Human Cancers
Bone marrow microenvironment Leukemia/Metastasis
Immune escape/Immunotherapy
Mitarbeiter Arnaud Descot
Cristóbal Fernández Santiago Alexander Schäffer Tel.: +49 69 63395-540 Fax: +49 69 63395-297 medyouf@gsh.uni-frankfurt.de
Although cancer is driven by cell intrinsic events, it is well-recognized that the tumor stroma contributes to this multistep process. The bone marrow microenviron-ment (BMME) is a complex ecosystem in which hematopoietic stem cells (HSCs) interact with a plethora of stromal cells (immune, endothelial, mesenchymal, neuronal) that modulate their behavior and ensure HSC’s ability to provide a lifelong supply of mature blood cells.
Whenever the stroma or hematopoietic cells are altered, this can result in hematopoietic damage. Our lab is actively exploring the specific mechanisms by which the stroma contributes to hemato-logical cancers, with a particular emphasis on its contribution to immune evasion and impact on cellular dynamics and clonal competition in pre-leukemic syndromes, referred to as myelodysplastic syndromes (MDS). Additionally, building on the knowledge gained in the context of hema-tological cancers, we began to explore the interplay between the BMME and disseminated tumor cells (DTCs) from solid cancer entities, particularly breast cancer.
Bone Marrow Microenvironment Hind Medyouf
Das Mikromilieu des Knochenmarks stellt ein komplexes Ökosys-tem dar in dem eine Vielzahl unterschiedlicher Zelltypen wichtige Aufgaben in der Aufrechterhaltung der Hämatopoese spielen.
Allerdings können diese Zelltypen krankheitsbedingte Verände-rungen aufweisen oder physiologische Funktionen werden durch Tumorzellen zweckentfremdet, um deren Entstehung und Ausbrei-tung zu fördern (Medyouf, CSC, 2014, Medyouf, Blood, 2017). Das Forschungsziel unserer Arbeitsgruppe besteht in der funktionellen Analyse des Einflusses der Gewebsumgebung des Knochenmarks auf das Verhalten von Tumorzellen im Kontext von Blutkrebs sowie Metastasen solider Tumorarten. Unsere Arbeit stützt sich hierbei auf die Hypothese, dass die Aufklärung der Mechanismen, durch die die Knochmarks-Mikroumgebung das Verhalten der Tumorzel-len beeinflusst, einen entscheidenden Beitrag zur Identifizierung neuartiger therapeutischer Ziele innerhalb der Knochenmarks-nische beiträgt und Grundlagen zur Entwicklung verbesserter Behandlungsmöglichkeiten schafft.
Wir verwenden unterschiedliche “Omic“-Methoden und Patienten-material, um die wechselseitigen Interaktionen zwischen Tumor-zellen und NischTumor-zellen zu analysieren. Ein besonderer Fokus wird hierbei auf die Rolle von Endothel-, Mesenchym- und Immunzellen gesetzt. Funktionelle und translationale Studien werden an einem breiten Spektrum experimenteller Systeme durchgeführt. Diese umfassen z.B. syngene Mausmodelle, xenotransplantierte Modelle ausgehend von Patientenmaterial (Tirado-Gonzalez, Leukemia, 2018) und humanisierte 2D und 3D Modelle der Knochenmarks-nische, die kürzlich in unserem Labor etabliert wurden (Schäffer et al., unpublished). Wir sind davon überzeugt, dass Therapien, die gezielt gegen Funktionen der Tumormikroumgebung gerich-tet sind, einen wichtigen Teil der Bemühungen zur Etablierung verbesserter Therapieansätze darstellen und uns dem Ziel der Krebsprävention oder gar Heilung näherbringen.
HSCs. Therefore, one of our projects is exploring whether the progressive clonal dominance of mutant HSCs stems from a niche-directed competitive advantage that may (i) confer increased fitness and self-renewal of the mutant HSCs per se and/or (ii) impose a selective disadvantage of the non-mutated HSCs in the altered environ-ment (Figure 1). These questions are being addressed using patient-derived xeno-grafts in genetically engineered models with niche alterations that recapitulate those associated with physiological aging, as well as state-of-the-art 3D Human
Organotypic Marrow Environments (3D HOMEs), in which human HSCs can be studied in multicellular and fully human engineered systems that are amenable to experimental manipulation. Building on our previous work that demonstrated the essential role of disease-associated mesenchymal niche cells in MDS (Medyouf, 2014), another project is using omics approaches to interrogate the reciprocal crosstalk between niche and MDS cells and unravel the molecular mediators by which MDS cells turn their environment into a self-reinforcing one.
Understanding and targeting these niche contributions to MDS represents a major focus in our lab (Medyouf, 2017). Our projects are supported by collaborations with clinical partners and funds from the European Research Council, the Marie Skłodowska-Curie Actions and the German Cancer Consortium.
I
Figure 1.
Schematic view depicting clonal evolution in MDS and potential niche contributions.
Immune evasion in
hematological malignancies Hematological malignancies are poorly immunogenic and devastating blood cancers that excel at immune evasion and are frequently refractory to adaptive checkpoint therapy. Acute leukemia in particular, is the leading cause of cancer-related deaths in children and is an appalling clinical challenge in adults and elderly patients. Treatment strategies are largely based on intensive chemotherapy
and targeted therapy in specific disease subtypes, but resistance remains a leading cause of death. Although new immunotherapeutic modalities (e.g. CAR-T cells) have raised hope for a subset of leukemia patients, both cell intrinsic (e.g.
antigen loss) and extrinsic events (e.g.
immune suppressive microenvironment) drive treatment failure and resistance. In this context, we are exploring novel strategies that could enhance the engagement of innate immune cells (myeloid cells, NK cells)
with the aim to potentiate the early steps of the “immunity cycle” (Chen & Mellman, 2013) and improve the immune sensing of the leukemic cells and/or the priming of downstream effector cells. In doing so, we recently discovered that leukemia cells actively establish a suppressive environment by co-opting macrophages to activate a signaling axis that skews them towards a tumor promoting fate, namely the GAS6/AXL axis. Importantly, we found that targeting AXL (inhibitor or ablation in macrophages) not only lifts the barriers towards effective anti-leukemic immunity (Figure 2) but also elicits a potent response to adaptive checkpoint therapy (Tirado-Gonzalez, Descot et al., 2021). This work puts AXL on the emerging list of promising myeloid-centered immunotherapeutic targets that could improve efficacy of current therapeutic strategies. Additional work on this topic is underway, with support from the German Cancer Aid, the German Cancer Foundation and the European Research Council.
Bone Marrow Microenvironment Hind Medyouf
Figure 2.
AXL ablation in macrophages elicits leukemic clearance. Representative IHC analysis depicting disease burden (brown = GFP+ Leukemia) in mice with AXL proficient (Axlf/f) or AXL deficient (Csf1r-Cre+ Axlf/f) macrophages, challenged with GFP+ Philadelphia-chromosome positive B-ALL.
Role of ECM-producing stromal cells in bone metastatic progression Despite substantial advances in the treatment of primary tumors, disseminated disease remains the major source of cancer-related deaths and a significant clinical hurdle for the management of patients with solid tumors. Bone is one of the major sites of metastasis in breast cancer (BC), along with brain and lung.
Breast cancer patients often show an indolent disease course, where their disseminated tumor cells (DTCs) presum-ably remain dormant for years (up to
decades) before reactivation and disease progression. DTCs detection at the time of diagnosis correlates with poor outcome.
Reciprocal crosstalk between DTCs and their niches is a dynamic process that is inevitably influenced by bone health. In this regard, it is important to note that age has been proposed to be an important risk factor for the development of overt bone metastasis. Our work is particularly focused on the role of mesenchymal stromal cells and how age-related dynamic changes in these cellular populations control the behavior of bone DTCs. Our goal is to
gain the necessary knowledge to devise new therapeutic strategies that could either (i) prevent the overt outgrowth of metastasis and/or (ii) sensitize bone homing DTCs to current treatments. This research line makes extensive use of PDX models and our 3D HOMEs system (Figure 3), and is supported by funding from the German Research Foundation.
Bone Marrow Microenvironment Hind Medyouf
... weitere Publikationen finden Sie auf Seite 57
I
Ausgewählte Publikationen
Tirado-Gonzalez I*, Descot A*, Soetopo D*, Nevmerzhitskaya A, Schäffer A, Kur IM, Czlonka E, Wachtel C, Tsoukala I, Müller L, Schäfer AL, Weitmann M, Dinse P, Alberto E, Buck MC, Landry JJ, Baying B, Slotta-Huspenina J, Roesler J, Harter PN, Kubasch AS, Meinel J, Elwakeel E, Strack E, Quang CT, Abdel-Wahab O, Schmitz M, Weigert A, Schmid T, Platzbecker U, Benes V, Ghysdael J, Bonig H, Götze KS, Rothlin CV, Ghosh S, Medyouf H.
AXL Inhibition in Macrophages Stimulates Host-versus-Leukemia Immunity and Eradicates Naïve and Treatment-Resistant Leukemia. (2021) Cancer Discov. Jun 8. doi:10.1158/2159-8290.CD-20-1378.
*Equal contribution
Tirado-Gonzalez I, Czlonka E, Nevmerzhitskaya A, Soetopo D, Bergonzani E, Mahmoud A, Contreras A, Jeremias I, Platzbecker U, Bourquin JP, Kloz U, Van der Hoeven F, Medyouf H.
CRISPR/Cas9-edited NSG mice as PDX models of human leukemia to address the role of niche-derived SPARC.
(2018) Leukemia. Apr;32(4):1049-1052. doi: 10.1038/leu.2017.346. Epub 2017 Dec 6.
Medyouf H.
The microenvironment in human myeloid malignancies: emerging concepts and therapeutic implications.
(2017) Blood. Mar 23;129(12):1617-1626. doi: 10.1182/blood-2016-11-696070. Epub 2017 Feb 3.
Mossner M, Jann JC, Wittig J, Nolte F, Fey S, Nowak V, Obländer J, Pressler J, Palme I, Xanthopoulos C, Boch T, Metzgeroth G, Röhl H, Witt SH, Dukal H, Klein C, Schmitt S, Gelß P, Platzbecker U, Balaian E, Fabarius A, Blum H, Schulze TJ, Meggendorfer M, Haferlach C, Trumpp A, Hofmann WK, Medyouf H*, D. Nowak*.
Mutational hierarchies in myelodysplastic syndromes dynamically adapt and evolve upon therapy response and failure. (2016) Blood. Sep 1;128(9):1246-59. doi: 10.1182/blood-2015-11-679167. Epub 2016 Jun 6.
*Co-senior and co-corresponding authors.
Figure 3.
Schematic view of the 3D HOMEs used to study reciprocal crosstalk between human HSCs/DTCs and the bone marrow niche accompanied by a representative image depicting human breast cencer cells (GFP) interacting with vessel like structure (tdTomato hEC = Red) and stromal cells (aSMA = white).