Biology subjects

Haeno, H.

Publications and source records attributed to Haeno, H..

4 recordsLinked to original sources

bioRxiv2026

Cycling persister clones with elevated NR2F1-mediated cholesterol biosynthesis cause chemotherapy resistance

While a subpopulation termed cycling persisters (CPs) that is characterized by sustained proliferation, even under chemotherapy drug exposure, contributes more directly to tumor relapse, the molecular basis for the emergence of CPs has been unclear. Here, we used the human tongue cancer organoid (TCO) library to continuously track the in vitro fate of individual cancer cell clones during and after chemotherapy exposure using time-lapse imaging. Among the heterogeneous clones, we identified CPs that formed larger clusters than the others, which barely grew and remained small (non-CPs). Using differences in cell cluster size as an indicator, thousands of CP and non-CP clones were directly sampled from 3D matrix organoid cultures and were analyzed. Notably, tumor-intrinsic interferon (IFN) signaling and hypoxic pathways were inactivated, whereas the NR2F1-mediated cholesterol biosynthesis pathway was distinctly activated in CPs compared to non-CPs. Indeed, inhibiting cholesterol biosynthesis with simvastatin significantly suppressed the appearance of CP clones, showing that elevated cholesterol biosynthesis is essential for the emergence of CPs. These findings suggest that clonal-level variations in the intensity of these signaling pathways determine the fate of individual tumor cells exposed to chemotherapeutic agents, which may provide insights into cancer relapse mechanisms and identify potential molecular targets of CPs.

cancer biology↗

bioRxiv2025

geneSCOPE: gene Spatial Co-Occurrence of Pairwise Expression

Spatial transcriptomics captures neighborhood-dependent gene expression, but existing workflows do not always fully account for measurement scale and often treat space implicitly. We present geneSCOPE, a framework that integrates ecology-inspired statistics with network analysis. Molecules are binned on a grid whose width is chosen near the mode of the per-gene unit-invariant knee (UIK) distribution derived from Morisitas I{delta} -width curves. Pairwise adjacency-weighted spatial association is quantified with Lees L. We then assemble a spatial gene network and identify gene modules by consensus clustering. To identify cell-cell interactions between different cell types, high Lees L and low Pearsons r is examined. Applied to human colorectal cancer (three Xenium sections) and a lymph node, geneSCOPE recovered spatial gene modules that map to microanatomy such as invasive margins, luminal epithelium, fibroblast-rich territories and germinal-center subdomains, and highlights intercellular neighborhood patterns at tumor-stroma interfaces between LGR5-marked stem-like tumor programs and C3-centered fibroblast/complement-associated niches. geneSCOPE thus provides a scalable, interpretable analytical foundation that generalizes across spatial omics and supports a wide range of applications.

bioinformatics↗

bioRxiv2024

Stable platelet production via the bypass pathway explains the long-term reconstitution capacity of hematopoietic stem cells

Precise understanding how hematopoietic stem cells (HSCs) differentiate in vivo is difficult because we can not trace the in vivo differentiation of HSCs. The single-cell transplantation assay and our own paired daughter cell assay of phenotypic HSCs has revealed the presence of HSCs with reconstitution capacity whose differentiation potential is restricted to the myeloid lineage (MySCs) and the presence of novel direct differentiation pathway form HSCs to MySCs (named myeloid bypass pathway). However, how HSCs differentiate in vivo during hematopoiesis has remained unclear since the paired daughter cell assay was performed partially ex vivo. Aiming to characterize HSCs, including the myeloid bypass pathway, we examined the kinetics of HSC differentiation using a mathematical model. We analyzed data from single-cell transplantation assays in which five blood cell lineages were followed successively after transplantation. An age-related skewing to the myeloid lineage was quantitatively indicated as the production of B cells reduced with age. Dependence on platelet bypass increased with aging and consistently high dependence was associated with long-term reconstitution capacity of the HSCs. Focusing on the ratio of chimerism among cell lineages, the characteristics of dependence on platelet bypass can be accurately determined by the ratio of erythrocyte to platelet chimerism at 8 weeks after transplantation. This new identification criterion is an indicator of long-term reconstitution of HSCs that does not rely on observation of long-term transplantation experiments. These findings reveal the novel characteristics of HSCs related to aging and stemness and highlight the importance of the bypass pathway in HSC differentiation. Significance statementIn vivo differentiation of hematopoietic stem cells (HSCs) is important for understanding blood cell production. Here we investigated the differentiation kinetics of HSCs in single-cell transplantation assays by using a mathematical model. Our findings demonstrate the importance of the bypass pathway in platelet production for the long-term reconstitution capacity of HSCs. These results also suggest the utility of studying time changes in HSC differentiation. The new HSC characteristics and its detection criteria identified in this study are expected to be useful in understanding HSC diversity and aging.

cell biology↗

bioRxiv2024

Clonal evolution of hematopoietic stem cells after cancer chemotherapy

Normal hematopoietic stem and progenitor cells (HSPCs) inherently accumulate somatic mutations and lose clonal diversity with age, processes implicated in the development of myeloid malignancies1. The impact of exogenous stressors, such as cancer chemotherapies, on the genomic integrity and clonal dynamics of normal HSPCs is not well defined. We conducted whole-genome sequencing on 1,032 single-cell-derived HSPC colonies from 10 patients with multiple myeloma (MM), who had undergone various chemotherapy regimens. Our findings reveal that melphalan treatment distinctly increases mutational burden with a unique mutation signature, whereas other MM chemotherapies do not significantly affect the normal mutation rate of HSPCs. Among these therapy-induced mutations were several oncogenic drivers such as TET2 and PPM1D. Phylogenetic analysis showed a clonal architecture in post-treatment HSPCs characterized by extensive convergent evolution of mutations in genes such as TP53 and PPM1D. Consequently, the clonal diversity and structure of post-treatment HSPCs mirror those observed in normal elderly individuals, suggesting an accelerated clonal aging due to chemotherapy. Furthermore, analysis of matched therapy-related myeloid neoplasm (t-MN) samples, which occurred 1-8 years later, enabled us to trace the clonal origin of t-MNs to a single HSPC clone among a group of clones with competing malignant potential, indicating the critical role of secondary mutations in dictating clonal dominance and malignant transformation. Our findings suggest that cancer chemotherapy promotes an oligoclonal architecture with multiple HSPC clones possessing competing leukemic potentials, setting the stage for the selective emergence of a singular clone that evolves into t-MNs after acquiring secondary mutations. These results underscore the importance of further systematic research to elucidate the long-term hematological consequences of cancer chemotherapy.

cancer biology↗