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Adipose-derived stromal cell secretome disrupts autophagy in glioblastoma

  • Giovana Ravizzoni Onzi
  • Juliano Luiz Faccioni
  • Luiza Cherobini Pereira
  • Marcos Paulo Thomé
  • Ana Paula Santin Bertoni
  • Julieti Huch Buss
  • Tiago Fazolo
  • Eduardo Filippi-Chiela
  • Márcia Rosângela Wink
  • Guido LenzEmail author
Original Article

Abstract

Mesenchymal stromal cells (MSCs) are frequently recruited to tumor sites to play a part in the tumor microenvironment (TME). However, their real impact on cancer cell behavior remains obscure. Here we investigated the effects of human adipose-derived stromal cell (hADSC) secretome in autophagy of glioblastoma (GBM), as a way to better comprehend how hADSCs influence the TME. GBM U-87 MG cells were treated with conditioned medium (CM) from hADSCs and autophagic flux was evaluated. hADSC CM treatment blocked the autophagic flux in tumor cells, as indicated by the accumulation of autophagosomes in the cytosol, the high LC3-II and p62/SQSTM1 protein levels, and the lack of increase in the amount of acidic vesicular organelles. These effects were further detected in other GBM cell lines tested and also in co-cultures of hADSCs and U-87 MG. hADSC CM did not compromise lysosomal acidification; however, it was able to activate mTORC1 signaling and, as a consequence, led to a decrease in the nuclear translocation of TFEB, a master transcriptional regulator of lysosomal biogenesis and autophagy, thereby contributing to a defective autophagic process. hADSCs secrete transforming growth factor beta 1 (TGFβ1) and this cytokine is an important mediator of CM effects on autophagy. A comprehensive knowledge of MSC roles in tumor biology is of great importance to shed light on the complex dialog between these cells and to explore such interactions therapeutically. The present results help to elucidate the paracrine effects of MSCs in tumors and bring attention to the potential to be explored in MSC secretome.

Key messages

  • hADSC secretome specifically affects the biology of GBM cells.

  • hADSCs block the late steps of autophagic flux in GBM cells.

  • hADSC secretome activates mTORC1 signaling and reduces TFEB nuclear translocation in GBM cells.

Keywords

Glioblastoma Tumor microenvironment Mesenchymal stromal cell Secretome Autophagy Autophagic flux blockage 

Abbreviations

MSC

Mesenchymal stromal cell

hADSC

Human adipose-derived stromal cell

CM

Conditioned medium

U87

U-87 MG

TME

Tumor microenvironment

GBM

Glioblastoma

LC3

Microtubule-associated protein 1 light chain 3

p62/SQSTM1

Sequestosome1

TGFβ1

Tumor growth factor β-1

AVOs1

Acidic vesicular organelles

AO

Acridine orange

TFEB

Transcription factor-EB

Notes

Acknowledgments

We thank Carlos F. Menck and Alexandre T. Vessoni (USP, São Paulo, Brazil) for U87 GFP-LC3 cells and the Centro de Microscopia e Microanálise (CMM) core facility at UFRGS for the confocal microscopy experiments.

Author contributions

Giovana Ravizzoni Onzi: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing

Juliano Luiz Faccioni: collection and/or assembly of data, data analysis and interpretation

Luiza Cherobini Pereira: collection and/or assembly of data, data analysis and interpretation

Marcos Paulo Thomé: collection and/or assembly of data, data analysis and interpretation

Ana Paula Santin Bertoni: collection and/or assembly of data, data analysis and interpretation

Julieti Huch Buss: collection and/or assembly of data, data analysis and interpretation

Tiago Fazolo: collection and/or assembly of data, data analysis and interpretation

Eduardo Filippi-Chiela: conception and design, data analysis and interpretation, final approval of manuscript

Márcia Rosângela Wink: conception and design, financial support, final approval of manuscript

Guido Lenz: conception and design, financial support, administrative support, final approval of manuscript

Funding information

This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico CNPq, Universal (475882/ 2012-1) and Novas Terapias Portadoras de Futuro (457394/2013-7); PROBITEC CAPES (907/2012); ICGEB (405231/2015-6); and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (Pronex 16/2551-0000473-0 and FAPERGS/MS/CNPq/SESRS n. 03/2017 – PPSUS (17/2551-0001). G.R. Onzi was recipient of a PhD fellowship from CNPq. M.P.T is recipient of a PhD fellowship from CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior). A.P.S. Bertoni is and E. Filippi-Chiela was recipient of post doc fellowships from CAPES-PNPD. M. Wink and G. Lenz are recipients of CNPq research productivity fellowships.

Compliance with ethical standards

hADSCs were collected from adipose tissue of patients undergoing abdominoplasty and/or reductive mammoplasty at the Plastic Surgery Service of Santa Casa de Misericórdia de Porto Alegre (ISCMPA) Hospital, in a protocol approved by UFCSPA and ISCMPA’s ethics committee (no. 846/11). LS12 cells were obtained from surgical resection of a patient GBM tumor (Hospital São Lucas – PUCRS, Brazil—ethical committee approval protocol at UFRGS: 420.856 and at PUCRS: 429.849).

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Giovana Ravizzoni Onzi
    • 1
  • Juliano Luiz Faccioni
    • 1
  • Luiza Cherobini Pereira
    • 1
  • Marcos Paulo Thomé
    • 1
  • Ana Paula Santin Bertoni
    • 2
  • Julieti Huch Buss
    • 1
  • Tiago Fazolo
    • 3
  • Eduardo Filippi-Chiela
    • 4
  • Márcia Rosângela Wink
    • 2
  • Guido Lenz
    • 1
    Email author
  1. 1.Departamento de Biofísica e Centro de BiotecnologiaUniversidade Federal do Rio Grande do Sul (UFRGS)Porto AlegreBrazil
  2. 2.Departamento de Ciências da SaúdeUniversidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA)Porto AlegreBrazil
  3. 3.Laboratório de Imunologia Celular e MolecularPontifícia Universidade Católica do Rio Grande do SulPorto AlegreBrazil
  4. 4.Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil

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