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oai:figshare.com:article/33421078 2026-09-23T05:51:26Z category_24160 category_24187 category_24193 category_24196 category_24139 category_24148 category_24298 category_24310 portal_886 item_type_3 month_year_09_2026

Supporting data for "Spatial and Temporal Adaptation in Cancer: From the Metastatic Niche to the Drug-Tolerant Persister State" Yu Liu (14421147) Proteomics and intermolecular interactions (excl. medical proteomics) Biological network analysis Genomics and transcriptomics Proteomics and metabolomics Cell development, proliferation and death Cellular interactions (incl. adhesion, matrix, cell wall) Gene expression (incl. microarray and other genome-wide approaches) Genomics oral squamos cell carcinoma Drug tolerant persister target therapy resistance multi-omics characterization <p dir="ltr"><b>Background</b></p><p dir="ltr">Cancer progression depends on the ability of malignant cells to adapt to changing tissue environments and therapeutic pressures. This thesis examined spatial adaptation during lymph node metastasis (LNM) in oral squamous cell carcinoma (OSCC) and temporal adaptation during the development of resistance to targeted therapy via a pan-cancer model.</p><p><br></p><p dir="ltr"><b>Methods</b></p><p dir="ltr">Spatial adaptation was investigated in a cohort of 46 patients with primary OSCC, including 10 with pathological LNM (pLN+), using whole-exome sequencing (WES), bulk RNA sequencing (RNAseq), quantitative proteomics, single-nucleus RNA sequencing (snRNAseq) and spatial transcriptomics (ST). Temporal adaptation was studied in longitudinal models of <i>BRAF</i>-mutant melanoma, <i>EGFR</i>-mutant non-small cell lung cancer (NSCLC) and <i>KRAS</i>-mutant colorectal cancer (CRC) exposed to targeted inhibitors. Molecular profiling was combined with telomerase and telomere-damage assays, genetic and pharmacological perturbation, clonogenic assays and xenograft experiments.</p><p><br></p><p dir="ltr"><b>Results</b></p><p dir="ltr">No recurrent genomic alteration consistently characterised OSCCs with LNM. More coherent differences emerged at the transcriptomic and proteomic levels, where pLN+ tumours were associated with cell-cycle, extracellular-matrix (ECM), TGF-β-related and immune-associated programmes. Proteomic network analysis identified periostin (POSTN) as a highly connected component of an ECM-related module, and higher POSTN abundance was associated with shorter overall survival. In the four tumours examined by snRNAseq, <i>POSTN</i> transcripts were concentrated predominantly in cancer-associated fibroblasts (CAFs), which were also important transcript-level sources of <i>TGFB1</i> and <i>TGFB2</i>. TGFBI-high malignant-cell states showed greater pooled representation in the two tumours with pathological LNM and were regionally associated with CAF-related programmes.</p><p dir="ltr">Across the targeted-therapy models, <i>telomerase reverse transcriptase</i> (<i>TERT)</i> expression and telomerase activity decreased during the adaptive and drug-tolerant persister (DTP) phases but recovered as stable resistance developed. Representative DTP models also showed increased telomere dysfunction-induced foci (TIF). Genetic disruption of <i>TERT</i>and treatment with the telomerase-mediated telomere-dysfunction agent, 6-thio-2′-deoxyguanosine (6-thio-dG), restricted clonogenic recovery and enhanced the effects of targeted inhibitors. Combination treatment produced more sustained tumour control in melanoma and lung cancer xenografts. Transcriptomic and functional analyses further prioritised <i>SUCLG2</i> as a candidate dependency associated with the response to 6-thio-dG. Exploratory chromatin accessibility analysis indicated lower accessibility at the <i>SUCLG2</i> locus in A375 cells, while tumour transcriptomics showed changes in mitochondrial-associated programmes.</p><p><br></p><p dir="ltr"><b>Conclusion</b></p><p dir="ltr">The two studies examined different forms of cancer adaptation. In OSCC, LNM was associated with the spatial organisation of stromal and malignant cell programmes. During targeted therapy, resistance development involved temporal changes in telomerase activity, telomere integrity and associated chromatin and mitochondrial transcriptional programmes. Both studies indicate that tumour behaviour depends on the current cellular state and the conditions under which that state is relied on.</p> 2026-09-23T05:51:26Z Dataset Dataset 10.25442/hku.33421078.v1 https://figshare.com/articles/dataset/Supporting_data_for_Spatial_and_Temporal_Adaptation_in_Cancer_From_the_Metastatic_Niche_to_the_Drug-Tolerant_Persister_State_/33421078 CC BY-NC 4.0