Biology subjects

Haapasalo, J.

Publications and source records attributed to Haapasalo, J..

4 recordsLinked to original sources

bioRxiv2026

Multi-region whole-genome and transcriptomic profiling uncovers plastic, subclone-linked cell states in high-grade diffuse astrocytomas

Intratumoral heterogeneity is a defining feature of high-grade astrocytomas and a major contributor to treatment resistance. Yet how genomic diversification intersects with transcriptional plasticity remains incompletely understood. We performed high-resolution multi-omic profiling of three complex, treatment-naive tumors (two IDH-wildtype glioblastomas and one IDH-mutant grade 4 astrocytoma). By integrating whole-genome sequencing (WGS), bulk and single-cell RNA sequencing (scRNA-seq), and histopathology across four anatomically distinct regions per tumor, we mapped the co-evolution of genome and transcriptome. Despite striking regional differences in morphology and cellular states, genomic evolution was predominantly trunk-dominated. Most driver alterations were clonal across regions, indicating early acquisition and stable genomic backbones. The IDH-mutant tumor showed linear evolution with localized hypermutation, whereas glioblastomas displayed modest late-branching subclones. In contrast, transcriptional heterogeneity was pronounced and spatially structured. Distinct genetic subclones preferentially occupied divergent transcriptional states. However, subclones shared across regions frequently adopted different phenotypes depending on local microenvironment. Single-cell reconstruction from matched patient-derived cell lines resolved subclone-associated trajectories, revealing dynamic transitions between proliferative and inflammatory states. This study provides a framework for understanding how early-established genomic backbones and regional transcriptional plasticity jointly drive phenotypic diversity. While single biopsies may capture truncal drivers, resolving clinically relevant heterogeneity requires multi-region and single-cell approaches.

cancer biology↗

bioRxiv2026

Hypoxia and Associated Acidosis Generate Cell-Type Specific Myeloid Responses in Glioblastoma

Hypoxia is a defining feature of glioblastoma (GBM), yet how it cooperates with hypoxia-associated acidosis to shape microglia and infiltrating monocyte-derived macrophages (MDM) remains poorly understood. We integrated cyclic immunohistochemistry, single-cell RNA sequencing, spatial transcriptomics, in vitro cell cultures, and DNA methylation profiling to outline hypoxia-driven responses in up to 136 GBMs. These hypoxic niches were selectively enriched for MDMs that activated carbonic anhydrase (CA) mediated pH buffering and other metabolic adaptation programs, enabling survival in acidic hypoxia, increasingly interacted with cancer cells, and show polarization toward immunosuppressive myeloid-derived suppressor cell (MDSC)-like states. In contrast, microglia were depleted in hypoxic areas, lacked compensatory CA isoenzymes, and developed TNF-linked stress responses and loss of homeostatic identity in acidic hypoxia. These findings identify metabolic adaptation to hypoxia-associated microenvironmental stress as a key determinant of GBM immune architecture, driving myeloid cell fates, spatial TME reorganization and the emergence of immunosuppressive tumor ecosystems.

cancer biology↗

bioRxiv2025

Integrative multi-modal analysis reveals the contribution of noncoding RNAs to post-treatment progression of IDH-mutant astrocytomas

IDH-mutant (IDHmut) astrocytomas typically arise as grade 2-3 tumors, but a subset of them progress to grade 4 after treatment, significantly worsening the prognosis. It is unresolved how noncoding RNAs (ncRNAs) contribute to this tumor progression. To characterize ncRNAs regulatory roles, we profiled and analyzed the coding and noncoding transcriptomes of matched tumor samples before and after progression to grade 4 in IDHmut astrocytoma patients. By integrating our data with public primary and matched tumor cohorts, we found that upregulated protein-coding genes in progressed tumors overlapped with those in primary grade 4 tumors and were linked to cell proliferation. In contrast, downregulated genes differed between primary and post-treatment grade 4 tumors. A large fraction of genes that were downregulated only in the post-treatment setting were associated with decreased cell differentiation. We identified 53 progression-related ncRNAs predicted to regulate 125 differentially expressed genes. Gene regulatory network analysis revealed their involvement in cell cycle control, extracellular matrix (ECM) organization, and neural differentiation. Notably, hsa-let-7b-3p, a tumor suppressor microRNA, showed recurrent hemizygous deletions and downregulation after post-therapy progression. The long noncoding RNA (lncRNA) PVT1 was recurrently gained and upregulated in grade 4 tumors. The lncRNA NEAT1, previously linked to treatment resistance, was especially upregulated post-treatment and had the highest number of predicted targets (n=38), many related to ECM organization. Overall, our findings highlight the role of ncRNAs in the post-treatment progression of IDHmut astrocytomas, offering new insights into mechanisms of their malignancy.

cancer biology↗

bioRxiv2022

Integrative DNA methylation analysis of pediatric brain tumors reveals tumor type-specific developmental trajectories and epigenetic signatures of malignancy

Atypical teratoid/rhabdoid tumors (AT/RTs) are pediatric brain tumors known for their aggressiveness, exceptionally low mutation rate, and aberrant but still unresolved epigenetic regulation. To evaluate methylation associated regulation in AT/RTs, we compared them to medulloblastomas and choroid plexus tumors by integrating DNA methylation (507 samples), gene expression (120 samples), and public transcription factor (TF) binding data. We showed that elevated DNA methylation masks the binding sites of TFs driving neural development and is associated with reduced transcription for specific neural regulators in AT/RTs. Part of the hypermethylated sites behaved similarly in AT/RTs and pluripotent stem cells, revealing DNA methylation -driven halted cell differentiation. AT/RT-unique DNA hypermethylation was associated with polycomb repressive complex 2 members, like EZH2, and linked to suppressed genes with a role in neural development and tumorigenesis. The obtained results highlight and characterize these DNA methylation programs as drivers of AT/RT malignancy.

cancer biology↗