Search bioRxiv⌕ Search

Biology subjects

Lutimba, S.

Publications and source records attributed to Lutimba, S..

2 recordsLinked to original sources
bioRxiv2026

Amplification-Driven S100A11 Overexpression in Hepatocellular Carcinoma Is Linked to Metabolic Reprogramming, ECM Remodelling, and Immune Evasion: A Pan-Cancer Genomic Study

BackgroundS100A11, a calcium-binding S100 family protein, is increasingly implicated in carcinogenesis, yet its molecular regulation and clinical relevance across cancers remain unclear. Hepatocellular Carcinoma (HCC) carries a dismal prognosis, in part due to a lack of reliable biomarkers for early detection and risk stratification. MethodsWe conducted a pan-cancer analysis of S100A11 genomic alterations across 43 studies (112,646 samples), encompassing copy number alterations, somatic mutations, and DNA methylation. HCC-specific analyses evaluated S100A11 expression, diagnostic performance, co-expression networks, and pathway enrichment using TCGA-LIHC data, with univariate and multivariate Cox regression to assess survival associations. ResultsS100A11 alterations were predominantly driven by copy number amplification, with the highest frequencies in lung, uterine, and hepatobiliary cancers. Copy number amplification showed a consistent inverse relationship with promoter methylation, indicating amplification-driven transcriptional activation. In HCC, S100A11 was markedly overexpressed compared with normal liver tissue, with strong diagnostic discriminatory capacity. Although high S100A11 expression trended towards inferior overall survival, this did not reach statistical significance in multivariate analysis. Co-expression and pathway analyses linked S100A11 to metabolic reprogramming, extracellular matrix remodelling, and immune dysregulation. ConclusionThese findings establish S100A11 as a context-dependent oncogenic regulator highly expressed and a candidate diagnostic marker in HCC. Simple SummaryS100A11, a calcium-binding S100 family protein, is increasingly implicated in carcinogenesis, yet its molecular regulation and clinical relevance across cancers remain unclear. Hepatocellular carcinoma (HCC) has a dismal prognosis, in part due to delayed detection and less effective risk stratification. In the present study, we integrated genomic, epigenetic, and transcriptomic data to characterize S100A11 alterations in HCC and assess their association with patient survival, with the aim of defining its potential as a prognostic biomarker. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/732272v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@184364eorg.highwire.dtl.DTLVardef@1095341org.highwire.dtl.DTLVardef@138d923org.highwire.dtl.DTLVardef@137c808_HPS_FORMAT_FIGEXP M_FIG C_FIG

Cancer Biology↗
bioRxiv2025

Neuroblastoma-associated ALK variants have distinct cellular and biochemical activities

Mutations in anaplastic lymphoma kinase (ALK) are associated with high-risk neuroblastoma, a childhood cancer arising in trunk neural crest cells. The role of ALK in undifferentiated NC is still unknown; however, the presence of activating mutations in ALK correlates with migratory and invasive cell behaviours in neuroblastoma cell lines. Here, we show the functional consequences of ALK overexpression on neural crest cells, by comparing wildtype ALK (ALKWT) protein to ALK gain-of-function variants ALKF1174L and ALKR1275Q. Elevated ALK activity, independent of mutational status leads to increased migration velocity and loss of directionality, while ALKF1174L overexpression presents additional effects on cytoskeletal protrusions. These results correlate with increased binding of ALKF1174L to GSK3, which has previously been shown to regulate cytoskeletal dynamics in neural crest cells. Further, molecular dynamics simulations of the ALK-GSK3 complex show high flexibility, suggestive of enhanced allosteric regulation. Together, our data show that activating mutations in ALK drive migratory changes in trunk NC cells, potentially mediated by its novel interacting partner GSK3. Significance StatementAnaplastic lymphoma kinase (ALK)-associated neuroblastoma phenotypes arise in the neural crest lineage, but the effects on neural crest cell behaviours are not well-studied. Here, we use primary mouse neural crest cells to study the functional relevance of ALK-activating mutations on cell migration, which we then biochemically link to interactions with GSK3-isoforms. We also directly compare the activities of wild-type ALK with two gain-of-function variants associated with metastatic disease, ALKF1174L and ALKR1275Q, and find that ALKF1174L causes increased cytoskeletal protrusions and GSK3 binding. Our study provides insights into a signalling pathway in neural crest that drives cytoskeletal rearrangements and pathological migration in neuroblastoma.

biochemistry↗