S2617
Radiobiology - Translational radiobiology
ESTRO 2026
1 Cancer Sciences, University of Manchester, Manchester, United Kingdom. 2 Laboratory of Phonetics and Phonology, Sorbonne Nouvelle, Paris, France. 3 Manchester Institute, CRUK, Manchester, United Kingdom. 4 Medicine Discovery, Catapult, Cheshire, United Kingdom. 5 Nuclear Futures Institute, Bangor University, Bangor, United Kingdom. 6 The Institute of Cancer Research, The Institute of Cancer Research, London, United Kingdom. 7 Life Sciences, Manchester Metropolitan University, Manchester, United Kingdom. 8 Cell Matrix Biology & Regenerative Medicine, University of Manchester, Manchester, United Kingdom Purpose/Objective: Hypoxia (<2% O ₂ ) is a poor prognostic factor ¹ and a known driver of radioresistance ² . One mechanism involves hypoxia-induced extracellular matrix (ECM) remodelling ³ ˒ ⁴ , although this process remains poorly understood. Here, we aimed to comprehensively characterise hypoxia-driven ECM alterations and develop a gene signature associated with radioresistance. Material/Methods: Pan-cancer transcriptomic alterations were identified through meta-analysis (n=21,920 patients; 10 cancer types) using validated hypoxia signatures and random- effects modelling. Multi-omics (RNAseq, ChIPSeq, proteomics) validated the findings in vitro (T24, J82, UMUC3, RT4) and in vivo (HT1376 mouse xenograft; hypoxia identified with pimonidazole staining). Spatial transcriptomics (n=66 ROIs) explored different contributions by hypoxic (CA9+ stained) tumour and stromal cells, identifying a signature. Cox regression established stratification cut-offs (high, medium, low), tested via meta-analysis of bladder cancer cohorts (n=1,102), and cross-validated against Buffa, Ragnum, and Yang hypoxia signatures using Kaplan–Meier, multivariate Cox, and neural network models. Mechanistic validation included immunofluorescence, adhesion, and migration assays in irradiated (2–8 Gy) and non-irradiated cells (T24, J82, UMUC3, RT4) cultured on hypoxic or normoxic ECMs produced by the tumour cells. Results: Meta-analysis identified 223 pan-cancer differentially expressed genes (fold change >1 or <-1, FDR<0.05), predominantly linked to ECM pathways. Multi-omics validation confirmed these changes, generating a 55- gene ECM atlas primarily regulated by HIF1/HIF2 (75%). Spatial transcriptomics further supported these findings, revealing distinct tumour- and stroma- specific hypoxia-associated ECM remodelling processes and defining a tumour-specific 5-gene ECM signature. Medium and high hypoxic-ECM scores were associated with poor overall survival (TCGA pan-cancer [n=12,185, p<0.00001]; glioblastoma [n=1,011,
immunochemotherapy. Metagenomic sequencing and metabolomic profiling were performed to assess microbial and metabolic alterations between complete response (CR) and non-CR groups. Results: SCRT transiently decreased the relative abundance of Bacteroidota and increased the proportion of Bacillota, both of which returned to baseline after iTNT completion. Microbial alpha diversity (Shannon and Simpson indices) remained stable in the CR group but significantly declined in the non-CR group after iTNT. Furthermore, linear discriminant analysis effect size (LEfSe) identified 30 taxonomic categories with differential relative abundances between CR and non- CR groups. Co-abundance network analysis showed that the CR group exhibited a Bacteroidota-dominant and more interconnected microbial community. Metabolic pathway analysis revealed that caffeine metabolism and galactose metabolism were significantly enriched in CR group, suggesting their potential role in favorable response. Correlation patterns between gut microbiota and metabolites further showed a significant negative correlation between non-CR-associated species and galactose
metabolites. Conclusion:
This study revealed the dynamic interaction between gut microbiota and metabolism during iTNT and provided valuable insights for identifying microbiome- related biomarkers predictive of treatment response in early low rectal cancer. References: 1.Xia F, Chen Y, Zhou D, Wan J, Shen L, Wang Y, Li J, Zhang H, Wang Y, Yang W, Zhou M, Wu R, Zhou S, Chen Y, Luo D, Gu W, Lian P, Peng J, Liu F, Sun Y, Wang L, Cai S, Zhang Z, Li X. Organ preservation via immunotherapy-based total neoadjuvant therapy in early low rectal cancer (TORCH-E): a multicenter, open- label, single-arm, phase 2 study. Clin Cancer Res. 2025 Sep 30. doi: 10.1158/1078-0432.CCR-25-0975. Keywords: gut microbiota,iTNT,early low rectal cancer unexpectedly associates severe hypoxia with radiotherapy benefit and enhanced extracellular matrix remodelling Conrado Guerrero Quiles 1 , Julia Gonzalez Abalos 1 , A. S. Foussat 2 , Mark Reardon 1 , Taha Lodhi 1 , Vicky Smith 1 , Rekaya Shabbir 1 , Sapna Lunj 1 , Kimberly Reeves 1 , Alex Baker 3 , Michael Eyres 4 , Gayle Marshall 4 , Tim Smith 1,5 , Peter Hoskin 1 , Nicholas James 6 , Emma Hall 1 , Robert Huddart 6 , Nuria Porta 6 , Vanesa Biolatti 1 , Jonathan Humphries 7 , Martin Humphries 8 , Catharine West 1 , Ananya Choudhury 1 Poster Discussion 1842 A pan-cancer multi-omics meta-analysis
Made with FlippingBook - Share PDF online