title: Microenvironmental autophagy promotes tumour growth.
abstract: As malignant tumours develop, they interact intimately with their microenvironment and can activate autophagy, a catabolic process which provides nutrients during starvation. How tumours regulate autophagy in vivo and whether autophagy affects tumour growth is controversial. Here we demonstrate, using a well characterized Drosophila melanogaster malignant tumour model, that non-cell-autonomous autophagy is induced both in the tumour microenvironment and systemically in distant tissues. Tumour growth can be pharmacologically restrained using autophagy inhibitors, and early-stage tumour growth and invasion are genetically dependent on autophagy within the local tumour microenvironment. Induction of autophagy is mediated by Drosophila tumour necrosis factor and interleukin-6-like signalling from metabolically stressed tumour cells, whereas tumour growth depends on active amino acid transport. We show that dormant growth-impaired tumours from autophagy-deficient animals reactivate tumorous growth when transplanted into autophagy-proficient hosts. We conclude that transformed cells engage surrounding normal cells as active and essential microenvironmental contributors to early tumour growth through nutrient-generating autophagy.
authors.affiliation: Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway.|Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway.
authors.forename: Nadja S
authors.initials: NS
authors.lastname: Katheder
authors.affiliation: Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway.|Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway.
authors.forename: Rojyar
authors.initials: R
authors.lastname: Khezri
authors.affiliation: Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway.|Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway.
authors.forename: Fergal
authors.initials: F
authors.lastname: O'Farrell
authors.affiliation: Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway.|Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway.
authors.forename: Sebastian W
authors.initials: SW
authors.lastname: Schultz
authors.affiliation: Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway.|Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway.|Molecular Cancer Research Group, Institute of Medical Biology, UiT - The Arctic University of Norway, 9037 Tromsø, Norway.
authors.forename: Ashish
authors.initials: A
authors.lastname: Jain
authors.affiliation: Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway.|Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway.
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Rahman
authors.affiliation: Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway.|Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway.
authors.forename: Kay O
authors.initials: KO
authors.lastname: Schink
authors.affiliation: Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway.
authors.forename: Theodossis A
authors.initials: TA
authors.lastname: Theodossiou
authors.affiliation: Molecular Cancer Research Group, Institute of Medical Biology, UiT - The Arctic University of Norway, 9037 Tromsø, Norway.
authors.forename: Terje
authors.initials: T
authors.lastname: Johansen
authors.affiliation: Institute of Genetics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, H-6726 Hungary.|Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Budapest H-1117, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Juhász
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720-3200, USA.
authors.forename: David
authors.initials: D
authors.lastname: Bilder
authors.affiliation: Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway.|Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway.
authors.forename: Andreas
authors.initials: A
authors.lastname: Brech
authors.affiliation: Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway.|Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway.
authors.forename: Harald
authors.initials: H
authors.lastname: Stenmark
authors.affiliation: Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway.|Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway.
authors.forename: Tor Erik
authors.initials: TE
authors.lastname: Rusten
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D001692:Biological Transport; D049109:Cell Proliferation; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics; D004331:Drosophila melanogaster / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015850:Interleukin-6 / Q000378:metabolism; D008565:Membrane Proteins; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D059016:Tumor Microenvironment; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: D000596:Amino Acids; D029721:Drosophila Proteins; D015850:Interleukin-6; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; C404683:Scrib protein, Drosophila; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins