Chloroquine targets pancreatic cancer stem cells via inhibition of CXCR4 and hedgehog signaling.
Pancreatic ductal adenocarcinoma is one of the deadliest carcinomas and is characterized by highly tumorigenic and metastatic cancer stem cells (CSC). CSCs evade available therapies, which preferentially target highly proliferative and more differentiated progenies, leaving behind CSCs as a putative source for disease relapse. Thus, to identify potentially more effective treatment regimens, we screened established and new compounds for their ability to eliminate CSCs in primary pancreatic cancer (stem) cells in vitro and corresponding patient-derived pancreatic cancer tissue xenografts in vivo. Intriguingly, we found that in vitro treatment with the antimalarial agent chloroquine significantly decreased CSCs, translating into diminished in vivo tumorigenicity and invasiveness in a large panel of pancreatic cancers. In vivo treatment in combination with gemcitabine was capable of more effectively eliminating established tumors and improved overall survival. The inhibitory effect of chloroquine was not related to inhibition of autophagy, but was due to inhibition of CXCL12/CXCR4 signaling, resulting in reduced phosphorylation of ERK and STAT3. Furthermore, chloroquine showed potent inhibition of hedgehog signaling by decreasing the production of Smoothened, translating into a significant reduction in sonic hedgehog-induced chemotaxis and downregulation of downstream targets in CSCs and the surrounding stroma. Our study demonstrates that via to date unreported effects, chloroquine is an effective adjuvant therapy to chemotherapy, offering more efficient tumor elimination and improved cure rates. Chloroquine should be further explored in the clinical setting as its success may help to more rapidly improve the poor prognosis of patients with pancreatic cancer.
Authors' Affiliations: Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO);
Anamaria
A
Balic
Authors' Affiliations: Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO); Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark;
Morten Dræby
MD
Sørensen
Authors' Affiliations: Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO); Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Sara Maria
SM
Trabulo
Authors' Affiliations: Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO);
Bruno
B
Sainz
Authors' Affiliations: Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO);
Michele
M
Cioffi
Authors' Affiliations: Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO);
Catarina R
CR
Vieira
Authors' Affiliations: Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO);
Irene
I
Miranda-Lorenzo
Gastrointestinal Cancer Clinical Research Unit, Clinical Research Programme, CNIO, Madrid, Spain;
Manuel
M
Hidalgo
Department of Surgery, Klinikum Rechts der Isar, Technical University, Munich, Germany; and.
Joerg
J
Kleeff
Department of Surgery, Klinikum Rechts der Isar, Technical University, Munich, Germany; and.
Mert
M
Erkan
Authors' Affiliations: Stem Cells & Cancer Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO); Barts Cancer Institute, Queen Mary University of London, London, United Kingdom c.heeschen@qmul.ac.uk.
Christopher
C
Heeschen
D000818:Animals; D001343:Autophagy / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
C527276:CXCR4 protein, human; D053823:Hedgehog Proteins; D019718:Receptors, CXCR4; D002738:Chloroquine