Differential transcriptional invasion signatures from patient derived organoid models define a functional prognostic tool for head and neck cancer

Peter D Haughton, Wisse Haakma, Theofilos Chalkiadakis, Gerben E Breimer, Else Driehuis, Hans Clevers, Stefan Willems, Stefan Prekovic*, Patrick W B Derksen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Clinical outcome for patients suffering from HPV-negative head and neck squamous cell carcinoma (HNSCC) remains poor. This is mostly due to highly invasive tumors that cause loco-regional relapses after initial therapeutic intervention and metastatic outgrowth. The molecular pathways governing the detrimental invasive growth modes in HNSCC remain however understudied. Here, we have established HNSCC patient derived organoid (PDO) models that recapitulate 3-dimensional invasion in vitro. Single cell mRNA sequencing was applied to study the differences between non-invasive and invasive conditions, and in a collective versus single cell invading PDO model. Differential expression analysis under invasive conditions in Collagen gels reveals an overall upregulation of a YAP-centered transcriptional program, irrespective of the invasion mode. However, we find that collectively invading HNSCC PDO cells show elevated levels of YAP transcription targets when compared to single cell invasion. Also, collectively invading cells are characterized by increased nuclear translocation of YAP within the invasive strands, which coincides with Collagen-I matrix alignment at the invasive front. Using gene set enrichment analysis, we identify immune cell-like migratory pathways in the single cell invading HNSCC PDO, while collective invasion is characterized by overt upregulation of adhesion and migratory pathways. Lastly, based on clinical head and neck cancer cohorts, we demonstrate that the identified collective invasion signature provides a candidate prognostic platform for survival in HNSCC. By uncoupling collective and single cell invasive programs, we have established invasion signatures that may guide new therapeutic options.

Original languageEnglish
Pages (from-to)2463-2474
Number of pages12
JournalOncogene
Volume43
Issue number32
Early online date28 Jun 2024
DOIs
Publication statusPublished - 2 Aug 2024

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