Functional exploration of colorectal cancer genomes using Drosophila

Bangi, Erdem; Murgia, Claudio; Teague, Alexander; Sansom, Owen J.; Cagan, Ross L.

doi:10.1038/ncomms13615

Cited by 93 publications

(136 citation statements)

References 66 publications

(84 reference statements)

Supporting

Mentioning

122

Contrasting

Order By: Relevance

“…The high degree of evolutionary conservation with human proteins make Drosophila a clinically relevant platform for understanding mechanisms human disease, and Drosophila tumor models have successfully identified new therapeutic candidates for colorectal, lung and thyroid and stem-cells derived cancers (Bangi et al, 2016;Levine and Cagan, 2016;Markstein et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Cytoneme-mediated signaling essential for tumorigenesis

Fereres

Hatori

et al. 2018

Preprint

View full text Add to dashboard Cite

Communication between neoplastic cells and cells of their microenvironment is critical to cancer progression. To investigate the role of cytoneme-mediated signaling as a mechanism for distributing growth factor signaling proteins between tumor and tumor-associated cells, we analyzed EGFR and RET Drosophila tumor models. We tested several genetic loss-of-function conditions that impair cytoneme-mediated signaling. diaphanous, Neuroglian, SCAR, capricious are genes that cytonemes require during normal development. Genetic inhibition of cytonemes restored apical basal polarity to tumor cells, reduced tumor growth, and increased organism survival. These findings suggest that cytonemes traffic the signaling proteins that move between tumor and stromal cells, and that cytoneme-mediated signaling is required for tumor growth and malignancy.

show abstract

Section: Discussionmentioning

confidence: 99%

Cytoneme-mediated signaling essential for tumorigenesis

Fereres

Hatori

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…Our recapitulation of TONDU peptide-mediated cancer suppression (18) in ISC tumors therefore demonstrates, for the first time, that Drosophila could be used to screen for peptide therapeutics. Indeed, the power of genetic tractability of Drosophila, which permits generation of multiple versions of tumors of a given cell type using distinct cooperative signaling partners or transcription factors, including those seen perturbed in cancers in human (4, 6, 21, 55–57), would make such a platform versatile on several counts: scalability, genetic tractability and rapid elucidation of the mechanistic underpinning of peptide-based tumor suppression.…”

Section: Resultsmentioning

confidence: 99%

“…Drosophila has emerged as an effective cancer model for the screening of small molecule therapeutics (1–4). Of interest, Drosophila adult gut tumors, such as Yki-driven intestinal stem cell (ISC) tumors (5) or a multigenic hindgut model of colon cancer (6), have been successfully used to screen for anti-proliferative small molecules. While cancer-promoting rogue kinases are amenable to inhibition by small molecules, others, such as transcription factors and co-factors, are largely considered undruggable (7, 8).…”

Section: Introductionmentioning

confidence: 99%

ADrosophilamodel of oral peptide therapeutics for adult Intestinal Stem Cell tumors

Bajpai

Ahmad

Tang

et al. 2020

Preprint

View full text Add to dashboard Cite

The 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.

show abstract

“…The novel invertebrate systems discussed here have taken crucial steps toward unraveling the complexity of cancer and responses to associated chemotherapeutic interventions [37,45,48,54,56,57]. However, we contend that the benefit of these invertebrate systems has not been fully realized because drug response measurements and natural variation are rarely combined.…”

Section: Where Do We Go From Here?mentioning

confidence: 99%

Natural diversity facilitates the discovery of conserved chemotherapeutic response mechanisms

Zdraljevic

Andersen

2017

Current Opinion in Genetics & Development

View full text Add to dashboard Cite

Organismal fitness depends on adaptation to complex niches where chemical compounds and pathogens are omnipresent. These stresses can lead to the fixation of alleles in both xenobiotic responses and proliferative signaling pathways that promote survival in these niches. However, both xenobiotic responses and proliferative pathways vary within and among species. For example, genetic differences can accumulate within populations because xenobiotic exposures are not constant and selection is variable. Additionally, neutral genetic variation can accumulate in conserved proliferative pathway genes because these systems are robust to genetic perturbations given their essential roles in normal cell-fate specification. For these reasons, sensitizing mutations or chemical perturbations can disrupt pathways and reveal cryptic variation. With this fundamental view of how organisms respond to cytotoxic compounds and cryptic variation in conserved signaling pathways, it is not surprising that human patients have highly variable responses to chemotherapeutic compounds and to the activities of proliferative pathways. These different patient responses result in the low FDA-approval rates for chemotherapeutics and underscore the need for new approaches to understand these diseases and therapeutic interventions. Model organisms, especially the classic invertebrate systems of Caenorhabditis elegans and Drosophila melanogaster, can be used to combine studies of natural variation across populations with responses to both xenobiotic compounds and chemotherapeutics targeted to conserved proliferative signaling pathways.

show abstract

Functional exploration of colorectal cancer genomes using Drosophila

Cited by 93 publications

References 66 publications

Cytoneme-mediated signaling essential for tumorigenesis

Cytoneme-mediated signaling essential for tumorigenesis

ADrosophilamodel of oral peptide therapeutics for adult Intestinal Stem Cell tumors

Natural diversity facilitates the discovery of conserved chemotherapeutic response mechanisms

Contact Info

Product

Resources

About