Spatial Transcriptomic Analysis of Surgical Resection Specimens of Primary Head and Neck Squamous Cell Carcinoma Treated with Afatinib in a Window-of-Opportunity Study (EORTC90111-24111)

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2025 Mar 13

PMID 40076457

Authors

Simon Beyaert

Axelle Loriot

Jean-Pascal Machiels

Sandra Schmitz

Affiliations

Soon will be listed here.

Abstract

Afatinib-induced tumor and microenvironment modifications in head and neck squamous cell carcinoma were evaluated by spatial transcriptomics in surgical specimens and RNA-sequencing in tumor biopsies of patients included in the EORTC-90111-24111 window-of-opportunity study. The aim was to explore tumor evolution and composition under anti-HER therapy. Based on our previous investigations by RNA-seq on tumor biopsies, surgical slides of ID08 and ID15 from the epithelial-to-mesenchymal (EMT) cluster and ID30 from the non-EMT cluster were investigated with spatial transcriptomics. Dimension reduction in ID30 revealed 14 clusters, with clusters overlapping three tumor nodules and the stroma. Differential expression analysis between tumor nodules showed enrichment of the hallmark EMT genelist, with 123 genes in common between the analyses. These genes were involved in PDGF and MET signaling pathways. By comparing gene expression in paired tumor biopsies and the 123 genes from differential analyses obtained in ID30, a list of 13 genes involved in cancer pathways and EMT emerged, which were also highly expressed in ID08 and ID15. These results show a progressive apparition of genes implicated in EMT, MET, and PDGF pathways in tumors after afatinib. Notably, a list of 13 genes emerged which may contain targets to prevent tumor evolution after anti-HER therapy.

References

Gonzalez-Gonzalez L, Alonso J . Periostin: A Matricellular Protein With Multiple Functions in Cancer Development and Progression. Front Oncol. 2018; 8:225. PMC: 6005831. DOI: 10.3389/fonc.2018.00225. View

Pal A, Barrett T, Paolini R, Parikh A, Puram S . Partial EMT in head and neck cancer biology: a spectrum instead of a switch. Oncogene. 2021; 40(32):5049-5065. PMC: 8934590. DOI: 10.1038/s41388-021-01868-5. View

Organ S, Tsao M . An overview of the c-MET signaling pathway. Ther Adv Med Oncol. 2011; 3(1 Suppl):S7-S19. PMC: 3225017. DOI: 10.1177/1758834011422556. View

Wang D, Qian G, Zhang H, Magliocca K, Nannapaneni S, Amin A . HER3 Targeting Sensitizes HNSCC to Cetuximab by Reducing HER3 Activity and HER2/HER3 Dimerization: Evidence from Cell Line and Patient-Derived Xenograft Models. Clin Cancer Res. 2016; 23(3):677-686. PMC: 5199640. DOI: 10.1158/1078-0432.CCR-16-0558. View

Yi Y, Zeng S, Wang Z, Wu M, Ma Y, Ye X . Cancer-associated fibroblasts promote epithelial-mesenchymal transition and EGFR-TKI resistance of non-small cell lung cancers via HGF/IGF-1/ANXA2 signaling. Biochim Biophys Acta Mol Basis Dis. 2017; 1864(3):793-803. DOI: 10.1016/j.bbadis.2017.12.021. View

Mak M, Tong P, Diao L, Cardnell R, Gibbons D, William W . A Patient-Derived, Pan-Cancer EMT Signature Identifies Global Molecular Alterations and Immune Target Enrichment Following Epithelial-to-Mesenchymal Transition. Clin Cancer Res. 2015; 22(3):609-20. PMC: 4737991. DOI: 10.1158/1078-0432.CCR-15-0876. View

Vermorken J, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S . Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008; 359(11):1116-27. DOI: 10.1056/NEJMoa0802656. View

Jung A, Jung C, Noh J, Lee Y, Eun Y . Epithelial-mesenchymal transition gene signature is associated with prognosis and tumor microenvironment in head and neck squamous cell carcinoma. Sci Rep. 2020; 10(1):3652. PMC: 7046610. DOI: 10.1038/s41598-020-60707-x. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

10.

Li X, Sun X, Kan C, Chen B, Qu N, Hou N . COL1A1: A novel oncogenic gene and therapeutic target in malignancies. Pathol Res Pract. 2022; 236:154013. DOI: 10.1016/j.prp.2022.154013. View

11.

Lopez-Moncada F, Torres M, Lavanderos B, Cerda O, Castellon E, Contreras H . SPARC Induces E-Cadherin Repression and Enhances Cell Migration through Integrin αvβ3 and the Transcription Factor ZEB1 in Prostate Cancer Cells. Int J Mol Sci. 2022; 23(11). PMC: 9180154. DOI: 10.3390/ijms23115874. View

12.

Zhan S, Wang T, Li J, Zhu H, Ge W, Li J . Asporin Interacts With HER2 to Promote Thyroid Cancer Metastasis the MAPK/EMT Signaling Pathway. Front Oncol. 2022; 12:762180. PMC: 9119632. DOI: 10.3389/fonc.2022.762180. View

13.

Pandey P, Khan F, Upadhyay T, Seungjoon M, Park M, Kim B . New insights about the PDGF/PDGFR signaling pathway as a promising target to develop cancer therapeutic strategies. Biomed Pharmacother. 2023; 161:114491. DOI: 10.1016/j.biopha.2023.114491. View

14.

Lopez-Novoa J, Nieto M . Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med. 2010; 1(6-7):303-14. PMC: 3378143. DOI: 10.1002/emmm.200900043. View

15.

Stahl P, Salmen F, Vickovic S, Lundmark A, Fernandez Navarro J, Magnusson J . Visualization and analysis of gene expression in tissue sections by spatial transcriptomics. Science. 2016; 353(6294):78-82. DOI: 10.1126/science.aaf2403. View

16.

Beyaert S, Loriot A, Huyghe N, Goebbels R, Mendola A, Govaerts A . Tumor Microenvironment Modifications Induced by Afatinib in Squamous Cell Carcinoma of the Head and Neck: A Window-of-Opportunity Study (EORTC-90111-24111). Clin Cancer Res. 2023; 29(20):4076-4087. DOI: 10.1158/1078-0432.CCR-23-0645. View

17.

Schutze C, Dorfler A, Eicheler W, Zips D, Hering S, Solca F . Combination of EGFR/HER2 tyrosine kinase inhibition by BIBW 2992 and BIBW 2669 with irradiation in FaDu human squamous cell carcinoma. Strahlenther Onkol. 2007; 183(5):256-64. DOI: 10.1007/s00066-007-1696-z. View

18.

Boeckx C, Baay M, Wouters A, Specenier P, Vermorken J, Peeters M . Anti-epidermal growth factor receptor therapy in head and neck squamous cell carcinoma: focus on potential molecular mechanisms of drug resistance. Oncologist. 2013; 18(7):850-64. PMC: 3720640. DOI: 10.1634/theoncologist.2013-0013. View

19.

Macha M, Rachagani S, Pai P, Gupta S, Lydiatt W, Smith R . MUC4 regulates cellular senescence in head and neck squamous cell carcinoma through p16/Rb pathway. Oncogene. 2014; 34(13):1698-708. PMC: 4205229. DOI: 10.1038/onc.2014.102. View

20.

Raudvere U, Kolberg L, Kuzmin I, Arak T, Adler P, Peterson H . g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 2019; 47(W1):W191-W198. PMC: 6602461. DOI: 10.1093/nar/gkz369. View