Autophagy mediates survival of pancreatic tumour-initiating cells in a hypoxic microenvironment

Vanessa Rausch, Li Liu, Anja Apel, Theresa Rettig, Jury Gladkich, Sabrina Labsch, Georgios Kallifatidis, Adam Kaczorowski, Ariane Groth, Wolfgang Gross, Martha M. Gebhard, Peter Schemmer, Jens Werner, Alexei V. Salnikov, Hanswalter Zentgraf, Markus W. Büchler, Ingrid Herr

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Involvement of dysregulated autophagy in cancer growth and progression has been shown in different tumour entities, including pancreatic ductal adenocarcinoma (PDA). PDA is an extremely aggressive tumour characterized by a small population of highly therapy-resistant cancer stem cells (CSCs) capable of self-renewal and migration. We examined whether autophagy might be involved in the survival of CSCs despite nutrition and oxygen deprivation typical for the hypoxic tumour microenvironment of PDA. Immunohistochemistry revealed that markers for hypoxia, CSCs and autophagy are co-expressed in patient-derived tissue of PDA. Hypoxia starvation (H/S) enhanced clonogenic survival and migration of established pancreatic cancer cells with stem-like properties (CSC high), while pancreatic tumour cells with fewer stem cell markers (CSC low) did not survive these conditions. Electron microscopy revealed more advanced autophagic vesicles in CSC high cells, which exhibited higher expression of autophagy-related genes under normoxic conditions and relative to CSC low cells, as found by RT-PCR and western blot analysis. LC3 was already fully converted to the active LC3-II form in both cell lines, as evaluated by western blot and detection of accumulated GFP-LC3 protein by fluorescence microscopy. H/S increased formation of autophagic and acid vesicles, as well as expression of autophagy-related genes, to a higher extent in CSC highcells. Modulation of autophagy by inhibitors and activators resensitized CSC high to apoptosis and diminished clonogenicity, spheroid formation, expression of CSC-related genes, migratory activity and tumourigenicity in mice. Our data suggest that enhanced autophagy levels may enable survival of CSC high cells under H/S. Interference with autophagy-activating or -inhibiting drugs disturbs the fine-tuned physiological balance of enhanced autophagy in CSC and switches survival signalling to suicide.

Original languageEnglish (US)
Pages (from-to)325-335
Number of pages11
JournalJournal of Pathology
Volume227
Issue number3
DOIs
StatePublished - Jul 1 2012

Fingerprint

Neoplastic Stem Cells
Autophagy
Adenocarcinoma
Starvation
Neoplasms
Stem Cells
Western Blotting
Genes
Tumor Microenvironment
Pancreatic Neoplasms
Fluorescence Microscopy
Suicide
Cell Survival
Electron Microscopy
Immunohistochemistry

Keywords

  • Autophagy
  • Pancreatic ductal adenocarcinoma
  • Tumour-initiating cells

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Rausch, V., Liu, L., Apel, A., Rettig, T., Gladkich, J., Labsch, S., ... Herr, I. (2012). Autophagy mediates survival of pancreatic tumour-initiating cells in a hypoxic microenvironment. Journal of Pathology, 227(3), 325-335. https://doi.org/10.1002/path.3994

Autophagy mediates survival of pancreatic tumour-initiating cells in a hypoxic microenvironment. / Rausch, Vanessa; Liu, Li; Apel, Anja; Rettig, Theresa; Gladkich, Jury; Labsch, Sabrina; Kallifatidis, Georgios; Kaczorowski, Adam; Groth, Ariane; Gross, Wolfgang; Gebhard, Martha M.; Schemmer, Peter; Werner, Jens; Salnikov, Alexei V.; Zentgraf, Hanswalter; Büchler, Markus W.; Herr, Ingrid.

In: Journal of Pathology, Vol. 227, No. 3, 01.07.2012, p. 325-335.

Research output: Contribution to journalArticle

Rausch, V, Liu, L, Apel, A, Rettig, T, Gladkich, J, Labsch, S, Kallifatidis, G, Kaczorowski, A, Groth, A, Gross, W, Gebhard, MM, Schemmer, P, Werner, J, Salnikov, AV, Zentgraf, H, Büchler, MW & Herr, I 2012, 'Autophagy mediates survival of pancreatic tumour-initiating cells in a hypoxic microenvironment', Journal of Pathology, vol. 227, no. 3, pp. 325-335. https://doi.org/10.1002/path.3994
Rausch, Vanessa ; Liu, Li ; Apel, Anja ; Rettig, Theresa ; Gladkich, Jury ; Labsch, Sabrina ; Kallifatidis, Georgios ; Kaczorowski, Adam ; Groth, Ariane ; Gross, Wolfgang ; Gebhard, Martha M. ; Schemmer, Peter ; Werner, Jens ; Salnikov, Alexei V. ; Zentgraf, Hanswalter ; Büchler, Markus W. ; Herr, Ingrid. / Autophagy mediates survival of pancreatic tumour-initiating cells in a hypoxic microenvironment. In: Journal of Pathology. 2012 ; Vol. 227, No. 3. pp. 325-335.
@article{feb74ac7eb294bed9ce3d214ab713538,
title = "Autophagy mediates survival of pancreatic tumour-initiating cells in a hypoxic microenvironment",
abstract = "Involvement of dysregulated autophagy in cancer growth and progression has been shown in different tumour entities, including pancreatic ductal adenocarcinoma (PDA). PDA is an extremely aggressive tumour characterized by a small population of highly therapy-resistant cancer stem cells (CSCs) capable of self-renewal and migration. We examined whether autophagy might be involved in the survival of CSCs despite nutrition and oxygen deprivation typical for the hypoxic tumour microenvironment of PDA. Immunohistochemistry revealed that markers for hypoxia, CSCs and autophagy are co-expressed in patient-derived tissue of PDA. Hypoxia starvation (H/S) enhanced clonogenic survival and migration of established pancreatic cancer cells with stem-like properties (CSC high), while pancreatic tumour cells with fewer stem cell markers (CSC low) did not survive these conditions. Electron microscopy revealed more advanced autophagic vesicles in CSC high cells, which exhibited higher expression of autophagy-related genes under normoxic conditions and relative to CSC low cells, as found by RT-PCR and western blot analysis. LC3 was already fully converted to the active LC3-II form in both cell lines, as evaluated by western blot and detection of accumulated GFP-LC3 protein by fluorescence microscopy. H/S increased formation of autophagic and acid vesicles, as well as expression of autophagy-related genes, to a higher extent in CSC highcells. Modulation of autophagy by inhibitors and activators resensitized CSC high to apoptosis and diminished clonogenicity, spheroid formation, expression of CSC-related genes, migratory activity and tumourigenicity in mice. Our data suggest that enhanced autophagy levels may enable survival of CSC high cells under H/S. Interference with autophagy-activating or -inhibiting drugs disturbs the fine-tuned physiological balance of enhanced autophagy in CSC and switches survival signalling to suicide.",
keywords = "Autophagy, Pancreatic ductal adenocarcinoma, Tumour-initiating cells",
author = "Vanessa Rausch and Li Liu and Anja Apel and Theresa Rettig and Jury Gladkich and Sabrina Labsch and Georgios Kallifatidis and Adam Kaczorowski and Ariane Groth and Wolfgang Gross and Gebhard, {Martha M.} and Peter Schemmer and Jens Werner and Salnikov, {Alexei V.} and Hanswalter Zentgraf and B{\"u}chler, {Markus W.} and Ingrid Herr",
year = "2012",
month = "7",
day = "1",
doi = "10.1002/path.3994",
language = "English (US)",
volume = "227",
pages = "325--335",
journal = "Journal of Pathology",
issn = "0022-3417",
publisher = "John Wiley and Sons Ltd",
number = "3",

}

TY - JOUR

T1 - Autophagy mediates survival of pancreatic tumour-initiating cells in a hypoxic microenvironment

AU - Rausch, Vanessa

AU - Liu, Li

AU - Apel, Anja

AU - Rettig, Theresa

AU - Gladkich, Jury

AU - Labsch, Sabrina

AU - Kallifatidis, Georgios

AU - Kaczorowski, Adam

AU - Groth, Ariane

AU - Gross, Wolfgang

AU - Gebhard, Martha M.

AU - Schemmer, Peter

AU - Werner, Jens

AU - Salnikov, Alexei V.

AU - Zentgraf, Hanswalter

AU - Büchler, Markus W.

AU - Herr, Ingrid

PY - 2012/7/1

Y1 - 2012/7/1

N2 - Involvement of dysregulated autophagy in cancer growth and progression has been shown in different tumour entities, including pancreatic ductal adenocarcinoma (PDA). PDA is an extremely aggressive tumour characterized by a small population of highly therapy-resistant cancer stem cells (CSCs) capable of self-renewal and migration. We examined whether autophagy might be involved in the survival of CSCs despite nutrition and oxygen deprivation typical for the hypoxic tumour microenvironment of PDA. Immunohistochemistry revealed that markers for hypoxia, CSCs and autophagy are co-expressed in patient-derived tissue of PDA. Hypoxia starvation (H/S) enhanced clonogenic survival and migration of established pancreatic cancer cells with stem-like properties (CSC high), while pancreatic tumour cells with fewer stem cell markers (CSC low) did not survive these conditions. Electron microscopy revealed more advanced autophagic vesicles in CSC high cells, which exhibited higher expression of autophagy-related genes under normoxic conditions and relative to CSC low cells, as found by RT-PCR and western blot analysis. LC3 was already fully converted to the active LC3-II form in both cell lines, as evaluated by western blot and detection of accumulated GFP-LC3 protein by fluorescence microscopy. H/S increased formation of autophagic and acid vesicles, as well as expression of autophagy-related genes, to a higher extent in CSC highcells. Modulation of autophagy by inhibitors and activators resensitized CSC high to apoptosis and diminished clonogenicity, spheroid formation, expression of CSC-related genes, migratory activity and tumourigenicity in mice. Our data suggest that enhanced autophagy levels may enable survival of CSC high cells under H/S. Interference with autophagy-activating or -inhibiting drugs disturbs the fine-tuned physiological balance of enhanced autophagy in CSC and switches survival signalling to suicide.

AB - Involvement of dysregulated autophagy in cancer growth and progression has been shown in different tumour entities, including pancreatic ductal adenocarcinoma (PDA). PDA is an extremely aggressive tumour characterized by a small population of highly therapy-resistant cancer stem cells (CSCs) capable of self-renewal and migration. We examined whether autophagy might be involved in the survival of CSCs despite nutrition and oxygen deprivation typical for the hypoxic tumour microenvironment of PDA. Immunohistochemistry revealed that markers for hypoxia, CSCs and autophagy are co-expressed in patient-derived tissue of PDA. Hypoxia starvation (H/S) enhanced clonogenic survival and migration of established pancreatic cancer cells with stem-like properties (CSC high), while pancreatic tumour cells with fewer stem cell markers (CSC low) did not survive these conditions. Electron microscopy revealed more advanced autophagic vesicles in CSC high cells, which exhibited higher expression of autophagy-related genes under normoxic conditions and relative to CSC low cells, as found by RT-PCR and western blot analysis. LC3 was already fully converted to the active LC3-II form in both cell lines, as evaluated by western blot and detection of accumulated GFP-LC3 protein by fluorescence microscopy. H/S increased formation of autophagic and acid vesicles, as well as expression of autophagy-related genes, to a higher extent in CSC highcells. Modulation of autophagy by inhibitors and activators resensitized CSC high to apoptosis and diminished clonogenicity, spheroid formation, expression of CSC-related genes, migratory activity and tumourigenicity in mice. Our data suggest that enhanced autophagy levels may enable survival of CSC high cells under H/S. Interference with autophagy-activating or -inhibiting drugs disturbs the fine-tuned physiological balance of enhanced autophagy in CSC and switches survival signalling to suicide.

KW - Autophagy

KW - Pancreatic ductal adenocarcinoma

KW - Tumour-initiating cells

UR - http://www.scopus.com/inward/record.url?scp=84862014301&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84862014301&partnerID=8YFLogxK

U2 - 10.1002/path.3994

DO - 10.1002/path.3994

M3 - Article

C2 - 22262369

AN - SCOPUS:84862014301

VL - 227

SP - 325

EP - 335

JO - Journal of Pathology

JF - Journal of Pathology

SN - 0022-3417

IS - 3

ER -