Biology subjects

Essers, M. A. G.

Publications and source records attributed to Essers, M. A. G..

4 recordsLinked to original sources

bioRxiv2026

Leukemic Stem Cell Subtypes Drive Distinct Niche Remodeling in Acute Myeloid Leukemia

Leukemic stem cells (LSCs) sustain acute myeloid leukemia (AML) and are implicated in therapy resistance and relapse. Yet, it remains unknown how LSCs remodel the bone marrow niche. AML is known to alter stromal and vascular microenvironments, but these effects are difficult to separate from bulk leukemic burden and immune inflammation. Here, we use isogenic human AML xenografts with distinct LSC characteristics but comparable engraftment to define LSC-associated niche remodeling in vivo. Single-cell profiling revealed that LSC-high AML shifts the mesenchymal niche toward fibro-inflammatory states, expanding Fmod+ fibroblasts and Cd34+ perivascular fibroblast-like cells while suppressing osteolineage differentiation. The leukemic compartment remained heterogeneous, with a specific MEP-like LSC population expressing niche-remodeling ligands including TGFB1, IL1B, and ANGPT1. LSC-high AML activated a TGF{beta}-responsive, CREB3L1-controlled fibroblast trajectory, and perturbing TGF{beta} signaling or CREB3L1 activation reduced stromal support for AML cells. These findings identify a specific LSC subtype as a source of niche-remodeling cues that shape specialized leukemia-supportive niches.

molecular biology↗

bioRxiv2023

Single-cell time series analysis reveals the dynamics of in vivo HSPC responses to inflammation

Hematopoietic stem and progenitor cells (HSPCs) are known to respond to acute inflammation; however, little is understood about the dynamics and heterogeneity of these stress responses in HSPCs. Here, we performed single-cell sequencing of HSPCs during the sensing, response and recovery phases of the inflammatory response of HSPCs to treatment with the pro-inflammatory cytokine IFN to investigate the HSPCs dynamic changes during acute inflammation. For the analysis of the resulting datasets, we developed a computational pipeline for single-cell time series. Using a semi-supervised response-pseudotime inference approach, we discover a variety of different gene responses of the HSPCs to the treatment. Interestingly, we were able to associate reduced myeloid differentiation programs in HSPCs with reduced myeloid progenitor and differentiated cells following IFN treatment. Altogether, single-cell time series analysis have allowed us to unbiasedly study the heterogeneous and dynamic impact of IFN on the HSPCs.

cell biology↗

bioRxiv2020

Hematopoietic stem cells fail to regenerate following inflammatory challenge.

Hematopoietic stem cells (HSCs) are canonically defined by their capacity to maintain the HSC pool via self-renewal divisions. However, accumulating evidence suggests that HSC function is instead preserved by sustaining long-term quiescence. Here, we study the kinetics of HSC recovery in mice, following an inflammatory challenge that induces HSCs to exit dormancy. Repeated inflammatory challenge resulted in a progressive depletion of functional HSCs, with no sign of later recovery. Underlying this observation, label retention experiments demonstrated that self-renewal divisions were absent or extremely rare during challenge, as well as during any subsequent recovery period. While depletion of functional HSCs held no immediate consequences, young mice exposed to inflammatory challenge developed blood and bone marrow hypocellularity in old age, similar to elderly humans. The progressive, irreversible attrition of HSC function demonstrates that discreet instances of inflammatory stress can have an irreversible and therefore cumulative impact on HSC function, even when separated by several months. These findings have important implications for our understanding of the role of inflammation as a mediator of dysfunctional tissue maintenance and regeneration during ageing.

cell biology↗

bioRxiv2019

CXCR3-expressing metastasis-initiating cells induce and exploit a fibroblast niche in the lungs to fuel metastatic colonization

Metastatic colonization relies on interactions between disseminated cancer cells and the microenvironment in secondary organs. Here, we show that disseminated breast cancer cells evoke major phenotypic changes in lung fibroblasts to form a metastatic niche that supports malignant growth. Colonization of the lungs by cancer cells confers an inflammatory phenotype in associated fibroblasts, where IL-1 and IL-1{beta}, secreted by breast cancer cells, induce CXCL9 and CXCL10 production in metastasis-associated fibroblasts via NF-{kappa}B signaling. These paracrine interactions fuel the growth of lung metastases. Notably, we find that the chemokine receptor CXCR3, that binds CXCL9/10, is specifically expressed in a small subset of breast cancer cells with stem/progenitor cell properties and high tumor-initiating ability when co-transplanted with fibroblasts. CXCR3-expressing cancer cells show high JNK signaling that drives IL-1/{beta} expression. Thus, CXCR3 marks a population of breast cancer cells that induces CXCL9/10 production in fibroblast, but can also respond to and benefit from these chemokines. Importantly, disruption of this intercellular JNK-IL-1-CXCL9/10-CXCR3 axis significantly reduces metastatic colonization in xenograft and syngeneic mouse models. These data mechanistically demonstrate an essential role for this molecular crosstalk between breast cancer cells and their fibroblast niche in the progression of metastasis.

cancer biology↗