2. Academic Validation
  3. DPPA3-HIF1α axis controls colorectal cancer chemoresistance by imposing a slow cell-cycle phenotype

DPPA3-HIF1α axis controls colorectal cancer chemoresistance by imposing a slow cell-cycle phenotype

  • Cell Rep. 2023 Aug 1;42(8):112927. doi: 10.1016/j.celrep.2023.112927.
Estefania Cuesta-Borràs 1,  Cándida Salvans 2,  Oriol Arqués 1,  Irene Chicote 3,  Lorena Ramírez 4,  Laia Cabellos 1,  Jordi Martínez-Quintanilla 1,  Alex Mur-Espinosa 2,  Alejandro García-Álvarez 4,  Jorge Hernando 4,  Juan Ramón Tejedor 5,  Oriol Mirallas 4,  Elena Élez 6,  Mario F Fraga 5,  Josep Tabernero 7,  Paolo Nuciforo 8,  Jaume Capdevila 9,  Héctor G Palmer 10,  Isabel Puig 11
Affiliations

Affiliations

  • 1 Stem Cells and Cancer Laboratory, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain.
  • 2 Stem Cells and Cancer Laboratory, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; University of Barcelona, Barcelona, Spain.
  • 3 Stem Cells and Cancer Laboratory, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; CIBERONC, 08029 Madrid, Spain.
  • 4 Gastrointestinal and Endocrine Tumors Group, Medical Oncology Department, Vall d'Hebron University Hospital (HUVH), Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain.
  • 5 Nanomaterials and Nanotechnology Research Center (CINN), Spanish National Research Council (CSIC), Health Research Institute of the Principality of Asturias (ISPA), Spanish Biomedical Research Network in Rare Diseases (CIBERER), Institute of Oncology of Asturias (IUOPA), University of Oviedo, 33011 Oviedo, Asturias, Spain.
  • 6 CIBERONC, 08029 Madrid, Spain; Gastrointestinal and Endocrine Tumors Group, Medical Oncology Department, Vall d'Hebron University Hospital (HUVH), Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain.
  • 7 CIBERONC, 08029 Madrid, Spain; Gastrointestinal and Endocrine Tumors Group, Medical Oncology Department, Vall d'Hebron University Hospital (HUVH), Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain; UVic-UCC, IOB-Quiron, 08023 Barcelona, Spain.
  • 8 CIBERONC, 08029 Madrid, Spain; Molecular Oncology Group, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain.
  • 9 Gastrointestinal and Endocrine Tumors Group, Medical Oncology Department, Vall d'Hebron University Hospital (HUVH), Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain; IOB-Teknon, 08023 Barcelona, Spain.
  • 10 Stem Cells and Cancer Laboratory, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; CIBERONC, 08029 Madrid, Spain. Electronic address: hgpalmer@vhio.net.
  • 11 Stem Cells and Cancer Laboratory, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; CIBERONC, 08029 Madrid, Spain. Electronic address: ipuig@vhio.net.
PMID: 37537841 DOI: 10.1016/j.celrep.2023.112927
Abstract

Tumor relapse is linked to rapid chemoresistance and represents a bottleneck for Cancer therapy success. Engagement of a reduced proliferation state is a non-mutational mechanism exploited by Cancer cells to bypass therapy-induced cell death. Through combining functional pulse-chase experiments in engineered cells and transcriptomic analyses, we identify DPPA3 as a master regulator of slow-cycling and chemoresistant phenotype in colorectal Cancer (CRC). We find a vicious DPPA3-HIF1α feedback loop that downregulates FOXM1 expression via DNA methylation, thereby delaying cell-cycle progression. Moreover, downregulation of HIF1α partially restores a chemosensitive proliferative phenotype in DPPA3-overexpressing Cancer cells. In cohorts of CRC patient samples, DPPA3 overexpression acts as a predictive biomarker of chemotherapeutic resistance that subsequently requires reduction in its expression to allow metastatic outgrowth. Our work demonstrates that slow-cycling Cancer cells exploit a DPPA3/HIF1α axis to support tumor persistence under therapeutic stress and provides insights on the molecular regulation of disease progression.

Keywords

3D organoids; CP: Cancer; DNA methylation; FOXM1; cancer persistence; drug-tolerant persister cancer cell; hypoxia; recurrence; relapse; slow-cycling cancer cell; therapy resistance.

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