Dankó Benedek, Hess Julia, Unger Kristian, Samaga Daniel, Walz Christoph, Walch Axel, Sun Na, Baumeister Philipp, Zeng Peter Y F, Walter Franziska, Marschner Sebastian, Späth Richard, Gires Olivier, Herkommer Timm, Dazeh Ramin, Matos Thaina, Kreutzer Lisa, Matschke Johann, Eul Katharina, Klauschen Frederick, Pflugradt Ulrike, Canis Martin, Ganswindt Ute, Mymryk Joe S, Wollenberg Barbara, Nichols Anthony C, Belka Claus, Zitzelsberger Horst, Lauber Kirsten, Selmansberger Martin
Research Unit Translational Metabolic Oncology, Institute for Diabetes and Cancer, Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany.
Clinical Cooperation Group "Personalized Radiotherapy in Head and Neck Cancer, " Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany.
NPJ Precis Oncol. 2024 May 23;8(1):116. doi: 10.1038/s41698-024-00602-0.
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.
头颈部鳞状细胞癌（HNSCC）是一种异质性恶性肿瘤，由于频繁的治疗失败和明显的治疗抵抗，在临床管理中仍然是一个重大挑战。虽然代谢失调似乎是这种情况下的一个关键因素，但缺乏对HNSCC代谢格局及其对临床结果影响的全面分析。本研究利用来自四个独立临床队列的转录组数据，研究HNSCC中的代谢异质性，并定义基于代谢途径的亚型（MPS）。在HPV阴性的HNSCC中，鉴定出了MPS1和MPS2，而MPS3在HPV阳性病例中富集。MPS分类与辅助放（化）疗后的临床结果相关，MPS1始终表现出最高的治疗失败风险。MPS1的独特特征是聚糖（特别是硫酸软骨素/硫酸皮肤素）代谢基因的上调。免疫组织化学和初步质谱成像分析在代谢物水平上证实了这一点。组织学背景和单细胞RNA测序数据确定恶性细胞是关键因素。在全球范围内，MPS1的特征是具有独特的转录组格局，与疾病侵袭性增加相关，具有与上皮-间质转化、免疫信号、癌症干性、肿瘤微环境组装和致癌信号相关的基序。这转化为一种独特的组织学外观，其特征是广泛的细胞外基质重塑、大量梭形癌相关成纤维细胞以及恶性和基质细胞紧密交织的群体。原位异种移植的概念验证数据在组织学和转录组水平上复制了MPS表型。总之，本研究引入了一种基于代谢途径的HNSCC分类，将富含聚糖代谢的MPS1确定为最具挑战性的亚组，需要替代治疗策略。
