Biology subjects

Koschut, D.

Publications and source records attributed to Koschut, D..

3 recordsLinked to original sources

bioRxiv2025

Reprogramming Immunosuppressive Bone Marrow Derived Cells via CD44 Targeting Impacts Pancreatic Cancer Metastasis

Pancreatic ductal adenocarcinoma (PDAC) is characterized by early dissemination and an aggressive metastatic course. In order to establish in the liver, metastatic cells require a metastatic niche providing pro-survival signals. Here, we demonstrate that bone marrow-derived cells (BMDCs) establish immunosuppressive niches in the liver that promote metastatic colonization in PDAC. Using an immunocompetent orthotopic PDAC mouse model, we show that BMDCs form clusters enriched in myeloid progenitors and display upregulation of migratory, adhesive, and immunoregulatory programs in response to tumor-derived cues. CD44 and its splice variant CD44v6 are found to be highly expressed on these cells. Hematopoietic-specific deletion of Cd44 or Cd44v6 using Cd44/Cd44v6fl/fl;VavCreERT2mice markedly impairs BMDC clustering, reshapes the BMDC transcriptome, disrupting pathways critical for migration, adhesion, and immunosuppression thereby reducing metastatic burden. Mechanistically, CD44 inhibition blocks BMDC migration toward CCL2, CCL5, and CXCL12, and impairs adhesion to VCAM-1 and fibronectin. Functionally, Cd44-deficient BMDCs exhibit reduced expression of immunosuppressive mediators such as Arginase 1, Ido1, and Il10, and fail to suppress T cell proliferation. Our findings position CD44 as a pleiotropic regulator of BMDC-mediated metastatic niche formation and identify it as a promising therapeutic target to disrupt the pro-metastatic microenvironment in PDAC.

cancer biology↗

bioRxiv2020

RAS activation via CRLF2 signaling is a widespread mechanism in Down syndrome acute lymphoblastic leukemia regardless of RAS mutations

BackgroundDown syndrome acute lymphoblastic leukemia (DS-ALL) is characterized by the high frequency of CRLF2-rearrangements, JAK2-mutations, or RAS-pathway mutations. Intriguingly, JAK2 and RAS mutations are mutually exclusive in leukemic sub-clones, causing dichotomy in therapeutic target choices. ResultsHere we show that in primary leukemic cells from DS-ALL, in the absence of RAS-mutations, wild-type (wt)RAS is active, and/or can be induced by the physiological ligand TSLP of the transmembrane-receptor CRLF2. We show active/inducible RAS in 14/20 (70%) of primary DS-ALL samples analyzed, 8 of which had no RAS-mutations, but 75% of those had either mutated or hyperphosphorylated JAK2. No wtRAS cases with mutated/hyperphosphorylated JAK2 were observed that lacked activated RAS protein. We prove in a cell model that elevated CRLF2 in combination with constitutionally active JAK2 is sufficient to activate wtRAS. We show that TSLP boosts the direct binding of active PTPN11 to wtRAS. Pre-inhibition of RAS or PTPN11, but not of PI3K or JAK signaling, prevented TSLP-induced RAS-GTP boost. Using multivariate-clustering based on RAS-activity/inducibility we show significant separation between standard-risk and high-risk DS-ALL groups. Cox proportional-hazards model showed protein-activity (but not mutation status) as independently predictive of outcome. ConclusionsOur data indicate that RAS protein activity levels (and not JAK2/RAS mutation profiles), are predictive of outcome. Importantly, our data suggest that inhibition of RAS and direct RAS-pathway components should be combined with PI3K/mTOR and/or JAK2 inhibitors for high-risk cases. Therapeutically this is relevant for >75% of DS-ALL and our additional data suggest that it warrants further investigation in high-risk non-DS-ALL.

cancer biology↗

bioRxiv2020

Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene-dose-sensitive AD-suppressor in human brain

A population of >6 million people worldwide at high risk of Alzheimers disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of {beta}-amyloid-(A{beta})-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar A{beta} deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome-21-gene BACE2, but prevented by combined chemical {beta} and {gamma}-secretase inhibition. We found that T21-organoids secrete increased proportions of A{beta}-preventing (A{beta}1-19) and A{beta}-degradation products (A{beta}1-20 and A{beta}1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1-inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in [~]30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.

neuroscience↗