Biology subjects

Staaf, J.

Publications and source records attributed to Staaf, J..

5 recordsLinked to original sources

bioRxiv2026

Extrafollicular plasma cells disable dendritic cell-T-cell priming in tumor-draining lymph nodes

How plasma cells (PCs) shape anti-tumor immunity is unclear. We hypothesized that conflicting prognostic associations reflect differences in immune context and PC ontogeny. We identify extrafollicular (EF)-PCs as an antibody-independent checkpoint that aborts priming by disabling the cDC1[->]CD8+ T-cell axis in tumor-draining lymph nodes (td-LNs). EF-PCs blunt cDC1 activation and CCR7-guided repositioning into T-cell zones, precluding formation of TCF1 stem-like CD8 T-cells. Depleting EF-PCs in vivo restores cDC1 trafficking, expands the stem-like reservoir, increases intratumoral CD8 infiltration, and restrains tumor growth; benefit is lost with CD8 T-cell ablation. Neither serum transfer nor Fc{gamma} receptor blockade reverses tumor control, supporting a non-canonical, antibody-independent mechanism. Across independent triple-negative breast cancer cohorts, we find EF-PC hyperplasia in td-LNs and tumors; and within immune-cold cases, EF-PC burden stratifies poor prognosis and metastatic risk. A cross-species EF-PC signature maps to a conserved PC-state across cancer types that is linked to poor outcome and immune-checkpoint blockade resistance. EF-PCs thus relocate the dominant failure point to td-LNs and offer a tractable upstream target to convert immune-cold tumors into immune-responsive disease.

immunology↗

bioRxiv2024

Multi-omic profiling of squamous cell lung cancer identifies metabolites and related genes associated with squamous cell carcinoma

BackgroundSquamous cell lung carcinoma (SqCC) is the second most common histological subtype of lung cancer. Besides -tumor-initiating and promoting DNA, RNA, and epigenetic alterations, aberrant tumor cell metabolism has been identified as one of the hallmarks of carcinogenesis. The aim of the current study was to identify SqCC-specific metabolites and key gene regulators that could eventually be used as new anticancer targets. MethodsTranscriptional (n=156), proteomics (n=118), and mass spectrometry-based metabolomic data (n=73) were gathered for a cohort of resected early-stage lung cancers representing all major histological subgroups. SqCC-specific differentially expressed genes were integrated with proteogenomic and metabolic data using genome scale metabolic models (GEMs). Findings were validated in cohorts of tumors, normal specimens, and cancer cell lines. In situ protein expression of SLC6A8 was investigated in 213 tumors. ResultsDifferential gene expression analysis identified 280 SqCC-specific genes, of which 57 were connected to metabolites through GEMs. Metabolic profiling identified 7 SqCC-specific metabolites, of which increased creatine and decreased phosphocholine levels matched to SqCC-specific elevated expression of SLC6A8 and decreased expression of CHKA, part of respective GEMs. Expression of both genes appeared tumor cell-associated, and in particular the elevated expression of SLC6A8 identified SqCC also in stage IV disease. ConclusionElevated creatine levels and the overexpression of its transporter protein SLC6A8 appear as a distinct metabolic feature of SqCC. Considering ongoing clinical trials focused on SLC6A8 inhibition in other malignancies, exploring SLC6A8 inhibition in SqCC appears motivated based on a metabolic addiction hypothesis.

cancer biology↗

bioRxiv2022

Tumor purity adjusted beta values improve biological interpretability of high-dimensional DNA methylation data

A common issue affecting DNA methylation analysis in tumor tissue is the presence of a substantial amount of non-tumor methylation signal derived from the surrounding microenvironment. Although approaches for quantifying and correcting for the infiltration component have been proposed previously, we believe these have not fully addressed the issue in a comprehensive and universally applicable way. We present a multi-population framework for adjusting DNA methylation beta values on the Illumina 450/850K platform using generic purity estimates to account for non-tumor signal. Our approach also provides an indirect estimate of the aggregate methylation state of the surrounding normal tissue. Using whole exome sequencing derived purity estimates and Illumina 450K methylation array data generated by The Cancer Genome Atlas project (TCGA), we provide a demonstration of this framework in breast cancer illustrating the effect of beta correction on the aggregate methylation beta value distribution, clustering accuracy, and global methylation profiles.

genomics↗

bioRxiv2020

Oncogenes hijack a constitutively active TP53 promoter in osteosarcoma

How massive genome rearrangements confer a competitive advantage to a cancer cell has remained an enigma. The malignant bone tumour osteosarcoma harbours an extreme number of structural variations and thereby holds the key to understand complex cancer genomes. Genome integrity in osteosarcoma is generally lost together with disruption of normal TP53 gene function, the latter commonly through either missense mutations or structural alterations that separate the promoter region from the coding parts of the gene. To unravel the consequences of a TP53 promoter relocated in this manner, we performed in-depth genetic analyses of osteosarcoma biopsies (n=148) and cell models. We show that TP53 structural variations are early events that not only facilitate further chromosomal alterations, but also allow the TP53 promoter to upregulate genes erroneously placed under its control. Paradoxically, many of the induced genes are part of the TP53-associated transcriptome, suggesting a need to counterbalance loss of TP53 function through separation-of-function mutations via promoter swapping. Our findings demonstrate how massive genome errors can functionally turn the promoter region of a tumour suppressor gene into a constitutively active oncogenic driver.

cancer biology↗

bioRxiv2018

Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation

Global loss of DNA methylation and CpG island (CGI) hypermethylation are regarded as key epigenomic aberrations in cancer. Global loss manifests itself in partially methylated domains (PMDs) which can extend up to megabases. However, the distribution of PMDs within and between tumor types, and their effects on key functional genomic elements including CGIs are poorly defined. Using whole genome bisulfite sequencing (WGBS) of breast cancers, we comprehensively show that loss of methylation in PMDs occurs in a large fraction of the genome and represents the prime source of variation in DNA methylation. PMDs are hypervariable in methylation level, size and distribution, and display elevated mutation rates. They impose intermediate DNA methylation levels incognizant of functional genomic elements including CGIs, underpinning a CGI methylator phenotype (CIMP). However, significant repression effects on cancer-genes are negligible as tumor suppressor genes are generally excluded from PMDs. The genomic distribution of PMDs reports tissue-of-origin of different cancers and may represent tissue-specific silent regions of the genome, which tolerate instability at the epigenetic, transcriptomic and genetic level.

cancer biology↗