2. Academic Validation
  3. IGF1R signaling induces epithelial-mesenchymal plasticity via ITGAV in cutaneous carcinoma

IGF1R signaling induces epithelial-mesenchymal plasticity via ITGAV in cutaneous carcinoma

  • J Exp Clin Cancer Res. 2024 Jul 29;43(1):211. doi: 10.1186/s13046-024-03119-3.
Marta Lopez-Cerda 1,  Laura Lorenzo-Sanz 2,  Victoria da Silva-Diz 2 3,  Sandra Llop 4,  Rosa M Penin 5,  Josep Oriol Bermejo 6,  Richard de Goeij-de Haas 7,  Sander R Piersma 7,  Thang V Pham 7,  Connie R Jimenez 7,  Juan Martin-Liberal 8,  Purificación Muñoz 9
Affiliations

Affiliations

  • 1 Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908, L'Hospitalet de Llobregat, Barcelona, Spain. mlopezc@idibell.cat.
  • 2 Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908, L'Hospitalet de Llobregat, Barcelona, Spain.
  • 3 Rutgers Cancer Institute of New Jersey, Rutgers University, 08901, New Brunswick, NJ, USA.
  • 4 Medical Oncology Department, Catalan Institute of Oncology (ICO) L'Hospitalet, 08908, L'Hospitalet de Llobregat, Barcelona, Spain.
  • 5 Pathology Service, Bellvitge University Hospital/IDIBELL, 08908, L'Hospitalet de Llobregat, Barcelona, Spain.
  • 6 Plastic Surgery Unit, Bellvitge University Hospital/IDIBELL, 08908, L'Hospitalet de Llobregat, Barcelona, Spain.
  • 7 OncoProteomics Laboratory, Department of Medical Oncology, Amsterdam UMC, 1081HV, Amsterdam, the Netherlands.
  • 8 Medical Oncology Department, Catalan Institute of Oncology (ICO) L'Hospitalet, 08908, L'Hospitalet de Llobregat, Barcelona, Spain. jmartinliberal@iconcologia.net.
  • 9 Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908, L'Hospitalet de Llobregat, Barcelona, Spain. p.munoz@idibell.cat.
PMID: 39075581 DOI: 10.1186/s13046-024-03119-3
Abstract

Background: Early cutaneous squamous cell carcinomas (cSCCs) generally show epithelial differentiation features and good prognosis, whereas advanced cSCCs present mesenchymal traits associated with tumor relapse, metastasis, and poor survival. Currently, the mechanisms involved in cSCC progression are unclear, and the established markers are suboptimal for accurately predicting the clinical course of the disease.

Methods: Using a mouse model of cSCC progression, expression microarray analysis, immunofluorescence and flow cytometry assays, we have identified a prognostic biomarker of tumor relapse, which has been evaluated in a cohort of cSCC patient samples. Phosphoproteomic analysis have revealed signaling pathways induced in epithelial plastic Cancer cells that promote epithelial-mesenchymal plasticity (EMP) and tumor progression. These pathways have been validated by genetic and pharmacological inhibition assays.

Results: We show that the emergence of epithelial Cancer cells expressing Integrin αV (ITGAV) promotes cSCC progression to a mesenchymal state. Consistently, ITGAV expression allows the identification of patients at risk of cSCC relapse above the currently employed clinical histopathological parameters. We also demonstrate that activation of insulin-like growth factor-1 receptor (IGF1R) pathway in epithelial Cancer cells is necessary to induce EMP and mesenchymal state acquisition in response to tumor microenvironment-derived factors, while promoting ITGAV expression. Likewise, ITGAV knockdown in epithelial plastic Cancer cells also blocks EMP acquisition, generating epithelial tumors.

Conclusions: Our results demonstrate that ITGAV is a prognostic biomarker of relapse in cSCCs that would allow improved patient stratification. ITGAV also collaborates with IGF1R to induce EMP in epithelial Cancer cells and promotes cSCC progression, revealing a potential therapeutic strategy to block the generation of advanced mesenchymal cSCCs.

Keywords

Cancer cell plasticity; EMP; IGF1R; ITGAV; Prognostic biomarker; cSCC.

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