in Drosophila
Kakemura, B., & Igaki, T. (2024) · Communications Biology · doi:10.1038/s42003-024-06897-w · Cited by 3 · see citing works
“Indeed, it has been shown that Yki contributes to Ras V12 /scrib − / − tumor growth 21,26,27 .”
BackgroundMutual repression between JNK/AP-1 and JAK/STAT stratifies cell behaviors during tissue regenerationPreprint
Jaiswal, J., Engesser, R., Peyrotón, A. A., Weichselberger, V., Crucianelli, C., Grass, I., Timmer, J., & Classen, A.-K. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.11.491445 · Cited by 2 · see citing works
Waghmare, I., Gangwani, K., Rai, A., Singh, A., & Kango-Singh, M. (2023) · doi:10.1101/2023.10.18.561369 · Cited by 1 · see citing works
Oncogenic Ras, Yki and Notch signals converge to confer clone competitiveness through Upd2
Wang, Y., Huang, R., Deng, M., He, J., Deng, M., Ishibashi, T., Yu, C., Zhai, Z., & Yan, Y. (2025) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2025.04.017 · Cited by 1 · see citing works
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Drosophila Cancer Modeling Using the Eye Imaginal Discs
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Self-citationBreaking Down Neighbors to Fuel Tumorigenesis
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“RasV12, scrib−/− tumors strongly deregulate JNK (c-Jun N-terminal kinase), Hippo, and JAK-STAT signaling pathways (Atkins et al., 2016).”
BackgroundAdditional file 1 of CEBPG promotes acute myeloid leukemia progression by enhancing EIF4EBP1
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Notch Signaling in Drosophila Tumor Models
Djiane, A. (2025) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-97035-1_2
Cohen, L. B., Hadzic, T., Sauer, C., Gibbs, J. R., & Wunderlich, Z. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.24.678314
“Crp, a known anti-apoptosis factor (Sopko et al. 2015; Atkins et al. 2016), could function to maintain the hemocyte population upon infection, with motifs enriched in mid-and late-expressed immune genes and among enhancers associated with effector and signaling genes.”
- Authors
- Atkins, M., Potier, D., Romanelli, L., Jacobs, J., Mach, J., Hamaratoglu, F., Aerts, S., & Halder, G.
- Affiliations
- KU Leuven (BE)
- Corresponding author
- Aerts, Stein
- Halder, Georg
- ORCID
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 26
- Issue
- 16
- Pages
- 2101-2113
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W2495853214
- Cited by
- 88
- References
- 50
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 6 · 2023: 6 · 2022: 11 · 2021: 15 · 2020: 10 · 2019: 6 · 2018: 15 · 2017: 12
- FWCI
- 7.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- IRIS (submittedVersion)
- Lirias (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Institutes of Health (P40OD018537)
- National Institute of General Medical Sciences (R01GM084947)
- 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 › Gene Regulatory Network Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- transcriptional regulatory networks, Hippo signaling pathway, Yorkie, tumor invasion, tumor growth, STAT, AP-1, c-Myc, AP-4, FTZ-F1, MEF2, gene regulatory networks, tumor-specific gene expression, cellular reprogramming, transcriptional co-regulation
- MeSH terms
- Animals, Drosophila melanogaster, Transcription Factors, Tumor Cells, Cultured, Signal Transduction, Gene Expression Regulation, Neoplastic, Drosophila Proteins, Gene Regulatory Networks, Carcinogenesis
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