Rxivist logo

Integrated single cell and bulk multi-omics reveals heterogeneity and early changes in pathways associated with cetuximab resistance in HNSCC sensitive cell lines

By Luciane T Kagohara, Fernando Zamuner, Michael Considine, Jawara Allen, Srinivasan Yegnasubramanian, Daria A Gaykalova, Elana J. Fertig

Posted 08 Aug 2019
bioRxiv DOI: 10.1101/729384

Identifying potential mechanisms of resistance while tumor cells still respond to therapy is critical to delay acquired resistance. We generated the first comprehensive multi-omics, bulk and single cell data in sensitive head and neck squamous cell carcinoma (HNSCC) cells to identify immediate responses to cetuximab. Two pathways potentially associated with resistance were focus of the study: regulation of receptor tyrosine kinases through the transcription factor TFAP2A, and epithelial-to-mesenchymal transition (EMT) process. Single cell RNA-seq demonstrates heterogeneity, with cell specific TFAP2A and VIM expression profiles in response to treatment. RNA-seq and ATAC-seq reveal global changes within five days of cetuximab therapy, suggesting early onset of mechanisms of resistance; and corroborates cell line heterogeneity, with different TFAP2A targets or EMT markers affected by therapy. Lack of TFAP2A reduces HNSCC growth and is enhanced by cetuximab and JQ1. Regarding the EMT process, short term cetuximab therapy has the strongest effect on inhibiting migration. TFAP2A silencing does not affect cell migration, supporting an independent role for both mechanisms in resistance. Overall, we show that immediate adaptive transcriptional and epigenetic changes induced by cetuximab are heterogeneous and cell type dependent; and independent mechanisms of resistance arise while tumor cells are still sensitive to therapy.

Download data

  • Downloaded 633 times
  • Download rankings, all-time:
    • Site-wide: 24,623 out of 94,912
    • In cancer biology: 774 out of 3,367
  • Year to date:
    • Site-wide: 13,960 out of 94,912
  • Since beginning of last month:
    • Site-wide: 31,920 out of 94,912

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


PanLingua

Sign up for the Rxivist weekly newsletter! (Click here for more details.)


News