Pharmacological targeting of the novel β-catenin chromatin-associated kinase p38α in colorectal cancer stem cell tumorspheres and organoids
Abstract The prognosis of locally advanced colorectal cancer (CRC) is currently unsatisfactory. This is mainly due to drug resistance, recurrence, and subsequent metastatic dissemination, which are sustained by the cancer stem cell (CSC) population. The main driver of the CSC gene expression program...
Main Authors: | , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Nature Publishing Group
2021-03-01
|
Series: | Cell Death and Disease |
Online Access: | https://doi.org/10.1038/s41419-021-03572-4 |
id |
doaj-577a3e64100b4860a320b3635b44b77f |
---|---|
record_format |
Article |
spelling |
doaj-577a3e64100b4860a320b3635b44b77f2021-03-28T11:05:18ZengNature Publishing GroupCell Death and Disease2041-48892021-03-0112411810.1038/s41419-021-03572-4Pharmacological targeting of the novel β-catenin chromatin-associated kinase p38α in colorectal cancer stem cell tumorspheres and organoidsMartina Lepore Signorile0Valentina Grossi1Simone Di Franco2Giovanna Forte3Vittoria Disciglio4Candida Fasano5Paola Sanese6Katia De Marco7Francesco Claudio Susca8Laura Rosa Mangiapane9Annalisa Nicotra10Gabriella Di Carlo11Francesco Dituri12Gianluigi Giannelli13Giuseppe Ingravallo14Gianluca Canettieri15Giorgio Stassi16Cristiano Simone17Medical Genetics, National Institute for Gastroenterology, IRCCS ‘S. de Bellis’ Research HospitalMedical Genetics, National Institute for Gastroenterology, IRCCS ‘S. de Bellis’ Research HospitalCellular & Molecular Pathophysiology Laboratory, Department of Surgical & Oncological Sciences, University of PalermoMedical Genetics, National Institute for Gastroenterology, IRCCS ‘S. de Bellis’ Research HospitalMedical Genetics, National Institute for Gastroenterology, IRCCS ‘S. de Bellis’ Research HospitalMedical Genetics, National Institute for Gastroenterology, IRCCS ‘S. de Bellis’ Research HospitalMedical Genetics, National Institute for Gastroenterology, IRCCS ‘S. de Bellis’ Research HospitalMedical Genetics, National Institute for Gastroenterology, IRCCS ‘S. de Bellis’ Research HospitalMedical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari Aldo MoroCellular & Molecular Pathophysiology Laboratory, Department of Surgical & Oncological Sciences, University of PalermoCellular & Molecular Pathophysiology Laboratory, Department of Surgical & Oncological Sciences, University of PalermoDepartment of Emergency and Organ Transplantation, Operating Unit of Pathological Anatomy, University of Bari Aldo MoroPersonalized Medicine, National Institute for Gastroenterology, IRCCS ‘S. de Bellis’ Research HospitalPersonalized Medicine, National Institute for Gastroenterology, IRCCS ‘S. de Bellis’ Research HospitalDepartment of Emergency and Organ Transplantation, Operating Unit of Pathological Anatomy, University of Bari Aldo MoroDepartment of Molecular Medicine, Sapienza University of RomeCellular & Molecular Pathophysiology Laboratory, Department of Surgical & Oncological Sciences, University of PalermoMedical Genetics, National Institute for Gastroenterology, IRCCS ‘S. de Bellis’ Research HospitalAbstract The prognosis of locally advanced colorectal cancer (CRC) is currently unsatisfactory. This is mainly due to drug resistance, recurrence, and subsequent metastatic dissemination, which are sustained by the cancer stem cell (CSC) population. The main driver of the CSC gene expression program is Wnt signaling, and previous reports indicate that Wnt3a can activate p38 MAPK. Besides, p38 was shown to feed into the canonical Wnt/β-catenin pathway. Here we show that patient-derived locally advanced CRC stem cells (CRC-SCs) are characterized by increased expression of p38α and are “addicted” to its kinase activity. Of note, we found that stage III CRC patients with high p38α levels display reduced disease-free and progression-free survival. Extensive molecular analysis in patient-derived CRC-SC tumorspheres and APCMin/+ mice intestinal organoids revealed that p38α acts as a β-catenin chromatin-associated kinase required for the regulation of a signaling platform involved in tumor proliferation, metastatic dissemination, and chemoresistance in these CRC model systems. In particular, the p38α kinase inhibitor ralimetinib, which has already entered clinical trials, promoted sensitization of patient-derived CRC-SCs to chemotherapeutic agents commonly used for CRC treatment and showed a synthetic lethality effect when used in combination with the MEK1 inhibitor trametinib. Taken together, these results suggest that p38α may be targeted in CSCs to devise new personalized CRC treatment strategies.https://doi.org/10.1038/s41419-021-03572-4 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Martina Lepore Signorile Valentina Grossi Simone Di Franco Giovanna Forte Vittoria Disciglio Candida Fasano Paola Sanese Katia De Marco Francesco Claudio Susca Laura Rosa Mangiapane Annalisa Nicotra Gabriella Di Carlo Francesco Dituri Gianluigi Giannelli Giuseppe Ingravallo Gianluca Canettieri Giorgio Stassi Cristiano Simone |
spellingShingle |
Martina Lepore Signorile Valentina Grossi Simone Di Franco Giovanna Forte Vittoria Disciglio Candida Fasano Paola Sanese Katia De Marco Francesco Claudio Susca Laura Rosa Mangiapane Annalisa Nicotra Gabriella Di Carlo Francesco Dituri Gianluigi Giannelli Giuseppe Ingravallo Gianluca Canettieri Giorgio Stassi Cristiano Simone Pharmacological targeting of the novel β-catenin chromatin-associated kinase p38α in colorectal cancer stem cell tumorspheres and organoids Cell Death and Disease |
author_facet |
Martina Lepore Signorile Valentina Grossi Simone Di Franco Giovanna Forte Vittoria Disciglio Candida Fasano Paola Sanese Katia De Marco Francesco Claudio Susca Laura Rosa Mangiapane Annalisa Nicotra Gabriella Di Carlo Francesco Dituri Gianluigi Giannelli Giuseppe Ingravallo Gianluca Canettieri Giorgio Stassi Cristiano Simone |
author_sort |
Martina Lepore Signorile |
title |
Pharmacological targeting of the novel β-catenin chromatin-associated kinase p38α in colorectal cancer stem cell tumorspheres and organoids |
title_short |
Pharmacological targeting of the novel β-catenin chromatin-associated kinase p38α in colorectal cancer stem cell tumorspheres and organoids |
title_full |
Pharmacological targeting of the novel β-catenin chromatin-associated kinase p38α in colorectal cancer stem cell tumorspheres and organoids |
title_fullStr |
Pharmacological targeting of the novel β-catenin chromatin-associated kinase p38α in colorectal cancer stem cell tumorspheres and organoids |
title_full_unstemmed |
Pharmacological targeting of the novel β-catenin chromatin-associated kinase p38α in colorectal cancer stem cell tumorspheres and organoids |
title_sort |
pharmacological targeting of the novel β-catenin chromatin-associated kinase p38α in colorectal cancer stem cell tumorspheres and organoids |
publisher |
Nature Publishing Group |
series |
Cell Death and Disease |
issn |
2041-4889 |
publishDate |
2021-03-01 |
description |
Abstract The prognosis of locally advanced colorectal cancer (CRC) is currently unsatisfactory. This is mainly due to drug resistance, recurrence, and subsequent metastatic dissemination, which are sustained by the cancer stem cell (CSC) population. The main driver of the CSC gene expression program is Wnt signaling, and previous reports indicate that Wnt3a can activate p38 MAPK. Besides, p38 was shown to feed into the canonical Wnt/β-catenin pathway. Here we show that patient-derived locally advanced CRC stem cells (CRC-SCs) are characterized by increased expression of p38α and are “addicted” to its kinase activity. Of note, we found that stage III CRC patients with high p38α levels display reduced disease-free and progression-free survival. Extensive molecular analysis in patient-derived CRC-SC tumorspheres and APCMin/+ mice intestinal organoids revealed that p38α acts as a β-catenin chromatin-associated kinase required for the regulation of a signaling platform involved in tumor proliferation, metastatic dissemination, and chemoresistance in these CRC model systems. In particular, the p38α kinase inhibitor ralimetinib, which has already entered clinical trials, promoted sensitization of patient-derived CRC-SCs to chemotherapeutic agents commonly used for CRC treatment and showed a synthetic lethality effect when used in combination with the MEK1 inhibitor trametinib. Taken together, these results suggest that p38α may be targeted in CSCs to devise new personalized CRC treatment strategies. |
url |
https://doi.org/10.1038/s41419-021-03572-4 |
work_keys_str_mv |
AT martinaleporesignorile pharmacologicaltargetingofthenovelbcateninchromatinassociatedkinasep38aincolorectalcancerstemcelltumorspheresandorganoids AT valentinagrossi pharmacologicaltargetingofthenovelbcateninchromatinassociatedkinasep38aincolorectalcancerstemcelltumorspheresandorganoids AT simonedifranco pharmacologicaltargetingofthenovelbcateninchromatinassociatedkinasep38aincolorectalcancerstemcelltumorspheresandorganoids AT giovannaforte pharmacologicaltargetingofthenovelbcateninchromatinassociatedkinasep38aincolorectalcancerstemcelltumorspheresandorganoids AT vittoriadisciglio pharmacologicaltargetingofthenovelbcateninchromatinassociatedkinasep38aincolorectalcancerstemcelltumorspheresandorganoids AT candidafasano pharmacologicaltargetingofthenovelbcateninchromatinassociatedkinasep38aincolorectalcancerstemcelltumorspheresandorganoids AT paolasanese pharmacologicaltargetingofthenovelbcateninchromatinassociatedkinasep38aincolorectalcancerstemcelltumorspheresandorganoids AT katiademarco pharmacologicaltargetingofthenovelbcateninchromatinassociatedkinasep38aincolorectalcancerstemcelltumorspheresandorganoids AT francescoclaudiosusca pharmacologicaltargetingofthenovelbcateninchromatinassociatedkinasep38aincolorectalcancerstemcelltumorspheresandorganoids AT laurarosamangiapane pharmacologicaltargetingofthenovelbcateninchromatinassociatedkinasep38aincolorectalcancerstemcelltumorspheresandorganoids AT annalisanicotra pharmacologicaltargetingofthenovelbcateninchromatinassociatedkinasep38aincolorectalcancerstemcelltumorspheresandorganoids AT gabrielladicarlo pharmacologicaltargetingofthenovelbcateninchromatinassociatedkinasep38aincolorectalcancerstemcelltumorspheresandorganoids AT francescodituri pharmacologicaltargetingofthenovelbcateninchromatinassociatedkinasep38aincolorectalcancerstemcelltumorspheresandorganoids AT gianluigigiannelli pharmacologicaltargetingofthenovelbcateninchromatinassociatedkinasep38aincolorectalcancerstemcelltumorspheresandorganoids AT giuseppeingravallo pharmacologicaltargetingofthenovelbcateninchromatinassociatedkinasep38aincolorectalcancerstemcelltumorspheresandorganoids AT gianlucacanettieri pharmacologicaltargetingofthenovelbcateninchromatinassociatedkinasep38aincolorectalcancerstemcelltumorspheresandorganoids AT giorgiostassi pharmacologicaltargetingofthenovelbcateninchromatinassociatedkinasep38aincolorectalcancerstemcelltumorspheresandorganoids AT cristianosimone pharmacologicaltargetingofthenovelbcateninchromatinassociatedkinasep38aincolorectalcancerstemcelltumorspheresandorganoids |
_version_ |
1724200480929742848 |