Biology subjects

Lengerke, C.

Publications and source records attributed to Lengerke, C..

3 recordsLinked to original sources

bioRxiv2024

Laminin Receptor Characterization in Acute Myeloid Leukemia: Integrin α7β1 Defines non-Leukemic Stem Cells with Migratory Potential

Interactions with the bone marrow (BM) niche are crucial for promoting self-renewal and survival of acute myeloid leukemia (AML) cells. Consequently, AML cells express a variety of surface receptors to engage with BM niche cells and extracellular matrix proteins, including laminins. Despite the association of laminin receptor expression with stemness in healthy hematopoiesis, the role of laminin receptors in AML remains poorly understood. In this study, we present a comprehensive examination of the laminin receptors integrin 3{beta}1, 6{beta}1, 7{beta}1 and basal cell adhesion molecule (BCAM) in AML. We demonstrate that high mRNA expression of all four laminin receptors correlates with poor overall survival. Notably, integrin 6 and 7 display the highest cell surface presentation among the examined laminin receptors and are higher expressed on AML cells compared to healthy controls. Moreover, our results indicate that integrin 7 expression allows to distinguish between leukemic stem cells (LSC) and non-LSC populations. Specifically, integrin 7 appears to mark non-LSC with enhanced migratory potential. Together, our results confirm the association of high laminin receptor expression with poor prognosis and establish integrin 7 as marker of high migratory non-LSC. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/587290v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@bdcc20org.highwire.dtl.DTLVardef@a45fd2org.highwire.dtl.DTLVardef@18f058forg.highwire.dtl.DTLVardef@b613fc_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Tuning of granulopoietic signaling by de novo designed agonists

Enhancing cytokine-based therapies by systematically tuning how an agonist associates its receptor is emerging as a powerful new concept in drug discovery. Here, we report the design and characterization of agonists that tune the granulocyte-colony stimulating factor receptor (G-CSFR) activity, which is central for the proliferation and granulocytic differentiation of hematopoietic stem cells. Using design agonists, we study the impact of varying the receptor-binding affinity and dimerization geometry on receptor association, downstream signaling, and cellular response. Hence, we achieved agonists with altered signaling specificities that are hyper-thermostable, can outcompete the native ligand (G-CSF), and bias granulopoietic differentiation over triggering proliferation. Furthermore, the design agonists differentially modulate the kinetics and amplitudes of signal transduction pathways, and gene expression patterns. Unlike G-CSF, they achieve selective activation of gene sets with hematopoietic functions with minimal unwanted effects on immunomodulatory signaling. These findings demonstrate the potential of dissecting the complex G-CSFR signaling, and open up ways for new therapeutic applications for designed cytokines. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/568662v3_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@af56e3org.highwire.dtl.DTLVardef@171920forg.highwire.dtl.DTLVardef@12c2c0aorg.highwire.dtl.DTLVardef@ff7556_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2020

GATA3 and MDM2 are synthetic lethal in estrogen receptor-positive breast cancers

Synthetic lethal interactions, where the simultaneous but not individual inactivation of two genes is lethal to the cell, have been successfully exploited to treat cancer. GATA3 is frequently mutated in estrogen receptor (ER)-positive breast cancers and its deficiency defines a subset of patients with poor response to hormonal therapy and poor prognosis. However, GATA3 is not targetable. Here we show that GATA3 and MDM2 are synthetically lethal in ER-positive breast cancer. Depletion and pharmacological inhibition of MDM2 induce apoptosis in GATA3-deficient models in vitro, in vivo and in patient-derived organoids (PDOs) harboring GATA3 somatic mutation. The synthetic lethality requires p53 and acts via the PI3K/Akt/mTOR pathway. Our results present MDM2 as a novel therapeutic target in the substantial cohort of ER-positive, GATA3-mutant breast cancer patients. With MDM2 inhibitors widely available, our findings can be rapidly translated into clinical trials to evaluate in-patient efficacy.

cancer biology↗