Metabolic pathway-based subtypes associate glycan biosynthesis and treatment response in head and neck cancer

Benedek Dankó; Julia Hess; Kristian Unger; Daniel Samaga; Christoph Walz; Axel Walch; Na Sun; Philipp Baumeister; Peter Y F Zeng; Franziska Walter; Sebastian Marschner; Richard Späth; Olivier Gires; Timm Herkommer; Ramin Dazeh; Thaina Matos; Lisa Kreutzer; Johann Matschke; Katharina Eul; Frederick Klauschen; Ulrike Pflugradt; Martin Canis; Ute Ganswindt; Joe S Mymryk; Barbara Wollenberg; Anthony C Nichols; Claus Belka; Horst Zitzelsberger; Kirsten Lauber; Martin Selmansberger

doi:10.1038/s41698-024-00602-0

Metabolic pathway-based subtypes associate glycan biosynthesis and treatment response in head and neck cancer

NPJ Precis Oncol. 2024 May 23;8(1):116. doi: 10.1038/s41698-024-00602-0.

Authors

Benedek Dankó^{1

2}, Julia Hess^{1

2

3}, Kristian Unger^{1

2

3

4

5}, Daniel Samaga^{1

2}, Christoph Walz⁶, Axel Walch⁷, Na Sun⁷, Philipp Baumeister^{2

4

8

9}, Peter Y F Zeng^{10

11}, Franziska Walter^{2

3}, Sebastian Marschner^{2

3

9}, Richard Späth^{2

3

9}, Olivier Gires^{2

8}, Timm Herkommer^{1

6}, Ramin Dazeh^{1

6}, Thaina Matos^{1

6}, Lisa Kreutzer^{1

2}, Johann Matschke^{12

13}, Katharina Eul¹², Frederick Klauschen^{4

5

6

9}, Ulrike Pflugradt^{2

3

9}, Martin Canis^{8

9}, Ute Ganswindt^{2

3

14

15}, Joe S Mymryk^{11

16

17}, Barbara Wollenberg^{9

18

19}, Anthony C Nichols^{10

11

17}, Claus Belka^{2

3

4

5

9}, Horst Zitzelsberger^#^{1

2

3}, Kirsten Lauber^#^{2

3

9}, Martin Selmansberger^#^{20

21}

Affiliations

¹ Research Unit Translational Metabolic Oncology, Institute for Diabetes and Cancer, Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany.
² Clinical Cooperation Group "Personalized Radiotherapy in Head and Neck Cancer, " Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany.
³ Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany.
⁴ Bavarian Cancer Research Center (BZKF), Munich, Germany.
⁵ German Cancer Consortium (DKTK), Partner Site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶ Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
⁷ Research Unit Analytical Pathology, Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany.
⁸ Department of Otorhinolaryngology, Head and Neck Surgery, LMU University Hospital, LMU Munich, Munich, Germany.
⁹ Comprehensive Cancer Center, Munich, Germany.
¹⁰ Department of Pathology and Laboratory Medicine, University of Western Ontario, London, ON, Canada.
¹¹ Department of Otolaryngology - Head and Neck Surgery, University of Western Ontario, London, ON, Canada.
¹² Institute of Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
¹³ German Cancer Consortium (DKTK) partner site Essen a partnership between DKFZ and University Hospital, Essen, Germany.
¹⁴ Department of Radiation Oncology, Innsbruck Medical University, Innsbruck, Austria.
¹⁵ Comprehensive Cancer Center Innsbruck, Innsbruck, Austria.
¹⁶ Department of Microbiology & Immunology, University of Western Ontario, London, ON, Canada.
¹⁷ Department of Oncology, University of Western Ontario, London, ON, Canada.
¹⁸ Clinic of Otorhinolaryngology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
¹⁹ Department of Otorhinolaryngology, University of Luebeck, Luebeck, Germany.
²⁰ Research Unit Translational Metabolic Oncology, Institute for Diabetes and Cancer, Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany. [email protected].
²¹ Clinical Cooperation Group "Personalized Radiotherapy in Head and Neck Cancer, " Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany. [email protected].

^# Contributed equally.

Abstract

Head and Neck Squamous Cell Carcinoma (HNSCC) is a heterogeneous malignancy that remains a significant challenge in clinical management due to frequent treatment failures and pronounced therapy resistance. While metabolic dysregulation appears to be a critical factor in this scenario, comprehensive analyses of the metabolic HNSCC landscape and its impact on clinical outcomes are lacking. This study utilized transcriptomic data from four independent clinical cohorts to investigate metabolic heterogeneity in HNSCC and define metabolic pathway-based subtypes (MPS). In HPV-negative HNSCCs, MPS1 and MPS2 were identified, while MPS3 was enriched in HPV-positive cases. MPS classification was associated with clinical outcome post adjuvant radio(chemo)therapy, with MPS1 consistently exhibiting the highest risk of therapeutic failure. MPS1 was uniquely characterized by upregulation of glycan (particularly chondroitin/dermatan sulfate) metabolism genes. Immunohistochemistry and pilot mass spectrometry imaging analyses confirmed this at metabolite level. The histological context and single-cell RNA sequencing data identified the malignant cells as key contributors. Globally, MPS1 was distinguished by a unique transcriptomic landscape associated with increased disease aggressiveness, featuring motifs related to epithelial-mesenchymal transition, immune signaling, cancer stemness, tumor microenvironment assembly, and oncogenic signaling. This translated into a distinct histological appearance marked by extensive extracellular matrix remodeling, abundant spindle-shaped cancer-associated fibroblasts, and intimately intertwined populations of malignant and stromal cells. Proof-of-concept data from orthotopic xenotransplants replicated the MPS phenotypes on the histological and transcriptome levels. In summary, this study introduces a metabolic pathway-based classification of HNSCC, pinpointing glycan metabolism-enriched MPS1 as the most challenging subgroup that necessitates alternative therapeutic strategies.

Abstract

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