Mitochondrial defects trigger proliferation of neighbouring cells via a senescence-associated secretory phenotype in Drosophila

Nakamura, Mitsuki; Ohsawa, Seiji; Igaki, Tatsushi

doi:10.1038/ncomms6264

Cited by 68 publications

(82 citation statements)

References 57 publications

(70 reference statements)

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“…9, 10, 11 In Ras-driven epithelial overgrowth, studies in Drosophila have revealed that impairment of cell polarity or mitochondrial functions enhance tumour growth and invasion via activation of the Jun kinase (JNK) stress response pathway, faithfully recapitulating some of the features responsible for tumour progression in human cancers. 11, 12, 13, 14, 15 …”

Section: Introductionmentioning

confidence: 99%

Autophagy suppresses Ras-driven epithelial tumourigenesis by limiting the accumulation of reactive oxygen species

et al. 2017

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Activation of Ras signalling occurs in ~30% of human cancers; however, activated Ras alone is not sufficient for tumourigenesis. In a screen for tumour suppressors that cooperate with oncogenic Ras (RasV12) in Drosophila, we identified genes involved in the autophagy pathway. Bioinformatic analysis of human tumours revealed that several core autophagy genes, including GABARAP, correlate with oncogenic KRAS mutations and poor prognosis in human pancreatic cancer, supporting a potential tumour-suppressive effect of the pathway in Ras-driven human cancers. In Drosophila, we demonstrate that blocking autophagy at any step of the pathway enhances RasV12-driven epithelial tissue overgrowth via the accumulation of reactive oxygen species and activation of the Jun kinase stress response pathway. Blocking autophagy in RasV12 clones also results in non-cell-autonomous effects with autophagy, cell proliferation and caspase activation induced in adjacent wild-type cells. Our study has implications for understanding the interplay between perturbations in Ras signalling and autophagy in tumourigenesis, which might inform the development of novel therapeutics targeting Ras-driven cancers.

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Section: Introductionmentioning

confidence: 99%

Autophagy suppresses Ras-driven epithelial tumourigenesis by limiting the accumulation of reactive oxygen species

et al. 2017

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“…Interestingly, Ras V12 / mito −/− cells cause cell‐cycle arrest through ROS production and undergo p53‐dependent cellular senescence (Fig. a) . Overexpression of p53 inside Ras V12 clones is sufficient to induce ONCs and non‐autonomous overgrowth.…”

Section: Non‐autonomous Tumor Progression By Oncsmentioning

confidence: 98%

Non‐autonomous overgrowth by oncogenic niche cells: Cellular cooperation and competition in tumorigenesis

2015

Self Cite

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Tumor progression is classically viewed as the Darwinian evolution of subclones that sequentially acquire genetic mutations and autonomously overproliferate. However, growing evidence suggests that tumor microenvironment and subclone heterogeneity contribute to non‐autonomous tumor progression. Recent Drosophila studies revealed a common mechanism by which clones of genetically altered cells trigger non‐autonomous overgrowth. Such “oncogenic niche cells” (ONCs) do not overgrow but instead stimulate neighbor overgrowth and metastasis. Establishment of ONCs depends on competition and cooperation between heterogeneous cell populations. This review characterizes diverse ONCs identified in Drosophila and describes the genetic basis of non‐autonomous tumor progression. Similar mechanisms may contribute to mammalian cancer progression and recurrence.

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“…Activated JNK coupled with oncogenic Ras could then inactivate the hippo pathway in senescent cells, stimulating secretion of Unpaired (an Interleukin-6 homologue) and Wingless (a Wnt homologue). Eventually, these secreted factors could cooperate with Ras signaling in neighboring cells (which have normal mitochondrial function), resulting in overgrowth of neighboring tissue 68,69 .…”

Section: Clonal Cooperation and Tumor Malignancymentioning

confidence: 99%

Clonal cooperativity in heterogenous cancers

Zhou

Neelakantan

Ford

2017

Seminars in Cell & Developmental Biology

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Tumor heterogeneity is a major obstacle to the development of effective therapies and is thus an important focus of cancer research. Genetic and epigenetic alterations, as well as altered tumor microenvironments, result in tumors made up of diverse subclones with different genetic and phenotypic characteristics. Intratumor heterogeneity enables competition, but also supports clonal cooperation via cell-cell contact or secretion of factors, resulting in enhanced tumor progression. Here, we summarize recent findings related to interclonal interactions within a tumor and the therapeutic implications of such interactions, with an emphasis on how different subclones collaborate with each other to promote proliferation, metastasis and therapy-resistance. Furthermore, we propose that disruption of clonal cooperation by targeting key factors (such as Wnt and Hedgehog, amongst others) can be an alternative approach to improving clinical outcomes.

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Mitochondrial defects trigger proliferation of neighbouring cells via a senescence-associated secretory phenotype in Drosophila

Cited by 68 publications

References 57 publications

Autophagy suppresses Ras-driven epithelial tumourigenesis by limiting the accumulation of reactive oxygen species

Autophagy suppresses Ras-driven epithelial tumourigenesis by limiting the accumulation of reactive oxygen species

Non‐autonomous overgrowth by oncogenic niche cells: Cellular cooperation and competition in tumorigenesis

Clonal cooperativity in heterogenous cancers

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