Tumors sap nutrients from surrounding cells -- Drosophila study related to cancer

Dev Biol. 2021 Aug;476:294-307. doi: 10.1016/j.ydbio.2021.04.008

Autophagy induction in tumor surrounding cells promotes tumor growth in adult Drosophila intestines

Zhao H, Shi L, Kong R, Li Z, Liu F, Zhao H, Li Z

Abstract:

During tumorigenesis, tumor cells interact intimately with their surrounding cells (microenvironment) for their growth and progression. However, the roles of tumor microenvironment in tumor development and progression are not fully understood. Here, using an established benign tumor model in adult Drosophila intestines, we find that non-cell autonomous autophagy (NAA) is induced in tumor surrounding neighbor cells. Tumor growth can be significantly suppressed by genetic ablation of autophagy induction in tumor neighboring cells, indicating that tumor neighboring cells act as tumor microenvironment to promote tumor growth. Autophagy in tumor neighboring cells is induced downstream of elevated ROS and activated JNK signaling in tumor cells. Interestingly, we find that active transport of nutrients, such as amino acids, from tumor neighboring cells sustains tumor growth, and increasing nutrient availability could significantly restore tumor growth. Together, these data demonstrate that tumor cells take advantage of their surrounding normal neighbor cells as nutrient sources through NAA to meet their high metabolic demand for growth and progression. Thus we provide insights into our understanding of the mechanisms underlying the interaction between tumor cells and their microenvironment in tumor development.

DOI: 10.1016/j.ydbio.2021.04.008
PMID: 33940033

Review: Fly Models of Liver Diseases

Front Physiol. 2021 Sep 16;12:728407

Drosophila melanogaster: A Powerful Tiny Animal Model for the Study of Metabolic Hepatic Diseases

Moraes KCM, Montagne J

Animal experimentation is limited by unethical procedures, time-consuming protocols, and high cost. Thus, the development of innovative approaches for disease treatment based on alternative models in a fast, safe, and economic manner is an important, yet challenging goal. In this paradigm, the fruit-fly Drosophila melanogaster has become a powerful model for biomedical research, considering its short life cycle and low-cost maintenance. In addition, biological processes are conserved and homologs of ∼75% of human disease-related genes are found in the fruit-fly. Therefore, this model has been used in innovative approaches to evaluate and validate the functional activities of candidate molecules identified via in vitro large-scale analyses, as putative agents to treat or reverse pathological conditions. In this context, Drosophila offers a powerful alternative to investigate the molecular aspects of liver diseases, since no effective therapies are available for those pathologies. Non-alcoholic fatty liver disease is the most common form of chronic hepatic dysfunctions, which may progress to the development of chronic hepatitis and ultimately to cirrhosis, thereby increasing the risk for hepatocellular carcinoma (HCC). This deleterious situation reinforces the use of the Drosophila model to accelerate functional research aimed at deciphering the mechanisms that sustain the disease. In this short review, we illustrate the relevance of using the fruit-fly to address aspects of liver pathologies to contribute to the biomedical area.

DOI: 10.3389/fphys.2021.728407
PMCID: PMC8481879
PMID: 34603083

Drosophila assay developed to test variants of human PTEN, a gene associate with cancers and ASD

A scalable Drosophila assay for clinical interpretation of human PTEN variants in suppression of PI3K/AKT induced cellular proliferation

Payel Ganguly, Landiso Madonsela, Jesse T. Chao, Christopher J. R. Loewen, Timothy P. O’Connor, Esther M. Verheyen, Douglas W. Allan

Abstract: "Gene variant discovery is becoming routine, but it remains difficult to usefully interpret the functional consequence or disease relevance of most variants. ... Drosophila melanogaster offers great potential as an assay platform, but was untested for high numbers of human variants adherent to these guidelines. Here, we wished to test the utility of Drosophila as a platform for scalable well-established assays. We took a genetic interaction approach to test the function of ~100 human PTEN variants in cancer-relevant suppression of PI3K/AKT signaling in cellular growth and proliferation. We validated the assay using biochemically characterized PTEN mutants as well as 23 total known pathogenic and benign PTEN variants, all of which the assay correctly assigned into predicted functional categories. ... Overall, we demonstrate that Drosophila offers a powerful assay platform for clinical variant interpretation, that can be used in conjunction with other well-established assays, to increase confidence in the accurate assessment of variant function and pathogenicity."

Access a Science in Vancouver feature on this article here.

Genetic and drug screens applied to a Drosophila model of acute myeloid leukemia reveal potential link to hypoxia signaling

Dis Model Mech. 2021 Sep 28:dmm.048953. doi: 10.1242/dmm.048953.  

Pharmacological or genetic inhibition of hypoxia signaling attenuates oncogenic
RAS-induced cancer phenotypes.

Zhu JY, Huang X, Fu Y, Wang Y, Zheng P, Liu Y, Han Z

Author information:
(1)Center for Precision Disease Modeling, Department of Medicine, University of
Maryland School of Medicine, Baltimore, MD 21201, USA.
(2)Division of Endocrinology, Diabetes and Nutrition, Department of Medicine,
University of Maryland School of Medicine, Baltimore, MD 21201, USA.
(3)Division of Immunotherapy, University of Maryland School of Medicine,
Baltimore, MD 21201, USA.

Abstract: "Oncogenic Ras mutations are highly prevalent in hematopoietic malignancies. However, it is difficult to directly target oncogenic RAS proteins for therapeutic intervention. We have developed a Drosophila Acute Myeloid Leukemia (AML) model induced by human KRASG12V, which exhibits a dramatic increase in myeloid-like leukemia cells. We performed both genetic and drug screens using this model. The genetic screen identified 24 candidate genes able to attenuate the oncogenic RAS-induced phenotype, including two key hypoxia pathway genes HIF1A and ARNT (HIF1B). The drug screen revealed echinomycin, an inhibitor of HIF1A, could effectively attenuate the leukemia phenotype caused by KRASG12V. Furthermore, we showed that echinomycin treatment could effectively suppress oncogenic RAS-driven leukemia cell proliferation using both human leukemia cell lines and a mouse xenograft model. These data suggest that inhibiting the hypoxia pathway could be an effective treatment approach for oncogenic RAS-induced cancer phenotype, and that echinomycin is a promising targeted drug to attenuate oncogenic RAS-induced cancer phenotypes."

DOI: 10.1242/dmm.048953
PMID: 34580712

Identification of protein interactors with fly GOLPH3 points to potential targets for cancer and other therapeutics

Cells. 2021 Sep 6;10(9):2336. doi: 10.3390/cells10092336.

Identification of GOLPH3 Partners in Drosophila Unveils Potential Novel Roles in Tumorigenesis and Neural Disorders.

Sechi S, Karimpour-Ghahnavieh A, Frappaolo A, Di Francesco L, Piergentili R, Schininà E, D'Avino PP, Giansanti MG

Author information:
(1)Istituto di Biologia e Patologia Molecolari del CNR, c/o Dipartimento di
Biologia e Biotecnologie, Sapienza Università di Roma, Piazzale A. Moro 5, 00185
Roma, Italy.
(2)Dipartimento di Scienze Biochimiche A. Rossi Fanelli, Sapienza Università di
Roma, Piazzale A. Moro 5, 00185 Roma, Italy.
(3)Department of Pathology, University of Cambridge, Tennis Court Road,
Cambridge CB2 1QP, UK.

Abstract: "Golgi phosphoprotein 3 (GOLPH3) is a highly conserved peripheral membrane protein localized to the Golgi apparatus and the cytosol. GOLPH3 binding to Golgi membranes depends on phosphatidylinositol 4-phosphate [PI(4)P] and regulates Golgi architecture and vesicle trafficking. GOLPH3 overexpression has been correlated with poor prognosis in several cancers, but the molecular mechanisms that link GOLPH3 to malignant transformation are poorly understood. We recently showed that PI(4)P-GOLPH3 couples membrane trafficking with contractile ring assembly during cytokinesis in dividing Drosophila spermatocytes. Here, we use affinity purification coupled with mass spectrometry (AP-MS) to identify the protein-protein interaction network (interactome) of Drosophila GOLPH3 in testes. Analysis of the GOLPH3 interactome revealed enrichment for proteins involved in vesicle-mediated trafficking, cell proliferation and cytoskeleton dynamics. In particular, we found that dGOLPH3 interacts with the Drosophila orthologs of Fragile X mental retardation protein and Ataxin-2, suggesting a potential role in the pathophysiology of disorders of the nervous system. Our findings suggest novel molecular targets associated with GOLPH3 that might be relevant for therapeutic intervention in cancers and other human diseases."

DOI: 10.3390/cells10092336
PMID: 34571985

Review: Drosophila accessory gland as a model organ for studies related to prostate cancer

Cells. 2021 Sep 10;10(9):2387. doi: 10.3390/cells10092387.

Drosophila Accessory Gland: A Complementary In Vivo Model to Bring New Insight  to Prostate Cancer.

Rambur A, Vialat M, Beaudoin C, Lours-Calet C, Lobaccaro JM, Baron S, Morel L, de Joussineau C

Author information:
(1)Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montréal, QC H3A 1A3, Canada.
(2)Institut de Génétique, Reproduction et Développement, Université Clermont Auvergne, CNRS UMR6293, INSERM U1103, 28 Place Henri Dunant, BP38, 63001 Clermont-Ferrand, France.

Abstract: "Prostate cancer is the most common cancer in aging men. ... there are still few effective treatments to cure its aggressive and metastatic stages. ... multiple research models, such as cell culture and mouse models, have been developed over the years and have improved our comprehension of the biology of the disease. Recently, a new model has been added with the use of the Drosophila accessory gland. ... this functional equivalent of the prostate represents a powerful, inexpensive, and rapid in vivo model to study epithelial carcinogenesis. The purpose of this review is to quickly overview the existing prostate cancer models, including their strengths and limitations. In particular, we discuss how the Drosophila accessory gland can be integrated as a convenient complementary model ..."

DOI: 10.3390/cells10092387
PMID: 34572036

Fly eye assay explored as a tool for assessing potential therapeutic treatments of chronic myeloid leukemia

Haematologica. 2020 Jan 31;105(2):387-397. doi: 10.3324/haematol.2019.219394. Print 2020.

Validation of a Drosophila model of wild-type and T315I mutated BCR-ABL1 in chronic myeloid leukemia: an effective platform for treatment screening.

Outa AA, Abubaker D, Bazarbachi A, Sabban ME, Shirinian M, Nasr R

Abstract:

Chronic myeloid leukemia is caused by a balanced chromosomal translocation resulting in the formation of BCR-ABL1 fusion gene encoding a constitutively active BCR-ABL1 tyrosine kinase, which activates multiple signal transduction pathways leading to malignant transformation. Standard treatment of chronic myeloid leukemia is based on tyrosine kinase inhibitors; however, some mutations have proven elusive particularly the T315I mutation. Drosophila melanogaster is an established in vivo model for human diseases including cancer. The targeted expression of chimeric human/fly and full human BCR-ABL1 in Drosophila eyes has been shown to result in detrimental effects. In this study, we expressed human BCR-ABL1p210 and the resistant BCR-ABL1p210/T315I fusion oncogenes in Drosophila eyes. Expression of BCR-ABL1p210/T315I resulted in a severe distortion of the ommatidial architecture of adult eyes with a more prominent rough eye phenotype compared to milder phenotypes in BCR-ABL1p210 reflecting a stronger oncogenic potential of the mutant. We then assessed the efficacy of the currently used tyrosine kinase inhibitors in BCR-ABL1p210 and BCR-ABL1p210/T315I expressing flies. Treatment of BCR-ABL1p210 expressing flies with potent kinase inhibitors (dasatinib and ponatinib) resulted in the rescue of ommatidial loss and the restoration of normal development. Taken together, we provide a chronic myeloid leukemia tailored BCR-ABL1p210 and BCR-ABL1p210/T315I fly model which can be used to test new compounds with improved therapeutic indices.

DOI: 10.3324/haematol.2019.219394
PMCID: PMC7012492
PMID: 31101753

Study of the fly embryo as a route to understanding cellular mechanisms of cancer

Mol Biol Cell. 2021 Jan 21:mbcE20100625. doi: 10.1091/mbc.E20-10-0625.
Molecular mechanisms underlying cellular effects of human MEK1 mutations.

Marmion RA(1), Yang L(1), Goyal Y(1)(2)(3), Jindal GA(1)(2)(4), Wetzel JL(1)(5),
Singh M(1)(5), Schüpbach T(6), Shvartsman SY(1)(2)(6)(7).

Abstract:

Terminal regions of Drosophila embryos are patterned by signaling through ERK, which is genetically deregulated in multiple human diseases. Quantitative studies of terminal patterning have been recently used to investigate gain-of-function variants of human MEK1, encoding the MEK kinase that directly activates ERK by dual phosphorylation. Unexpectedly, several mutations reduced ERK activation by extracellular signals, possibly through a negative feedback triggered by signal-independent activity of the mutant variants. Here we present experimental evidence supporting this model. Using a MEK variant that combines a mutation within the negative regulatory region with alanine substitutions in the activation loop, we prove that pathogenic variants indeed acquire signal-independent kinase activity. We also demonstrate that signal-dependent activation of these variants is independent of KSR, a conserved adaptor that is indispensable for activation of normal MEK. Finally, we show that attenuation of ERK activation by extracellular signals stems from transcriptional induction of Mkp3, a dual specificity phosphatase that deactivates ERK by dephosphorylation. These findings in the Drosophila embryo highlight its power for investigating diverse effects of human disease mutations.

DOI: 10.1091/mbc.E20-10-0625
PMID: 33476180

Genetic screen in flies aims to identify new targets for cancer treatment

Cancers (Basel). 2021 Jan 14;13(2):E293. doi: 10.3390/cancers13020293.

Genetic Screening for Potential New Targets in Chronic Myeloid Leukemia Based on
Drosophila Transgenic for Human BCR-ABL1.

Lo Iacono M(1), Signorino E(1), Petiti J(1), Pradotto M(1), Calabrese C(1),
Panuzzo C(1), Caciolli F(1), Pergolizzi B(1), De Gobbi M(1), Rege-Cambrin G(1),
Fava C(1), Giachino C(1), Bracco E(2), Saglio G(1), Frassoni F(1), Cilloni D(1).

Author information:
(1)Department of Clinical and Biological Sciences, University of Turin, 10043
Turin, Italy.
(2)Department of Oncology, University of Turin, 10043 Turin, Italy.

Chronic myeloid leukemia is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome that originates from the reciprocal translocation t(9;22)(q34;q11.2) and encodes for the constitutively active tyrosine kinase protein BCR-ABL1 from the Breakpoint Cluster Region (BCR) sequence and the Abelson (ABL1) gene. Despite BCR-ABL1 being one of the most studied oncogenic proteins, some molecular mechanisms remain enigmatic, and several of the proteins, acting either as positive or negative BCR-ABL1 regulators, are still unknown. The Drosophila melanogaster represents a powerful tool for genetic investigations and a promising model to study the BCR-ABL1 signaling pathway. To identify new components involved in BCR-ABL1 transforming activity, we conducted an extensive genetic screening using different Drosophila mutant strains carrying specific small deletions within the chromosomes 2 and 3 and the gmrGal4,UAS-BCR-ABL1 4M/TM3 transgenic Drosophila as the background. From the screening, we identified several putative candidate genes that may be involved either in sustaining chronic myeloid leukemia (CML) or in its progression. We also identified, for the first time, a tight connection between the BCR-ABL1 protein and Rab family members, and this correlation was also validated in CML patients. In conclusion, our data identified many genes that, by interacting with BCR-ABL1, regulate several important biological pathways and could promote disease onset and progression.

DOI: 10.3390/cancers13020293
PMID: 33466839

Expression of human genes in the fly eye reveals interaction with potential relevance to breast cancer

HumanaFly: high-throughput transgenesis and expression of breast cancer transcripts in Drosophila eye discovers the RPS12-Wingless signaling axis  

Katanaev, Kryuchkov, Averkov, Savitsky, Nikolaeva, Klimova, Khaustov & Solis  

Scientific Reports  (2020) vol. 10, no. 21013

 

Abstract: "Drosophila melanogaster has been a model for multiple human disease conditions, including cancer. Among Drosophila tissues, the eye development is particularly sensitive to perturbations of the embryonic signaling pathways, whose improper activation in humans underlies various forms of cancer. We have launched the HumanaFly project, whereas human genes expressed in breast cancer patients are screened for their ability to aberrate development of the Drosophila eye, hoping to thus identify novel oncogenes. Here we report identification of a breast cancer transgene, which upon expression in Drosophila produces eye malformation similar to the famous Glazed phenotype discovered by Thomas Morgan and decades later dissected to originate from mis-expression of Wingless (Wg). Wg is the ortholog of human Wnt proteins serving as ligands to initiate the developmental/oncogenic Wnt signaling pathway. Through genetic experiments we identified that this transgene interacted with the Wg production machinery, rather than with Wg signal transduction. In Drosophila imaginal discs, we directly show that the transgene promoted long-range diffusion of Wg, affecting expression of the Wg target genes. The transgene emerged to encode RPS12—a protein of the small ribosomal subunit overexpressed in several cancer types and known to also possess extra-ribosomal functions. Our work identifies RPS12 as an unexpected regulator of secretion and activity of Wnts. As Wnt signaling is particularly important in the context of breast cancer initiation and progression, RPS12 might be implicated in tumorigenesis in this and other Wnt-dependent cancers. Continuation of our HumanaFly project may bring further discoveries on oncogenic mechanisms."

Drosophila studies point to potential relevance of voltage-gated sodium channels in cell proliferation and cancer

Piggott BJ, Peters CJ, He Y, Huang X, Younger S, Jan LY, Jan YN. Paralytic, the Drosophila voltage-gated sodium channel, regulates proliferation of neural progenitors. Genes Dev. 2019 Dec 1;33(23-24):1739-1750. PubMed PMID: 31753914.

From the abstract: "... voltage-gated sodium channels (VGSC) that are crucial for neuronal excitability are also found in progenitors and up-regulated in cancer. Here, we identify a role for VGSC in proliferation of Drosophila neuroblast (NB) lineages within the central nervous system. Loss of paralytic (para), the sole gene that encodes Drosophila VGSC, reduces neuroblast progeny cell number. ... Our data suggests that loss of Para induces apoptosis in this population, whereas overexpression leads to an increase in INPs and overall neuroblast progeny cell numbers. These effects are cell autonomous and depend on Para channel activity. Reduction of Para expression not only affects normal NB development, but also strongly suppresses brain tumor mass, implicating a role for Para in cancer progression. To our knowledge, our studies are the first to identify a role for VGSC in neural progenitor proliferation. Elucidating the contribution of VGSC in proliferation will advance our understanding of bioelectric signaling within development and disease states."

New drug target for renal cancer identified based on fly and human studies--work from the lab of 2019 Nobel prize winner W. Kaelin

Nicholson HE, Tariq Z, Housden BE, Jennings RB, Stransky LA, Perrimon N, Signoretti S, Kaelin WG Jr. HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species. Sci Signal. 2019 Oct 1;12(601). PubMed PMID: 31575731.

Abstract: "Inactivation of the VHL tumor suppressor gene is the signature initiating event in clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, and causes the accumulation of hypoxia-inducible factor 2α (HIF-2α). HIF-2α inhibitors are effective in some ccRCC cases, but both de novo and acquired resistance have been observed in the laboratory and in the clinic. Here, we identified synthetic lethality between decreased activity of cyclin-dependent kinases 4 and 6 (CDK4/6) and VHL inactivation in two species (human and Drosophila) and across diverse human ccRCC cell lines in culture and xenografts. Although HIF-2α transcriptionally induced the CDK4/6 partner cyclin D1, HIF-2α was not required for the increased CDK4/6 requirement of VHL-/- ccRCC cells. Accordingly, the antiproliferative effects of CDK4/6 inhibition were synergistic with HIF-2α inhibition in HIF-2α-dependent VHL-/- ccRCC cells and not antagonistic with HIF-2α inhibition in HIF-2α-independent cells. These findings support testing CDK4/6 inhibitors as treatments for ccRCC, alone and in combination with HIF-2α inhibitors."

Review highlights Drosophila research contribution to understanding mTOR and tuberous sclerosis

Franz DN, Krueger DA. mTOR inhibitor therapy as a disease modifying therapy for tuberous sclerosis complex. Am J Med Genet C Semin Med Genet. 2018 Sep;178(3):365-373. doi: 10.1002/ajmg.c.31655. Review. PubMed PMID: 30307123.

Abstract: "Between 1993 and 2003, through experiments involving Drosophila sp., cancer biologists identified the protein kinase known as the mammalian target of rapamycin, its pathway, and its relationship to the genes responsible for tuberous sclerosis. Thereafter, clinical research has resulted in regulatory approval of mTOR inhibitors for four distinct manifestations of the disease: giant cell astrocytoma, angiomyolipoma, lymphangioleiomyomatosis, and epilepsy. These developments are summarized and the practical use of mTOR inhibitors to improve the lives of patients with tuberous sclerosis reviewed."

Advanced Review on the use of Drosophila in drug screening

Su TT. Drug screening in Drosophila; why, when, and when not? Wiley Interdiscip Rev Dev Biol. 2019 May 5:e346. doi: 10.1002/wdev.346. PubMed PMID: 31056843.

Abstract: "The best global seller among oncology drugs in 2018 is lenalidomide, an analog of thalidomide. It took 53 years and a circuitous route from the discovery of thalidomide to approval of an analog for use in treatment of cancer. We understand now a lot more about the genetic and molecular basis of diseases than we did in 1953 when thalidomide was discovered. We have also no shortage of chemical libraries with hundreds of thousands of compounds, both synthetic and natural. What we need are better ways to search among these rich resources for compounds with the potential to do what we want them to do. This review summarizes examples from the literature that make Drosophila melanogaster a good model to screen for drugs, and discusses knowledge gaps and technical challenges that make Drosophila models not as widely used as they could or should be."

Whole-animal fly system facilitates study relevant to cancer metastasis

Mishra-Gorur K, Li D, Ma X, Yarman Y, Xue L, Xu T. Spz/Toll-6 signal guides organotropic metastasis in Drosophila. Dis Model Mech. 2019 Sep 2. pii: dmm.039727. doi: 10.1242/dmm.039727. PubMed PMID: 31477571.

Abstract: "Targeted cell migration plays important roles in developmental biology and disease processes including metastasis. Drosophila tumors exhibit traits characteristic of human cancers, providing a powerful model to study developmental and cancer biology. We now find that cells derived from Drosophila eye disc tumors also display organ specific metastasis to invade receptive organs but not wing disc. Toll receptors are known to affect innate immunity and tumor inflammatory microenvironment by modulating the NF-κB pathway. Our RNAi screen and genetic analyses show that Toll-6 is required for migration and invasion of the tumor cells. Further, receptive organs express Toll-ligands, Spz family molecules, and ectopic Spz expression renders wing disc receptive to metastasis. Finally, Toll-6 promotes metastasis by activating JNK signaling, a key regulator of cell migration. Hence, we report Toll-6 and Spätzle as a new pair of guidance molecules mediating organ-specific metastasis behavior and highlight a novel signaling mechanism for Toll family receptors."

Fly model of glioma used to identify potential therapeutic target

Chi KC, Tsai WC, Wu CL, Lin TY, Hueng DY. An Adult Drosophila Glioma Model for Studying Pathometabolic Pathways of Gliomagenesis. Mol Neurobiol. 2019 Jun;56(6):4589-4599. doi: 10.1007/s12035-018-1392-2. Epub 2018 Oct 24. PubMed PMID: 30357574.

Abstract: "Glioblastoma multiforme (GBM), the most prevalent brain tumor in adults, has extremely poor prognosis. Frequent genetic alterations that activate epidermal growth factor receptor (EGFR) and phosphatidylinositol-3 kinase (PI3K) signaling, as well as metabolic remodeling, have been associated with gliomagenesis. To establish a whole-animal approach that can be used to readily identify individual pathometabolic signaling factors, we induced glioma formation in the adult Drosophila brain by activating the EGFR-PI3K pathway. Glioma-induced animals showed significantly enlarged brain volume, early locomotor abnormalities, memory deficits, and a shorter lifespan. Combining bioinformatics analysis and glial-specific gene knockdown in the adult fly glioma model, we identified four evolutionarily conserved metabolic genes, including ALDOA, ACAT1, ELOVL6, and LOX, that were involved in gliomagenesis. Silencing of ACAT1, which controls cholesterol homeostasis, reduced brain enlargement and increased the lifespan of the glioma-bearing flies. In GBM patients, ACAT1 is overexpressed and correlates with poor survival outcomes. Moreover, pharmacological inhibition of ACAT1 in human glioma cell lines revealed that it is essential for tumor proliferation. Collectively, these results imply that ACAT1 is a potential therapeutic target, and cholesterol homeostasis is strongly related to glioma formation. This in vivo model provides several rapid and robust phenotypic readouts, allowing determination of the pathometabolic pathways involved in gliomagenesis, as well as providing valuable information for novel therapeutic strategies."

Fly study reveals potential mechanism of male vs. female differences in cancer malignancy

The histone code reader PHD finger protein 7 controls sex-linked disparities in gene expression and malignancy in Drosophila

Cristina Molnar, Jan Peter Heinen, Jose Reina, Salud Llamazares, Emilio Palumbo, Alessandra Breschi, Marina Gay, Laura Villarreal, Marta Vilaseca, Giulia Pollarolo and Cayetano Gonzalez

Science Advances  14 Aug 2019:
Vol. 5, no. 8, eaaw7965
DOI: 10.1126/sciadv.aaw7965

https://advances.sciencemag.org/content/5/8/eaaw7965.full

Abstract: "The notable male predominance across many human cancer types remains unexplained. Here, we show that Drosophila l(3)mbt brain tumors are more invasive and develop as malignant neoplasms more often in males than in females. By quantitative proteomics, we have identified a signature of proteins that are differentially expressed between male and female tumor samples. Prominent among them is the conserved chromatin reader PHD finger protein 7 (Phf7). We show that Phf7 depletion reduces sex-dependent differences in gene expression and suppresses the enhanced malignant traits of male tumors. Our results identify potential regulators of sex-linked tumor dimorphism and show that these genes may serve as targets to suppress sex-linked malignant traits."

Personalized platform that includes a complex fly genetic model used to identify a treatment strategy for a specific patient

A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer.

Erdem Bangi1,*, Celina Ang2,3, Peter Smibert1,†, Andrew V. Uzilov4,5, Alexander G. Teague1, Yevgeniy Antipin4,5, Rong Chen4,5, Chana Hecht1, Nelson Gruszczynski1,‡, Wesley J. Yon1, Denis Malyshev1, Denise Laspina1, Isaiah Selkridge2, Hope Rainey2, Aye S. Moe4,5, Chun Yee Lau4,5, Patricia Taik4,5, Eric Wilck6, Aarti Bhardwaj2, Max Sung2,3, Sara Kim7, Kendra Yum7, Robert Sebra4,5, Michael Donovan3,8, Krzysztof Misiukiewicz2,3, Eric E. Schadt4,5,3, Marshall R. Posner2,3 and Ross L. Cagan1,3,§

1Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
2Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
3Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
4Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5SEMA4, a Mount Sinai Venture, 333 Ludlow Street, South Tower, 3rd floor, Stamford, CT 06902, USA.
6Department of Radiology, The Mount Sinai Hospital, New York, NY 10029, USA.
7Department of Pharmacy, The Mount Sinai Hospital, New York, NY 10029, USA.
8Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Abstract: "Colorectal cancer remains a leading source of cancer mortality worldwide. Initial response is often followed by emergent resistance that is poorly responsive to targeted therapies, reflecting currently undruggable cancer drivers such as KRAS and overall genomic complexity. Here, we report a novel approach to developing a personalized therapy for a patient with treatment-resistant metastatic KRAS-mutant colorectal cancer. An extensive genomic analysis of the tumor’s genomic landscape identified nine key drivers. A transgenic model that altered orthologs of these nine genes in the Drosophila hindgut was developed; a robotics-based screen using this platform identified trametinib plus zoledronate as a candidate treatment combination. Treating the patient led to a significant response: Target and nontarget lesions displayed a strong partial response and remained stable for 11 months. By addressing a disease’s genomic complexity, this personalized approach may provide an alternative treatment option for recalcitrant disease such as KRAS-mutant colorectal cancer."

 

Read the article at Science Advances.

See also, coverage of the story in The Scientist.

Arginine and a Drosophila model of von Hippel-Lindau syndrome

Shmueli MD, Levy-Kanfo L, Haj E, Schoenfeld AR, Gazit E, Segal D. Arginine refolds, stabilizes, and restores function of mutant pVHL proteins in animal model of the VHL cancer syndrome. Oncogene. 2019 Feb;38(7):1038-1049. PMID: 30194449.

Abstract: "The von Hippel-Lindau (VHL) syndrome is a rare inherited cancer, caused by mutations in the VHL gene, many of which render the VHL protein (pVHL) unstable. pVHL is a tumor-suppressor protein implicated in a variety of cellular processes, most notably in response to changes in oxygen availability, due to its role as part of an E3-ligase complex which targets the hypoxia-inducible factor (HIF) for degradation. Previously we reported, using in silico and in vitro analyses, that common oncogenic VHL mutations render pVHL less stable than the wild-type protein, distort its core domain and as a result reduce the ability of the protein to bind its target HIF-1α. Among various chemical chaperones tested, arginine was the most effective in refolding mutant of pVHL. Here we examined the consequences of administering L- or D-arginine to a Drosophila VHL model and to human renal carcinoma cells, both expressing misfolded versions of human pVHL. Arginine treatment increased pVHL solubility in both models and increased the half-life of the mutant pVHL proteins in the cell culture. In both models, L- as well as D-arginine enhanced the ability of wild-type pVHL and certain misfolded mutant versions of pVHL to bind ODD, the HIF-derived target peptide, reflecting restoration of pVHL function. Moreover, continuous feeding of Drosophila expressing misfolded versions of pVHL either L- or D-arginine rich diet rescued their lethal phenotype. Collectively, these in vivo results suggest that arginine supplementation should be examined as a potential novel treatment for VHL cancer syndrome."

Drosophila as "providing an unparalleled opportunity to combine dietary manipulation with models of human metabolic disease and cancer" (Review Article)

Warr CG, Shaw KH, Azim A, Piper MDW, Parsons LM. Using Mouse and Drosophila Models to Investigate the Mechanistic Links between Diet, Obesity, Type II Diabetes, and Cancer. Int J Mol Sci. 2018 Dec 18;19(12). pii: E4110. PMID: 30567377.

The abstract: "Many of the links between diet and cancer are controversial and over simplified. To date, human epidemiological studies consistently reveal that patients who suffer diet-related obesity and/or type II diabetes have an increased risk of cancer, suffer more aggressive cancers, and respond poorly to current therapies. However, the underlying molecular mechanisms that increase cancer risk and decrease the response to cancer therapies in these patients remain largely unknown. Here, we review studies in mouse cancer models in which either dietary or genetic manipulation has been used to model obesity and/or type II diabetes. These studies demonstrate an emerging role for the conserved insulin and insulin-like growth factor signaling pathways as links between diet and cancer progression. However, these models are time consuming to develop and expensive to maintain. As the world faces an epidemic of obesity and type II diabetes we argue that the development of novel animal models is urgently required. We make the case for Drosophila as providing an unparalleled opportunity to combine dietary manipulation with models of human metabolic disease and cancer. Thus, combining diet and cancer models in Drosophila can rapidly and significantly advance our understanding of the conserved molecular mechanisms that link diet and diet-related metabolic disorders to poor cancer patient prognosis."