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1.
Dev Cell ; 56(15): 2223-2236.e5, 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34324859

RESUMO

Cancer tissue often comprises multiple tumor clones with distinct oncogenic alterations such as Ras or Src activation, yet the mechanism by which tumor heterogeneity drives cancer progression remains elusive. Here, we show in Drosophila imaginal epithelium that clones of Ras- or Src-activated benign tumors interact with each other to mutually promote tumor malignancy. Mechanistically, Ras-activated cells upregulate the cell-surface ligand Delta while Src-activated cells upregulate its receptor Notch, leading to Notch activation in Src cells. Elevated Notch signaling induces the transcriptional repressor Zfh1/ZEB1, which downregulates E-cadherin and cell death gene hid, leading to Src-activated invasive tumors. Simultaneously, Notch activation in Src cells upregulates the cytokine Unpaired/IL-6, which activates JAK-STAT signaling in neighboring Ras cells. Elevated JAK-STAT signaling upregulates the BTB-zinc-finger protein Chinmo, which downregulates E-cadherin and thus generates Ras-activated invasive tumors. Our findings provide a mechanistic explanation for how tumor heterogeneity triggers tumor progression via cell-cell interactions.

2.
Development ; 148(14)2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34313318

RESUMO

Heterozygosity of ribosomal protein genes causes a variety of developmental abnormalities in humans, which are collectively known as ribosomopathies, yet the underlying mechanisms remain elusive. Here, we analyzed Drosophila Minute (M)/+ mutants, a group of mutants heterozygous for ribosomal protein genes that exhibit a characteristic thin-bristle phenotype. We found that, although M/+ flies develop essentially normal wings, simultaneous deletion of one copy of the Hippo pathway effector yki resulted in severe wing growth defects. These defects were caused by JNK-mediated cell death in the wing pouch via Eiger/TNF signaling. The JNK activation in M/+, yki/+ wing discs required the caspase Dronc, which is normally blocked by DIAP1. Notably, heterozygosity of yki reduced DIAP1 expression in the wing pouch, leading to elevation of Dronc activity. Dronc and JNK formed a positive-feedback loop that amplifies Dronc activation, leading to apoptosis. Our observations suggest a mechanism of robust tissue growth whereby tissues with reduced ribosomal protein prevent ectopic apoptosis via Yki activity.


Assuntos
Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Animais , Apoptose , Morte Celular , Regulação para Baixo , Drosophila/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas Nucleares/genética , Transdução de Sinais , Transativadores/genética , Asas de Animais/anatomia & histologia , Asas de Animais/metabolismo
3.
Sci Signal ; 14(685)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34074704

RESUMO

The activation of Ras signaling is a major early event of oncogenesis in many contexts, yet paradoxically, Ras signaling induces cellular senescence, which prevents tumorigenesis. Thus, Ras-activated cells must overcome senescence to develop into cancer. Through a genetic screen in Drosophila melanogaster, we found that the ETS family transcriptional activator Pointed (Pnt) was necessary and sufficient to trigger cellular senescence upon Ras activation and blocked Ras-induced tumor growth in eye-antennal discs. Through analyses of mosaic discs using various genetic tools, we identified a mechanism of tumor progression in which loss of cell polarity, a common driver of epithelial oncogenesis, abrogated Ras-induced cellular senescence through microRNA-mediated inhibition of Pnt. Mechanistically, polarity defects in Ras-activated cells caused activation of the Hippo effector Yorkie (Yki), which induced the expression of the microRNA bantam bantam-mediated repression of the E3 ligase-associated protein Tribbles (Trbl) relieved Ras- and Akt-dependent inhibition of the transcription factor FoxO. The restoration of FoxO activity in Ras-activated cells induced the expression of the microRNAs miR-9c and miR-79, which led to reduced pnt expression, thereby abrogating cellular senescence and promoting tumor progression. Our findings provide a mechanistic explanation for how Ras-activated tumors progress toward malignancy by overcoming cellular senescence.

4.
PLoS Genet ; 17(1): e1009300, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33507966

RESUMO

Highly reproducible tissue development is achieved by robust, time-dependent coordination of cell proliferation and cell death. To study the mechanisms underlying robust tissue growth, we analyzed the developmental process of wing imaginal discs in Drosophila Minute mutants, a series of heterozygous mutants for a ribosomal protein gene. Minute animals show significant developmental delay during the larval period but develop into essentially normal flies, suggesting there exists a mechanism ensuring robust tissue growth during abnormally prolonged developmental time. Surprisingly, we found that both cell death and compensatory cell proliferation were dramatically increased in developing wing pouches of Minute animals. Blocking the cell-turnover by inhibiting cell death resulted in morphological defects, indicating the essential role of cell-turnover in Minute wing morphogenesis. Our analyses showed that Minute wing discs elevate Wg expression and JNK-mediated Dilp8 expression that causes developmental delay, both of which are necessary for the induction of cell-turnover. Furthermore, forced increase in Wg expression together with developmental delay caused by ecdysone depletion induced cell-turnover in the wing pouches of non-Minute animals. Our findings suggest a novel paradigm for robust coordination of tissue growth by cell-turnover, which is induced when developmental time axis is distorted.


Assuntos
Proteínas de Drosophila/genética , Discos Imaginais/crescimento & desenvolvimento , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas Ribossômicas/genética , Proteína Wnt1/genética , Animais , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Ecdisona/genética , Células Epiteliais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Discos Imaginais/metabolismo , Larva/genética , Larva/crescimento & desenvolvimento , Metamorfose Biológica/genética , Organogênese/genética , Transdução de Sinais/genética , Fatores de Transcrição/genética , Asas de Animais/crescimento & desenvolvimento , Asas de Animais/metabolismo
5.
Cancer Sci ; 111(10): 3409-3415, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32677169

RESUMO

Oncogenic mutations often trigger antitumor cellular response such as induction of apoptosis or cellular senescence. Studies in the last decade have identified the presence of the third guardian against mutation-induced tumorigenesis, namely "cell competition." Cell competition is a context-dependent cell elimination whereby cells with higher fitness eliminate neighboring cells with lower fitness by inducing cell death. While oncogene-induced apoptosis or oncogene-induced senescence acts as a cell-autonomous tumor suppressor, cell competition protects the tissue from tumorigenesis via cell-cell communication. For instance, in Drosophila epithelium, oncogenic cells with cell polarity mutations overproliferate and develop into tumors on their own but are eliminated from the tissue when surrounded by wild-type cells. Genetic studies in flies have unraveled that such tumor-suppressive cell competition is regulated by at least three mechanisms: direct cell-cell interaction between polarity-deficient cells and wild-type cells, secreted factors from epithelial cells, and systemic factors from distant organs. Molecular manipulation of tumor-suppressive cell competition could provide a novel therapeutic strategy against human cancers.


Assuntos
Competição entre as Células/genética , Competição entre as Células/fisiologia , Drosophila/genética , Drosophila/fisiologia , Animais , Comunicação Celular/genética , Comunicação Celular/fisiologia , Células Epiteliais/fisiologia , Humanos , Mutação/genética , Oncogenes/genética
6.
Dev Cell ; 53(4): 379-389.e5, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32386602

RESUMO

Metabolic diseases such as type 2 diabetes are associated with increased cancer incidence. Here, we show that hyperinsulinemia promotes epithelial tumorigenesis by abrogating cell competition. In Drosophila eye imaginal epithelium, oncogenic scribble (scrib) mutant cells are eliminated by cell competition when surrounded by wild-type cells. Through a genetic screen, we find that flies heterozygous for the insulin receptor substrate chico allow scrib cells to evade cell competition and develop into tumors. Intriguingly, chico is required in the brain's insulin-producing cells (IPCs) to execute cell competition remotely. Mechanistically, chico downregulation in IPCs causes hyperinsulinemia by upregulating a Drosophila insulin Dilp2, which activates insulin-mTOR signaling and thus boosts protein synthesis in scrib cells. A diet-induced increase in insulin levels also triggers scrib tumorigenesis, and pharmacological repression of protein synthesis prevents hyperinsulinemia-induced scrib overgrowth. Our findings provide an in vivo mechanistic link between metabolic disease and cancer risk via systemic regulation of cell competition.


Assuntos
Carcinogênese/patologia , Competição entre as Células , Diabetes Mellitus Tipo 2/fisiopatologia , Drosophila melanogaster/metabolismo , Hiperinsulinismo/complicações , Proteínas de Membrana/genética , Neoplasias Epiteliais e Glandulares/patologia , Proteínas Supressoras de Tumor/genética , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Polaridade Celular , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Feminino , Humanos , Masculino , Proteínas de Membrana/metabolismo , Mutação , Neoplasias Epiteliais e Glandulares/etiologia , Neoplasias Epiteliais e Glandulares/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo
7.
Sci Rep ; 9(1): 19549, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31863086

RESUMO

Multicellular organisms repair injured epithelium by evolutionarily conserved biological processes including activation of c-Jun N-terminal kinase (JNK) signaling. Here, we show in Drosophila imaginal epithelium that physical injury leads to the emergence of dying cells, which are extruded from the wounded tissue by JNK-induced Slit-Roundabout2 (Robo2) repulsive signaling. Reducing Slit-Robo2 signaling in the wounded tissue suppresses extrusion of dying cells and generates aberrant cells with highly upregulated growth factors Wingless (Wg) and Decapentaplegic (Dpp). The inappropriately elevated Wg and Dpp impairs wound repair, as halving one of these growth factor genes cancelled wound healing defects caused by Slit-Robo2 downregulation. Our data suggest that JNK-mediated Slit-Robo2 signaling contributes to epithelial wound repair by promoting extrusion of dying cells from the wounded tissue, which facilitates transient and appropriate induction of growth factors for proper wound healing.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Transdução de Sinais/fisiologia , Animais , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Proteína Wnt1/genética , Proteína Wnt1/metabolismo , Cicatrização/genética , Cicatrização/fisiologia
8.
Dev Cell ; 51(1): 99-112.e4, 2019 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-31543447

RESUMO

Cell competition is a quality control process that selectively eliminates unfit cells from the growing tissue via cell-cell interaction. Despite extensive mechanistic studies, the mechanism by which cell elimination is triggered has been elusive. Here, through a genetic screen in Drosophila, we discover that V-ATPase, an essential factor for autophagy, is required for triggering cell competition. Strikingly, autophagy is specifically elevated in prospective "loser" cells nearby wild-type "winner" cells, and blocking autophagy in loser cells abolishes their elimination. Mechanistically, elevated autophagy upregulates a proapoptotic gene hid through NFκB, and the elevated hid cooperates with JNK signaling to effectively induce loser's death. Crucially, this mechanism generally applies to cell competition caused by differences in protein synthesis between cells. Our findings establish a common mechanism of cell competition whereby cells with higher protein synthesis induce autophagy in their neighboring cells, leading to elimination of unfit cells.


Assuntos
Autofagia , Drosophila melanogaster/genética , MAP Quinase Quinase 4/metabolismo , NF-kappa B/metabolismo , Animais , Apoptose , Ligação Competitiva , Comunicação Celular , Morte Celular , Proliferação de Células , Proteínas de Drosophila/metabolismo , Feminino , Genótipo , Masculino , Mutação , Interferência de RNA , Transdução de Sinais , Ativação Transcricional , Regulação para Cima
9.
Dev Growth Differ ; 60(9): 522-530, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30443922

RESUMO

Cell competition is a context-dependent cell elimination through short-range cell-cell interaction, in which cells with higher fitness eliminate neighboring less-fit or oncogenic cells within the growing tissue. Cell competition can be triggered by many different factors such as heterozygous mutations in the ribosomal protein genes (which are called "Minute" mutations), elevated Myc, Yorkie/YAP, Wg/Wnt, JAK-STAT, Ras, or Src activity, and loss of Mahjong/VprBP, endocytic pathway components, or apicobasal cell polarity. Studies on the mechanisms and roles of cell competition have suggested that cell competition can be divided into two types: selection of fitter cells or elimination of oncogenic cells. The former type of cell competition includes Minute or Myc-induced cell competition that is considered to be dependent on the relative level of protein synthesis. The later type of cell competition includes tumor-suppressive cell competition triggered by loss of cell polarity genes such as scribble (scrib) or discs large (dlg). Genetic studies in Drosophila during the past decade have provided significant progress in understanding the mechanisms of these phenomena. At the same time, these studies have now raised new questions; how do different mechanisms contribute or cooperate to drive cell competition, do common mechanisms exist in different types of cell competition, and what are the physiological roles of these cell competition phenomena?


Assuntos
Adaptação Fisiológica/fisiologia , Comunicação Celular/fisiologia , Proliferação de Células/fisiologia , Modelos Biológicos , Adaptação Fisiológica/genética , Animais , Comunicação Celular/genética , Proliferação de Células/genética , Humanos , Mutação , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas pp60(c-src)/genética , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Transdução de Sinais/genética
10.
Curr Biol ; 28(13): 2115-2128.e5, 2018 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-29910075

RESUMO

During the initial stage of tumor progression, oncogenic cells spread despite spatial confinement imposed by surrounding normal tissue. This spread of oncogenic cells (winners) is thought to be governed by selective killing of surrounding normal cells (losers) through a phenomenon called "cell competition" (i.e., supercompetition). Although the mechanisms underlying loser elimination are increasingly apparent, it is not clear how winner cells selectively occupy the space made available following loser apoptosis. Here, we combined live imaging analyses of two different oncogenic clones (Yki/YAP activation and Ras activation) in the Drosophila epithelium with computer simulation of tissue mechanics to elucidate such a mechanism. Contrary to the previous expectation that cell volume loss after apoptosis of loser cells was simply compensated for by the faster proliferation of winner cells, we found that the lost volume was compensated for by rapid cell expansion of winners. Mechanistically, the rapid winner-dominated cell expansion was driven by apoptosis-induced epithelial junction remodeling, which causes re-connection of local cellular connectivity (cell topology) in a manner that selectively increases winner apical surface area. In silico experiments further confirmed that repetition of loser elimination accelerates tissue-scale winner expansion through topological changes over time. Our proposed mechanism for linking loser death and winner expansion provides a new perspective on how tissue homeostasis disruption can initiate from an oncogenic mutation.


Assuntos
Apoptose/fisiologia , Proliferação de Células/fisiologia , Drosophila melanogaster/fisiologia , Células Epiteliais/fisiologia , Transdução de Sinais/fisiologia , Animais , Fenômenos Biomecânicos , Simulação por Computador , Homeostase
11.
Adv Exp Med Biol ; 1076: 173-194, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29951820

RESUMO

Over the last few decades, Drosophila cancer models have made great contributions to our understanding toward fundamental cancer processes. Particularly, the development of genetic mosaic technique in Drosophila has enabled us to recapitulate basic aspects of human cancers, including clonal evolution, tumor microenvironment, cancer cachexia, and anticancer drug resistance. The mosaic technique has also led to the discovery of important tumor-suppressor pathways such as the Hippo pathway and the elucidation of the mechanisms underlying tumor growth and metastasis via regulation of cell polarity, cell-cell cooperation, and cell competition. Recent approaches toward identification of novel therapeutics using fly cancer models have further proved Drosophila as a robust system with great potentials for cancer research as well as anti-cancer therapy.


Assuntos
Modelos Animais de Doenças , Drosophila melanogaster , Neoplasias , Animais , Humanos
12.
Curr Biol ; 28(11): 1756-1767.e6, 2018 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-29804808

RESUMO

Normal epithelial tissue exerts an intrinsic tumor-suppressive effect against oncogenically transformed cells. In Drosophila imaginal epithelium, clones of oncogenic polarity-deficient cells mutant for scribble (scrib) or discs large (dlg) are eliminated by cell competition when surrounded by wild-type cells. Here, through a genetic screen in Drosophila, we identify Serpin5 (Spn5), a secreted negative regulator of Toll signaling, as a crucial factor for epithelial cells to eliminate scrib mutant clones from epithelium. Downregulation of Spn5 in wild-type cells leads to elevation of Toll signaling in neighboring scrib cells. Strikingly, forced activation of Toll signaling or Toll-related receptor (TRR) signaling in scrib clones transforms scrib cells from losers to supercompetitors, resulting in tumorous overgrowth of mutant clones. Mechanistically, Toll activation in scrib clones leads to c-Jun N-terminal kinase (JNK) activation and F-actin accumulation, which cause strong activation of the Hippo pathway effector Yorkie that blocks cell death and promotes cell proliferation. Our data suggest that Spn5 secreted from normal epithelial cells acts as a component of the extracellular surveillance system that facilitates elimination of pre-malignant cells from epithelium.


Assuntos
Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Regulação da Expressão Gênica/fisiologia , Serpinas/genética , Transdução de Sinais/genética , Receptores Toll-Like/fisiologia , Animais , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Células Epiteliais/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Serpinas/metabolismo , Receptores Toll-Like/genética , Transativadores/genética , Transativadores/metabolismo
13.
Oncogene ; 37(23): 3088-3097, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29535423

RESUMO

Epithelial cancer tissues often possess polyploid giant cells, which are thought to be highly oncogenic. However, the mechanisms by which polyploid giant cells are generated in tumor tissues and how such cells contribute to tumor progression remain elusive. We previously noticed in Drosophila imaginal epithelium that cells mutant for the endocytic gene rab5 exhibit enlarged nuclei. Here we find that mutations in endocytic 'neoplastic tumor-suppressor' genes, such as rab5, vps25, erupted, or avalanche result in generation of polyploid giant cells. Genetic analyses on rab5-defective cells reveal that cooperative activation of JNK and Yorkie generates polyploid giant cells via endoreplication. Mechanistically, Yorkie-mediated upregulation of Diap1 cooperates with JNK to downregulate the G2/M cyclin CycB, thereby inducing endoreplication. Interestingly, malignant tumors induced by Ras activation and cell polarity defect also consist of polyploid giant cells, which are generated by JNK and Yorkie-mediated downregulation of CycB. Strikingly, elimination of polyploid giant cells from such malignant tumors by blocking endoreplication strongly suppressed tumor growth and metastatic behavior. Our observations suggest that JNK and Yorkie, two oncogenic proteins activated in many types of human cancers, cooperatively drive tumor progression by generating oncogenic polyploid giant cells.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/patogenicidade , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Nucleares/metabolismo , Poliploidia , Transativadores/metabolismo , Animais , Animais Geneticamente Modificados , Ciclina B/genética , Ciclina B/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Regulação da Expressão Gênica , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Mutação , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Proteínas Nucleares/genética , Transativadores/genética , Proteínas rab5 de Ligação ao GTP/genética , Proteínas rab5 de Ligação ao GTP/metabolismo
15.
Genes Cells ; 23(3): 234-240, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29431244

RESUMO

Cells heterozygously mutant for a ribosomal protein gene, called Minute/+ mutants, are eliminated from epithelium by cell competition when surrounded by wild-type cells. Whereas several factors that regulate Minute cell competition have been identified, the mechanisms how winner/loser status is determined and thereby triggers cell competition are still elusive. To address this, we established two assay systems for Minute cell competition, namely (i) the CORE (competitive elimination of RpS3-RNAi-expressing cells) system in which RpS3-RNAi-expressing wing pouch cells are eliminated from wild-type wing disc and (ii) the SURE (supercompetition of RpS3-expressing clones in RpS3/+ tissue) system in which RpS3-over-expressing clones generated in RpS3/+ wing disc outcompete surrounding RpS3/+ cells. An ectopic over-expression screen using the CORE system identified Wg signaling as a critical regulator of Minute cell competition. Activation of Wg signaling in loser cells suppressed their elimination, whereas down-regulation of Wg signaling in loser cells enhanced their elimination. Furthermore, using the SURE system, we found that down-regulation of Wg signaling in winner cells suppressed elimination of neighboring losers. Our observations suggest that cellular Wg signaling activity is crucial for determining winner/loser status and thereby triggering Minute cell competition.


Assuntos
Drosophila melanogaster/crescimento & desenvolvimento , Transdução de Sinais , Animais , Animais Geneticamente Modificados/crescimento & desenvolvimento , Animais Geneticamente Modificados/fisiologia , Apoptose , Comunicação Celular , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Proteína Wnt1/genética , Proteína Wnt1/metabolismo
16.
Dev Cell ; 44(3): 284-296, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29408235

RESUMO

Epithelial tissues robustly respond to internal and external stressors via dynamic cellular rearrangements. Cell extrusion acts as a key regulator of epithelial homeostasis by removing apoptotic cells, orchestrating morphogenesis, and mediating competitive cellular battles during tumorigenesis. Here, we delineate the diverse functions of cell extrusion during development and disease. We emphasize the expanding role for apoptotic cell extrusion in exerting morphogenetic forces, as well as the strong intersection of cell extrusion with cell competition, a homeostatic mechanism that eliminates aberrant or unfit cells. While cell competition and extrusion can exert potent, tumor-suppressive effects, dysregulation of either critical homeostatic program can fuel cancer progression.


Assuntos
Fenômenos Fisiológicos Celulares , Células Epiteliais/fisiologia , Homeostase , Morfogênese/fisiologia , Estresse Fisiológico , Animais , Sobrevivência Celular , Células Epiteliais/citologia , Humanos
17.
Dev Cell ; 40(3): 219-220, 2017 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-28171745

RESUMO

Autophagy supports cell growth and survival autonomously by recycling intracellular proteins and/or organelles. Reporting in Nature, Katheder and colleagues (2017) find that tumors trigger non-autonomous autophagy in neighboring cells and distant organs, thus fueling tumor growth and metastasis. This opens new avenues for understanding and manipulating cancers through cell-cell communication.


Assuntos
Carcinogênese , Transformação Celular Neoplásica , Autofagia , Comunicação Celular , Humanos , Neoplasias
18.
Nature ; 542(7640): 246-250, 2017 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-28092921

RESUMO

Normal epithelial cells often exert anti-tumour effects against nearby oncogenic cells. In the Drosophila imaginal epithelium, clones of oncogenic cells with loss-of-function mutations in the apico-basal polarity genes scribble or discs large are actively eliminated by cell competition when surrounded by wild-type cells. Although c-Jun N-terminal kinase (JNK) signalling plays a crucial role in this cell elimination, the initial event, which occurs at the interface between normal cells and polarity-deficient cells, has not previously been identified. Here, through a genetic screen in Drosophila, we identify the ligand Sas and the receptor-type tyrosine phosphatase PTP10D as the cell-surface ligand-receptor system that drives tumour-suppressive cell competition. At the interface between the wild-type 'winner' and the polarity-deficient 'loser' clones, winner cells relocalize Sas to the lateral cell surface, whereas loser cells relocalize PTP10D there. This leads to the trans-activation of Sas-PTP10D signalling in loser cells, which restrains EGFR signalling and thereby enables elevated JNK signalling in loser cells, triggering cell elimination. In the absence of Sas-PTP10D, elevated EGFR signalling in loser cells switches the role of JNK from pro-apoptotic to pro-proliferative by inactivating the Hippo pathway, thereby driving the overgrowth of polarity-deficient cells. These findings uncover the mechanism by which normal epithelial cells recognize oncogenic polarity-deficient neighbours to drive cell competition.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Neoplasias/patologia , Proteínas Tirosina Fosfatases/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Apoptose , Polaridade Celular , Proliferação de Células , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Receptores ErbB/metabolismo , Feminino , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Ligantes , Masculino , Proteínas de Membrana/genética , Neoplasias/metabolismo , Transdução de Sinais , Ativação Transcricional , Proteínas Supressoras de Tumor/genética
19.
Methods Mol Biol ; 1534: 211-218, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27812882

RESUMO

Cellular senescence is induced by various cellular stresses, including activation of the Ras oncogene. In Drosophila imaginal epithelia, clones of cells expressing oncogenic Ras (RasV12) show several markers of cellular senescence, such as elevation of SA-ß-gal activity, upregulation of the Cdk inhibitor Dacapo (Dap), and heterochromatinization. However, these cells do not undergo cell cycle arrest or exhibit a DNA damage response (DDR), cellular hypertrophy, or a senescence-associated secretory phenotype (SASP), other essential markers of cellular senescence. However, we found that inducing mitochondrial dysfunction within RasV12-expressing cells caused all above-mentioned aspects of cellular senescence. This provided the first evidence that cellular senescence occurs in invertebrates and is intriguing because mitochondrial dysfunction is frequently observed in human cancers. Here, we describe the procedures for the induction and detection of cellular senescence in Drosophila epithelia.


Assuntos
Senescência Celular , Drosophila/genética , Drosophila/metabolismo , Oncogenes , Animais , Senescência Celular/genética , Dano ao DNA , Expressão Gênica , Técnicas de Inativação de Genes , Genes Reporter , Genes ras/genética , Histonas/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , beta-Galactosidase/metabolismo
20.
Dev Cell ; 39(6): 683-695, 2016 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-27997825

RESUMO

Cells dynamically interact throughout animal development to coordinate growth and deter disease. For example, cell-cell competition weeds out aberrant cells to enforce homeostasis. In Drosophila, tumorigenic cells mutant for the cell polarity gene scribble (scrib) are actively eliminated from epithelia when surrounded by wild-type cells. While scrib cell elimination depends critically on JNK signaling, JNK-dependent cell death cannot sufficiently explain scrib cell extirpation. Thus, how JNK executed cell elimination remained elusive. Here, we show that repulsive Slit-Robo2-Ena signaling exerts an extrusive force downstream of JNK to eliminate scrib cells from epithelia by disrupting E-cadherin. While loss of Slit-Robo2-Ena in scrib cells potentiates scrib tumor formation within the epithelium, Robo2-Ena hyperactivation surprisingly triggers luminal scrib tumor growth following excess extrusion. This extrusive signaling is amplified by a positive feedback loop between Slit-Robo2-Ena and JNK. Our observations provide a potential causal mechanism for Slit-Robo dysregulation in numerous human cancers.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Epitélio/metabolismo , Epitélio/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas do Tecido Nervoso/metabolismo , Receptores Imunológicos/metabolismo , Transdução de Sinais , Animais , Caderinas/metabolismo , Carcinogênese/metabolismo , Carcinogênese/patologia , Células Clonais , Retroalimentação Fisiológica , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Modelos Biológicos , Regulação para Cima
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