SNAI1-expressing fibroblasts and derived-extracellular matrix as mediators of drug resistance in colorectal cancer patients

  1. Gemma Julia Muñoz Mier
  2. M. Collado
  3. M.E.Castillo
  4. J.Barquín
  5. E.Romio
  6. M.J.Larribabe
  7. Gemma Julia Muñoz Mier
  8. Carrato, Alfredo 3
  9. de la Pinta, Carolina 2
  10. Peña, Cristina 1
  1. 1 Universidad Alfonso X el Sabio
    info

    Universidad Alfonso X el Sabio

    Villanueva de la Cañada, España

    ROR https://ror.org/054ewwr15

  2. 2 Hospital Ramón y Cajal
    info

    Hospital Ramón y Cajal

    Madrid, España

    ROR https://ror.org/050eq1942

  3. 3 Centro de Investigación Biomédica en Red de Cáncer
    info

    Centro de Investigación Biomédica en Red de Cáncer

    Madrid, España

Revista:
Toxicology and Applied Pharmacology

ISSN: ISSN: 0041-008X

Año de publicación: 2022

Volumen: 450

Tipo: Artículo

Resumen

Resistance to antitumor treatments is one of the most important problems faced by clinicians in the management of colorectal cancer (CRC) patients. Cancer-Associated Fibroblasts (CAFs) are the main producers and remodelers of the extracellular matrix (ECM), which is directly involved in drug resistance mechanisms. Primary Normal Fibroblasts (NFs) and CAFs and cell lines (fibroblasts and tumor cells), were used to generate ECM and to identify its role in the oxaliplatin and cetuximab chemoresistance processes of CRC cells mediated by SNAI1-expressing fibroblasts. Matrices generated by Snai1 KO MEFs (Knockout Mouse Embryonic Fibroblasts) confer less resistance on oxaliplatin and cetuximab than wild-type MEF-derived matrices. Similarly, matrices derived from CAFs cause greater survival of colorectal cancer cells than NF-derived matrices, in a similar way to Snai1 expression levels. In addition, Snail1 expression in fibroblasts regulates drug resistance and metabolism gene expression in tumor cells mediated by ECM. Finally, a series of 531 patients (TCGA) with CRC was used to assess the role of SNAI1 expression in patients' prognosis indicating an association between tumor SNAI1 expression and overall survival in colon cancer patients but not in rectal cancer patients. SNAI1 expression in CRC cancer patients, together with in vitro experimentation, suggests the possible use of SNAI1 expression in tumor-associated fibroblasts as a predictive biomarker of response to oxaliplatin and cetuximab treatments in patients with CRC.