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Area of Science:

  • Oncology
  • Stem Cell Biology
  • Cancer Microenvironment

Background:

  • Therapy resistance is a significant challenge in bone cancer treatment, often influenced by the tumor microenvironment.
  • A specific subtype of mesenchymal stem cells with inflammatory features (iMSCs) has been implicated in therapy resistance, but their origin and function are poorly understood.

Purpose of the Study:

  • To investigate the role of cancer-secreted extracellular vesicles (EVs) in the development of iMSCs.
  • To elucidate the mechanisms by which EVs induce iMSCs and contribute to therapy resistance.
  • To identify strategies to counteract iMSC-mediated resistance in bone cancer.

Main Methods:

  • An orthotopic xenograft mouse model of osteosarcoma was used to evaluate iMSCs' role in therapy resistance.
  • Transcriptome analysis of EV-altered mesenchymal stem cells (MSCs) was performed and compared with patient data.
  • Functional assays identified key EV components driving iMSC development.
  • The efficacy of clinical drugs in blocking iMSC-induced resistance was assessed in vivo.

Main Results:

  • Cancer EVs induce the development of iMSCs, which abrogate the antimetastatic effect of TGFβ signaling inhibition.
  • EV-induced iMSCs mirror the inflammatory signature of stromal cells found in patient biopsies of osteosarcoma and multiple myeloma.
  • Cancer EVs activate distinct pathways: EV-associated TGFβ induces IL6, and EV-RNA cargo enhances TLR3-mediated chemokine production.
  • Simultaneous blockade of EV-activated pathways with ladarixin and tocilizumab inhibited metastasis and overcame iMSC-induced resistance.

Conclusions:

  • iMSCs are key drivers of drug resistance in bone cancer, induced by cancer EVs.
  • Extracellular vesicles are identified as critical triggers for iMSC development.
  • A combination therapy targeting ladarixin and tocilizumab presents a promising strategy to enhance therapeutic response in bone cancer patients.