Nanostructured toxins for the selective destruction of drug-resistant human CXCR4(+) colorectal cancer stem cells
Por:
Serna, N, Alamo, P, Ramesh, P, Vinokurova, D, Sanchez-Garcia, L, Unzueta, U, Gallardo, A, Cespedes, MV, Vazquez, E, Villaverde, A, Mangues, R, Medema, JP
Publicada:
10 abr 2020
Resumen:
Current therapies fail to eradicate colorectal Cancer Stem Cells (CSCs). One of the proposed reasons for this failure is the selection, by chemotherapy exposure, of resistant cells responsible for tumor recurrence. In this regard, CXCR4 overexpression in tumor associates with resistance and poor prognosis in colorectal cancer (CRC) patients. In this study, the effectiveness of engineered CXCR4-targeted self-assembling toxin nanoparticles has been explored in the selective killing of CXCR4(+) human colon-CSCs compared to 5-Fluorouracil and Oxaliplatin, both classical CRC chemotherapeutic agents. To assess this, 3D spheroid colon-CSCs cultures directly derived from CRC patients and CRC-CSC spheroid-derived tumor mouse models were developed. In these animal models, nanostructured toxins show highly selective induction of pyroptosis in the absence of apoptosis, thus having a great potential to overcome tumor resistance, since the same tumor models show resistance to chemotherapeutics. Results set the basis for further development of more efficient therapies focused on selective CXCR4+ CSCs elimination activating non-apoptotic mechanisms and represent a pre-clinical proof of concept for the use of CSCs-targeted nanostructured toxins as protein drugs for CRC therapy.
Filiaciones:
Serna, N:
Univ Autonoma Barcelona, Inst Biotecnol & Biomed, E-08193 Barcelona, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, E-08193 Barcelona, Spain
CIBER BBN, Barcelona 08193, Spain
Alamo, P:
CIBER BBN, Barcelona 08193, Spain
Ramesh, P:
Univ Amsterdam, Amsterdam UMC, LEXOR, Ctr Expt & Mol Med,Canc Ctr Amsterdam, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands
Oncode Inst, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands
Vinokurova, D:
Univ Amsterdam, Amsterdam UMC, LEXOR, Ctr Expt & Mol Med,Canc Ctr Amsterdam, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands
Oncode Inst, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands
Sanchez-Garcia, L:
Univ Autonoma Barcelona, Inst Biotecnol & Biomed, E-08193 Barcelona, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, E-08193 Barcelona, Spain
CIBER BBN, Barcelona 08193, Spain
Unzueta, U:
CIBER BBN, Barcelona 08193, Spain
Hosp Santa Creu & Sant Pau, Biomed Res Inst St Pau IIB St Pau, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, Josep Carreras Res Inst, Barcelona 08025, Spain
Gallardo, A:
CIBER BBN, Barcelona 08193, Spain
Hosp Santa Creu & Sant Pau, Biomed Res Inst St Pau IIB St Pau, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, Josep Carreras Res Inst, Barcelona 08025, Spain
Cespedes, MV:
CIBER BBN, Barcelona 08193, Spain
Hosp Santa Creu & Sant Pau, Biomed Res Inst St Pau IIB St Pau, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, Josep Carreras Res Inst, Barcelona 08025, Spain
Vazquez, E:
Univ Autonoma Barcelona, Inst Biotecnol & Biomed, E-08193 Barcelona, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, E-08193 Barcelona, Spain
CIBER BBN, Barcelona 08193, Spain
Villaverde, A:
Univ Autonoma Barcelona, Inst Biotecnol & Biomed, E-08193 Barcelona, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, E-08193 Barcelona, Spain
CIBER BBN, Barcelona 08193, Spain
Mangues, R:
CIBER BBN, Barcelona 08193, Spain
Hosp Santa Creu & Sant Pau, Biomed Res Inst St Pau IIB St Pau, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, Josep Carreras Res Inst, Barcelona 08025, Spain
Medema, JP:
Univ Amsterdam, Amsterdam UMC, LEXOR, Ctr Expt & Mol Med,Canc Ctr Amsterdam, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands
Oncode Inst, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands
Green Accepted
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