TY  - JOUR
AB  - 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.
AU  - Danko, B.
AU  - Hess J.
AU  - Unger, K.
AU  - Samaga, D.
AU  - Walz, C.*
AU  - Walch, A.K.
AU  - Sun, N.
AU  - Baumeister, P.
AU  - Zeng, P.Y.F.*
AU  - Walter, F.
AU  - Marschner, S.
AU  - Späth, R.
AU  - Gires, O.
AU  - Herkommer, T.
AU  - Dazeh, R.
AU  - Matos, T.
AU  - Kreutzer, L.
AU  - Matschke, J.B.*
AU  - Eul, K.*
AU  - Klauschen, F.*
AU  - Pflugradt, U.
AU  - Canis, M.*
AU  - Ganswindt, U.
AU  - Mymryk, J.S.*
AU  - Wollenberg, B.*
AU  - Nichols, A.C.*
AU  - Belka, C.
AU  - Zitzelsberger, H.
AU  - Lauber, K.
AU  - Selmansberger, M.
C1  - 70756
C2  - 56290
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Metabolic pathway-based subtypes associate glycan biosynthesis and treatment response in head and neck cancer.
JO  - npj Precis. Oncol.
VL  - 8
IS  - 1
PB  - Nature Portfolio
PY  - 2024
SN  - 2397-768X
ER  - 

TY  - JOUR
AB  - Molecular subtyping of lung squamous cell carcinoma (LUSC) has been performed at the genomic, transcriptomic, and proteomic level. However, LUSC stratification based on tissue metabolomics is still lacking. Combining high-mass-resolution imaging mass spectrometry with consensus clustering, four tumor- and four stroma-specific subtypes with distinct metabolite patterns were identified in 330 LUSC patients. The first tumor subtype T1 negatively correlated with DNA damage and immunological features including CD3, CD8, and PD-L1. The same features positively correlated with the tumor subtype T2. Tumor subtype T4 was associated with high PD-L1 expression. Compared with the status of subtypes T1 and T4, patients with subtype T3 had improved prognosis, and T3 was an independent prognostic factor with regard to UICC stage. Similarly, stroma subtypes were linked to distinct immunological features and metabolic pathways. Stroma subtype S4 had a better prognosis than S2. Subsequently, analyses based on an independent LUSC cohort treated by neoadjuvant therapy revealed that the S2 stroma subtype was associated with chemotherapy resistance. Clinically relevant patient subtypes as determined by tissue-based spatial metabolomics are a valuable addition to existing molecular classification systems. Metabolic differences among the subtypes and their associations with immunological features may contribute to the improvement of personalized therapy.
AU  - Wang, J.
AU  - Sun, N.
AU  - Kunzke, T.
AU  - Shen, J.
AU  - Zens, P.*
AU  - Prade, V.M.
AU  - Feuchtinger, A.
AU  - Berezowska, S.*
AU  - Walch, A.K.
C1  - 68729
C2  - 54938
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Spatial metabolomics identifies distinct tumor-specific and stroma-specific subtypes in patients with lung squamous cell carcinoma.
JO  - npj Precis. Oncol.
VL  - 7
IS  - 1
PB  - Nature Portfolio
PY  - 2023
SN  - 2397-768X
ER  - 

TY  - JOUR
AB  - Limited efforts have been made in assessing the effect of genome-wide profiling of RNA splicing-related variation on lung cancer risk. In the present study, we first identified RNA splicing-related genetic variants linked to lung cancer in a genome-wide profiling analysis and then conducted a two-stage (discovery and replication) association study in populations of European ancestry. Discovery and validation were conducted sequentially with a total of 29,266 cases and 56,450 controls from both the Transdisciplinary Research in Cancer of the Lung and the International Lung Cancer Consortium as well as the OncoArray database. For those variants identified as significant in the two datasets, we further performed stratified analyses by smoking status and histological type and investigated their effects on gene expression and potential regulatory mechanisms. We identified three genetic variants significantly associated with lung cancer risk: rs329118 in JADE2 (P = 8.80E−09), rs2285521 in GGA2 (P = 4.43E−08), and rs198459 in MYRF (P = 1.60E−06). The combined effects of all three SNPs were more evident in lung squamous cell carcinomas (P = 1.81E−08, P = 6.21E−08, and P = 7.93E−04, respectively) than in lung adenocarcinomas and in ever smokers (P = 9.80E−05, P = 2.70E−04, and P = 2.90E−05, respectively) than in never smokers. Gene expression quantitative trait analysis suggested a role for the SNPs in regulating transcriptional expression of the corresponding target genes. In conclusion, we report that three RNA splicing-related genetic variants contribute to lung cancer susceptibility in European populations. However, additional validation is needed, and specific splicing mechanisms of the target genes underlying the observed associations also warrants further exploration.
AU  - Yang, W.*
AU  - Liu, H.*
AU  - Zhang, R.*
AU  - Freedman, J.A.*
AU  - Han, Y.*
AU  - Hung, R.J.*
AU  - Brhane, Y.*
AU  - McLaughlin, J.*
AU  - Brennan, P.*
AU  - Bickeboeller, H.*
AU  - Rosenberger, A.*
AU  - Houlston, R.S.*
AU  - Caporaso, N.E.*
AU  - Landi, M.T.*
AU  - Brüske, I.
AU  - Risch, A.*
AU  - Christiani, D.C.*
AU  - Amos, C.I.*
AU  - Chen, X.*
AU  - Patierno, S.R.*
AU  - Wei, Q.*
C1  - 65587
C2  - 52394
TI  - Deciphering associations between three RNA splicing-related genetic variants and lung cancer risk.
JO  - npj Precis. Oncol.
VL  - 6
IS  - 1
PY  - 2022
SN  - 2397-768X
ER  -