Doctor of Philosophy, Universitat Bern (2012)
Doctor of Medicine, Universitat Bern (2007)
View details for Web of Science ID 000429308603413
View details for Web of Science ID 000459341002413
Acute myelogenous leukemia (AML) is initiated and maintained by leukemia stem cells (LSC). LSCs are therapy-resistant, cause relapse, and represent a major obstacle for the cure of AML. Resistance to therapy is often mediated by aberrant tyrosine kinase (TK) activation. These TKs primarily activate downstream signaling via STAT3/STAT5. In this study, we analyzed the potential to therapeutically target aberrant TK signaling and to eliminate LSCs via the multi-TK inhibitor Debio 0617B. Debio 0617B has a unique profile targeting key kinases upstream of STAT3/STAT5 signaling such as JAK, SRC, ABL, and class III/V receptor TKs. We demonstrate that expression of phospho-STAT3 (pSTAT3) in AML blasts is an independent prognostic factor for overall survival. Furthermore, phospho-STAT5 (pSTAT5) signaling is increased in primary CD34(+) AML stem/progenitors. STAT3/STAT5 activation depends on tyrosine phosphorylation, mediated by several upstream TKs. Inhibition of single upstream TKs did not eliminate LSCs. In contrast, the multi-TK inhibitor Debio 0617B reduced maintenance and self-renewal of primary human AML CD34(+) stem/progenitor cells in vitro and in xenotransplantation experiments resulting in long-term elimination of human LSCs and leukemia. Therefore, inhibition of multiple TKs upstream of STAT3/5 may result in sustained therapeutic efficacy of targeted therapy in AML and prevent relapses. Mol Cancer Ther; 16(8); 1497-510. ©2017 AACR.
View details for DOI 10.1158/1535-7163.MCT-16-0889
View details for PubMedID 28468777
Aberrant proliferation, symmetric self-renewal, increased survival, and defective differentiation of malignant blasts are key oncogenic drivers in acute myeloid leukemia (AML). Stem cell gene signatures predict poor prognosis in AML patients; however, with few exceptions, these deregulated molecular pathways cannot be targeted therapeutically. In this study, we demonstrate that the TNF superfamily ligand-receptor pair CD70/CD27 is expressed on AML blasts and AML stem/progenitor cells. CD70/CD27 signaling in AML cells activates stem cell gene expression programs, including the Wnt pathway, and promotes symmetric cell divisions and proliferation. Soluble CD27, reflecting the extent of CD70/CD27 interactions in vivo, was significantly elevated in the sera of newly diagnosed AML patients and is a strong independent negative prognostic biomarker for overall survival. Blocking the CD70/CD27 interaction by mAb induced asymmetric cell divisions and differentiation in AML blasts and AML stem/progenitor cells, inhibited cell growth and colony formation, and significantly prolonged survival in murine AML xenografts. Importantly, hematopoietic stem/progenitor cells from healthy BM donors express neither CD70 nor CD27 and were unaffected by blocking mAb treatment. Therefore, targeting CD70/CD27 signaling represents a promising therapeutic strategy for AML.
View details for DOI 10.1084/jem.20152008
View details for Web of Science ID 000394251400008
View details for PubMedID 28031480
View details for PubMedCentralID PMC5294846
The facts that cancer represents tissues consisting of heterogeneous neoplastic, as well as reactive, cell populations and that cancers of the same histotype may show profound differences in clinical behavior have long been recognized. With the advent of new technologies and the demands of precision medicine, the investigation of tumor heterogeneity has gained much interest. An understanding of intertumoral heterogeneity in patients with the same disease entity is necessary to optimally guide personalized treatment. In addition, increasing evidence indicates that different tumor areas or primary tumors and metastases in an individual patient can show significant intratumoral heterogeneity on different levels. This phenomenon can be driven by genomic instability, epigenetic events, the tumor microenvironment, and stochastic variations in cellular function and antitumoral therapies. These mechanisms may lead to branched subclonal evolution from a common progenitor clone, resulting in spatial variation between different tumor sites, disease progression, and treatment resistance. This review addresses tumor heterogeneity in lymphomas from a pathologist's viewpoint. The relationship between morphologic, immunophenotypic, and genetic heterogeneity is exemplified in different lymphoma entities and reviewed in the context of high-grade transformation and transdifferentiation. In addition, factors driving heterogeneity, as well as clinical and therapeutic implications of lymphoma heterogeneity, will be discussed.
View details for DOI 10.1159/000475530
View details for PubMedID 28719907
Citrobacter rodentium infection is a mouse model for the important human diarrheal infection caused by enteropathogenic E. coli (EPEC). The pathogenesis of both species is very similar and depends on their unique ability to form intimately epithelium-adherent microcolonies, also known as "attachment/effacement" (A/E) lesions. These microcolonies must be dynamic and able to self-renew by continuous re-infection of the rapidly regenerating epithelium. It is unknown whether sustained epithelial A/E lesion pathogenesis is achieved through re-infection by planktonic bacteria from the luminal compartment or local spread of sessile bacteria without a planktonic phase. Focusing on the earliest events as C. rodentium becomes established, we show here that all colonic epithelial A/E microcolonies are clonal bacterial populations, and thus depend on local clonal growth to persist. In wild-type mice, microcolonies are established exclusively within the first 18 hours of infection. These early events shape the ongoing intestinal geography and severity of infection despite the continuous presence of phenotypically virulent luminal bacteria. Mechanistically, induced resistance to A/E lesion de-novo formation is mediated by TLR-MyD88/Trif-dependent signaling and is induced specifically by virulent C. rodentium in a virulence gene-dependent manner. Our data demonstrate that the establishment phase of C. rodentium pathogenesis in vivo is restricted to a very short window of opportunity that determines both disease geography and severity.
View details for DOI 10.1371/journal.ppat.1006476
View details for PubMedID 28662171
View details for PubMedCentralID PMC5507559
Bile acids, important mediators of lipid absorption, also act as hormone-like regulators and as antimicrobial molecules. In all these functions their potency is modulated by a variety of chemical modifications catalyzed by bacteria of the healthy gut microbiota, generating a complex variety of secondary bile acids. Intestinal commensal organisms are well-adapted to normal concentrations of bile acids in the gut. In contrast, physiological concentrations of the various intestinal bile acid species play an important role in the resistance to intestinal colonization by pathogens such as Clostridium difficile. Antibiotic therapy can perturb the gut microbiota and thereby impair the production of protective secondary bile acids. The most important bile acid transformation is 7?-dehydroxylation, producing deoxycholic acid (DCA) and lithocholic acid (LCA). The enzymatic pathway carrying out 7?-dehydroxylation is restricted to a narrow phylogenetic group of commensal bacteria, the best-characterized of which is Clostridium scindens. Like many other intestinal commensal species, 7-dehydroxylating bacteria are understudied in vivo. Conventional animals contain variable and uncharacterized indigenous 7?-dehydroxylating organisms that cannot be selectively removed, making controlled colonization with a specific strain in the context of an undisturbed microbiota unfeasible. In the present study, we used a recently established, standardized gnotobiotic mouse model that is stably associated with a simplified murine 12-species "oligo-mouse microbiota" (Oligo-MM(12)). It is representative of the major murine intestinal bacterial phyla, but is deficient for 7?-dehydroxylation. We find that the Oligo-MM(12) consortium carries out bile acid deconjugation, a prerequisite for 7?-dehydroxylation, and confers no resistance to C. difficile infection (CDI). Amendment of Oligo-MM(12) with C. scindens normalized the large intestinal bile acid composition by reconstituting 7?-dehydroxylation. These changes had only minor effects on the composition of the native Oligo-MM(12), but significantly decreased early large intestinal C. difficile colonization and pathogenesis. The delayed pathogenesis of C. difficile in C. scindens-colonized mice was associated with breakdown of cecal microbial bile acid transformation.
View details for DOI 10.3389/fcimb.2016.00191
View details for PubMedID 28066726
View details for PubMedCentralID PMC5168579
In chronic myelogenous leukemia (CML), oncogenic BCR-ABL1 activates the Wnt pathway, which is fundamental for leukemia stem cell (LSC) maintenance. Tyrosine kinase inhibitor (TKI) treatment reduces Wnt signaling in LSCs and often results in molecular remission of CML; however, LSCs persist long term despite BCR-ABL1 inhibition, ultimately causing disease relapse. We demonstrate that TKIs induce the expression of the tumor necrosis factor (TNF) family ligand CD70 in LSCs by down-regulating microRNA-29, resulting in reduced CD70 promoter DNA methylation and up-regulation of the transcription factor specificity protein 1. The resulting increase in CD70 triggered CD27 signaling and compensatory Wnt pathway activation. Combining TKIs with CD70 blockade effectively eliminated human CD34(+) CML stem/progenitor cells in xenografts and LSCs in a murine CML model. Therefore, targeting TKI-induced expression of CD70 and compensatory Wnt signaling resulting from the CD70/CD27 interaction is a promising approach to overcoming treatment resistance in CML LSCs.
View details for DOI 10.1126/scitranslmed.aab1740
View details for Web of Science ID 000358739300005
View details for PubMedID 26223302