A Drosophila model of oral peptide therapeutics for adult Intestinal Stem Cell tumors

ABSTRACTThe proto-oncogene YAP /Yki, a transcription co-factor of the Hippo pathway, has been linked to many cancers. YAP interacts with DNA-binding TEAD/Sd proteins to regulate expression of its transcriptional targets. Disruption of YAP-TEAD therefore offers a potential therapeutic strategy. The mammalian Vestigial Like (VGLL) protein, specifically its TONDU domain, has been shown to competitively inhibit YAP-TEAD interaction and a TONDU peptide can suppress YAP-induced cancer. As TONDU could potentially be developed into a therapeutic peptide for multiple cancers, we evaluated its efficacy in Yki-driven adult Intestinal Stem Cell (ISC) tumors in Drosophila. We show that oral uptake of the TONDU peptide is highly effective at inhibiting Yki-driven gut tumors by suppressing YAP-TEAD interaction. Comparative proteomics of early and late stage Yki-driven ISC tumors revealed enrichment of a number of proteins, including members of the integrin signaling pathway, such as Talin, Vinculin and Paxillin. These, in turn displayed a decrease in their levels in TONDU-peptide treated tumors. Further, we show that Sd binds to the regulatory region of integrin-coding gene, mew, which codes for αPS1, a key integrin of the ISCs. In support to a possible role of integrins in Yki-driven ISC tumors, we show that genetic downregulation of mew arrests Yki-driven ISC proliferation, reminiscent of the effects of TONDU peptide. Altogether, our findings present a novel platform for screening therapeutic peptides and provide insights into tumor suppression mechanisms.SIGNIFICANCE STATEMENTDiscovering novel strategies to inhibit oncogene activity is a priority in cancer biology. As signaling pathways are widely conserved between mammals and Drosophila, these questions can be effectively addressed in this model organism. Here, we show that progression of Drosophila Intestinal Stem Cell (ISC) tumors induced by gain of an oncogenic form of the transcription co-factor Yki can be suppressed by feeding a peptide corresponding to the conserved TONDU domain of Vestigial (Vg), which blocks binding of Yki to the Sd transcription factor. Further, we show that down regulation of the integrin signaling pathway is causally linked to TONDU-peptide-mediated ISC tumor suppression. Our findings reveal that Drosophila can be successfully used to screen peptides for their therapeutic applications.

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A Drosophila model of oral peptide therapeutics for adult intestinal stem cell tumors

Disease Models & Mechanisms ◽

10.1242/dmm.044420 ◽

2020 ◽

Vol 13 (7) ◽

pp. dmm044420 ◽

Cited By ~ 1

Author(s):

Anjali Bajpai ◽

Taushif Ahmad Quazi ◽

Hong-Wen Tang ◽

Nishat Manzar ◽

Virender Singh ◽

...

Keyword(s):

Stem Cell ◽

Hippo Pathway ◽

Intestinal Stem Cell ◽

Peptide Therapeutics ◽

Small Molecule Drugs ◽

Drosophila Model ◽

Therapeutic Peptides ◽

Oral Therapeutic ◽

The Hippo Pathway

ABSTRACTPeptide therapeutics, unlike small-molecule drugs, display crucial advantages of target specificity and the ability to block large interacting interfaces, such as those of transcription factors. The transcription co-factor of the Hippo pathway, YAP/Yorkie (Yki), has been implicated in many cancers, and is dependent on its interaction with the DNA-binding TEAD/Sd proteins via a large Ω-loop. In addition, the mammalian vestigial-like (VGLL) proteins, specifically their TONDU domain, competitively inhibit YAP-TEAD interaction, resulting in arrest of tumor growth. Here, we show that overexpression of the TONDU peptide or its oral uptake leads to suppression of Yki-driven intestinal stem cell tumors in the adult Drosophila midgut. In addition, comparative proteomic analyses of peptide-treated and untreated tumors, together with chromatin immunoprecipitation analysis, reveal that integrin pathway members are part of the Yki-oncogenic network. Collectively, our findings establish Drosophila as a reliable in vivo platform to screen for cancer oral therapeutic peptides and reveal a tumor suppressive role for integrins in Yki-driven tumors.This article has an associated First Person interview with the first author of the paper.

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The Hippo pathway regulates intestinal stem cell proliferation during Drosophila adult midgut regeneration

Development ◽

10.1242/dev.052506 ◽

2010 ◽

Vol 137 (24) ◽

pp. 4147-4158 ◽

Cited By ~ 216

Author(s):

R. L. Shaw ◽

A. Kohlmaier ◽

C. Polesello ◽

C. Veelken ◽

B. A. Edgar ◽

...

Keyword(s):

Cell Proliferation ◽

Stem Cell ◽

Hippo Pathway ◽

Intestinal Stem Cell ◽

Stem Cell Proliferation ◽

The Hippo Pathway

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Nanotopography Drives Stem Cell Fate Toward Osteoblast Differentiation Through α1β1 Integrin Signaling Pathway

Journal of Cellular Biochemistry ◽

10.1002/jcb.24688 ◽

2014 ◽

Vol 115 (3) ◽

pp. 540-548 ◽

Cited By ~ 47

Author(s):

A.L. Rosa ◽

R.B. Kato ◽

L.M.S. Castro Raucci ◽

L.N. Teixeira ◽

F.S. de Oliveira ◽

...

Keyword(s):

Stem Cell ◽

Signaling Pathway ◽

Cell Fate ◽

Osteoblast Differentiation ◽

Integrin Signaling ◽

Stem Cell Fate

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Zinc L-Aspartate enhances intestinal stem cell activity to protect the integrity of the intestinal mucosa against deoxynivalenol through activation of the Wnt/β-catenin signaling pathway

Environmental Pollution ◽

10.1016/j.envpol.2020.114290 ◽

2020 ◽

Vol 262 ◽

pp. 114290 ◽

Cited By ~ 3

Author(s):

Jia-yi Zhou ◽

Hua-lin Lin ◽

Zhe Wang ◽

Sai-wu Zhang ◽

Deng-gui Huang ◽

...

Keyword(s):

Stem Cell ◽

Signaling Pathway ◽

Intestinal Mucosa ◽

Cell Activity ◽

Intestinal Stem Cell ◽

Stem Cell Activity

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Lola regulates Drosophila adult midgut homeostasis via non-canonical hippo signaling

eLife ◽

10.7554/elife.47542 ◽

2020 ◽

Vol 9 ◽

Author(s):

Xue Hao ◽

Shimin Wang ◽

Yi Lu ◽

Wentao Yu ◽

Pengyue Li ◽

...

Keyword(s):

Transcription Factor ◽

Stem Cell ◽

Hippo Pathway ◽

Tissue Homeostasis ◽

Intestinal Stem Cell ◽

Hippo Signaling ◽

Intestinal Function ◽

Independent Manner ◽

The Hippo Pathway ◽

Basal Proliferation

Tissue homeostasis and regeneration in the Drosophila midgut is regulated by a diverse array of signaling pathways including the Hippo pathway. Hippo signaling restricts intestinal stem cell (ISC) proliferation by sequestering the transcription co-factor Yorkie (Yki) in the cytoplasm, a factor required for rapid ISC proliferation under injury-induced regeneration. Nonetheless, the mechanism of Hippo-mediated midgut homeostasis and whether canonical Hippo signaling is involved in ISC basal proliferation are less characterized. Here we identify Lola as a transcription factor acting downstream of Hippo signaling to restrict ISC proliferation in a Yki-independent manner. Not only that Lola interacts with and is stabilized by the Hippo signaling core kinase Warts (Wts), Lola rescues the enhanced ISC proliferation upon Wts depletion via suppressing Dref and SkpA expressions. Our findings reveal that Lola is a non-canonical Hippo signaling component in regulating midgut homeostasis, providing insights on the mechanism of tissue maintenance and intestinal function.

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Map3k2-Regulated Intestinal Stromal Cells (MRISC) Define a Distinct Sub-cryptic Stem Cell Niche for Damage Induced Wnt Agonist R-spondin1 Production

10.1101/723221 ◽

2019 ◽

Author(s):

Ningbo Wu ◽

Hongxiang Sun ◽

Xiaoyun Zhao ◽

Lei Chen ◽

Yuanyuan Qi ◽

...

Keyword(s):

Stem Cell ◽

Signaling Pathway ◽

Stromal Cells ◽

Stem Cell Niche ◽

Molecular Mechanisms ◽

Intestinal Stem Cell ◽

List Type ◽

Intestinal Damage ◽

Specific Function ◽

Cell Niche

SummaryIntestinal stem cell propagation and differentiation are essential for rapid repair of tissue damage in the gut. While intestinal stromal cells were recently identified as key mediators of this process, the cellular and molecular mechanisms by which this diverse population induces tissue repair remains poorly understood. Here we show that Map3k2 has a colon stromal cell specific function critically required for maintenance of Lgr5+ intestinal stem cells and protection against acute intestinal damage. This Map3k2-specific function is mediated by enhancing Wnt agonist R-spondin1 production. We further reveal a unique novel cell population, named Map3k2-regulated intestinal stromal cells (MRISC), as the primary cellular source of R-spondin1 following intestinal injury. Together, our data identify a novel intestinal stem cell niche organized by MRISC, which specifically dependent on the Map3k2-signaling pathway to augment the production of Wnt agonist R-spondin1 and promote regeneration of the acutely damaged intestine.HighlightsMap3k2 protects mice from DSS-induced colitis by promoting intestinal stem cell regeneration.Map3k2-MAPK pathway cross-talks with Wnt signaling pathway via upregulation of R-spondin1.Map3k2-Regulated Intestinal Stromal Cells (MRISC) marked by co-expression of CD90, CD34 and CD81 defines a novel colonic stem cell niche.

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The Hippo pathway regulates intestinal stem cell proliferation during Drosophila adult midgut regeneration

Journal of Cell Science ◽

10.1242/jcs.084137 ◽

2010 ◽

Vol 123 (24) ◽

pp. e1-e1 ◽

Cited By ~ 1

Author(s):

R. L. Shaw ◽

A. Kohlmaier ◽

C. Polesello ◽

C. Veelken ◽

B. A. Edgar ◽

...

Keyword(s):

Cell Proliferation ◽

Stem Cell ◽

Hippo Pathway ◽

Intestinal Stem Cell ◽

Stem Cell Proliferation ◽

The Hippo Pathway

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P126 MULTIPLE SIGNALING PATHWAY DEFECTS IN THE INTESTINAL STEM CELL NICHE LIKELY TRIGGER CD-LIKE ILEITIS IN SAMP1/YITFC MICE

Inflammatory Bowel Diseases ◽

10.1093/ibd/izy393.142 ◽

2019 ◽

Vol 25 (Supplement_1) ◽

pp. S61-S61

Author(s):

Ludovica F Buttò ◽

Adam Pelletier ◽

Nan Zhao ◽

Abdullah Osme ◽

Christopher Hager ◽

...

Keyword(s):

Stem Cell ◽

Signaling Pathway ◽

Stem Cell Niche ◽

Intestinal Stem Cell ◽

Cell Niche ◽

Multiple Signaling

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Hippo Signaling Pathway in Gliomas

Cells ◽

10.3390/cells10010184 ◽

2021 ◽

Vol 10 (1) ◽

pp. 184

Author(s):

Konstantin Masliantsev ◽

Lucie Karayan-Tapon ◽

Pierre-Olivier Guichet

Keyword(s):

Brain Tumors ◽

Signaling Pathway ◽

Cancer Biology ◽

Nuclear Translocation ◽

Hippo Pathway ◽

Binding Motif ◽

Hippo Signaling ◽

Central Nervous System Neoplasms ◽

Hippo Signaling Pathway

The Hippo signaling pathway is a highly conserved pathway involved in tissue development and regeneration that controls organ size through the regulation of cell proliferation and apoptosis. The core Hippo pathway is composed of a block of kinases, MST1/2 (Mammalian STE20-like protein kinase 1/2) and LATS1/2 (Large tumor suppressor 1/2), which inhibits nuclear translocation of YAP/TAZ (Yes-Associated Protein 1/Transcriptional co-activator with PDZ-binding motif) and its downstream association with the TEAD (TEA domain) family of transcription factors. This pathway was recently shown to be involved in tumorigenesis and metastasis in several cancers such as lung, breast, or colorectal cancers but is still poorly investigated in brain tumors. Gliomas are the most common and the most lethal primary brain tumors representing about 80% of malignant central nervous system neoplasms. Despite intensive clinical protocol, the prognosis for patients remains very poor due to systematic relapse and treatment failure. Growing evidence demonstrating the role of Hippo signaling in cancer biology and the lack of efficient treatments for malignant gliomas support the idea that this pathway could represent a potential target paving the way for alternative therapeutics. Based on recent advances in the Hippo pathway deciphering, the main goal of this review is to highlight the role of this pathway in gliomas by a state-of-the-art synthesis.

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