Periodic Reporting for period 4 - HemNichMDS (Functional and Molecular Analyses of the Interplay between Hematopoietic and Mesenchymal Niche Cells in Human Myelodysplastic Syndromes.)
Reporting period: 2020-02-01 to 2022-01-31
Myelodysplastic syndromes (MDS) are heterogenous blood disorders mainly affecting the elderly (45/100,000 in >70 years). MDS is characterized by ineffective production of mature blood cells and a propensity to evolve to a highly aggressive form of blood cancer called acute myeloid leukemia. Because of both quantitative (e.g. anemia) and qualitative (e.g. presence of dysplastic cells with altered morphology) alterations in mature blood cells, MDS patients often need blood transfusions resulting in reduced quality of life, increased risk of secondary complications that can lead to patient deaths, and significant costs to healthcare systems. Clinical outcomes vary tremendously, even for patients considered to have the same MDS subtype, making MDS truly challenging diseases to manage in the clinical setting. The prevalence of MDS is expected to rise as an unavoidable consequence of an aging population.
Thus far, the only potential curative treatment for MDS is hematopoietic stem cells (HSC) transplantation, where stem cells from a healthy donor are transferred to the MDS patient, with the intent to restore output of healthy and functional mature blood cells. Unfortunately, this treatment modality is often limited to younger patients which can tolerate the conditioning regimen required for donor engraftment, and patients with suitable donors (<10% of MDS patients).
Although driven by genetic mutations that affect hematopoietic stem cells, we and others have provided robust evidence that MDS is a disease of a tissue rather than hematopoietic cells alone, by highlighting the functional importance of the non-malignant cellular components of the bone marrow niche, as major contributors to MDS pathogenesis.
The aims of this action were to characterize alterations that affect the non-malignant cellular components of the bone marrow niche in MDS, understand how such changes may support MDS pathogenesis and decipher the cellular and molecular underpinning. The overarching goal being to propose and evaluate rationally designed new therapeutic strategies that could benefit MDS patients.
Thus far, the only potential curative treatment for MDS is hematopoietic stem cells (HSC) transplantation, where stem cells from a healthy donor are transferred to the MDS patient, with the intent to restore output of healthy and functional mature blood cells. Unfortunately, this treatment modality is often limited to younger patients which can tolerate the conditioning regimen required for donor engraftment, and patients with suitable donors (<10% of MDS patients).
Although driven by genetic mutations that affect hematopoietic stem cells, we and others have provided robust evidence that MDS is a disease of a tissue rather than hematopoietic cells alone, by highlighting the functional importance of the non-malignant cellular components of the bone marrow niche, as major contributors to MDS pathogenesis.
The aims of this action were to characterize alterations that affect the non-malignant cellular components of the bone marrow niche in MDS, understand how such changes may support MDS pathogenesis and decipher the cellular and molecular underpinning. The overarching goal being to propose and evaluate rationally designed new therapeutic strategies that could benefit MDS patients.
Although suspected to be of critical relevance to MDS pathogenesis, little is known about how alterations in MDS-associated niche cells (e.g. Mesenchymal stem progenitor cells, Endothelial cells, Macrophages, etc.) contribute and support the disease phenotype, and which molecular mechanisms are at play. By working closely with clinical collaborators, and using patient-derived materials, we explored molecular changes that are preferentially seen in MDS-associated niche cells compared to age-matched control donors. In doing so, we identified alterations that we hypothesized could have biological significance in MDS. With the support of the ERC funding, we were able to develop the necessary tools and model systems (Tirado-Gonzalez and Czlonka, 2018, Leukemia and unpublished) to explore the biological significance of these changes in experimental models that are of relevance to the human disease. Our findings indicate the co-existence of both direct and indirect mechanisms by which niche cells promote MDS expansion. For instance, we discovered a factor, produced by several niche cells in the MDS microenvironment (macrophages and MSCs) that supports MDS progression both directly, by acting as a growth factor on malignant cells and indirectly by negatively impacting the immune micromilieu, and ultimately enabling MDS/sAML cells to evade immune control (Tirado-Gonzalez and Descot, 2021, Cancer Discovery). These results were widely disseminated to the scientific community through presentations at highly visible international meetings (Several International MDS Symposiums; annual meeting of the American Society of Hematology, annual meeting of the American Association for Cancer Research, etc.) but also exploited, in collaboration with industrial partners, to support a clinical trial, which outcome could have direct impact on patients suffering from MDS/sAML. Besides these major achievements, knowledge and tools from this ERC action have spurred the development of new research lines in our laboratory, as well as new scientific collaborations with colleagues from and outside the life-sciences.
Dissecting the biology of MDS has been a challenge due to limitations in model systems that faithfully recapitulate MDS pathogenesis, with most models primarily recapitulating advanced stage disease, i.e. progression towards acute myeloid leukemia, which is referred to as secondary AML from MDS (sAML). Previous work from our lab, had demonstrated that propagation of patient-derived MDS cells in a xenograft setting (meaning human cells engraftment into a mouse environment) requires the co-injection of patient-derived niche cells, thereby hinting towards a strong niche dependency of those pre-leukemic stem cells. To overcome the need for these cost-intensive and time-consuming (6-8 months) models, as well as reduce the number of animals used in experiments (3R), we went beyond state-of-the-art and developed fully human and highly modular 3D human organotypic marrow environments (3D HOMEs) that recapitulate the complexity and cellular architecture of the human bone marrow niche. These engineered HOMEs are being explored and exploited for their ability to maintain difficult to culture MDS cells both ex-vivo and in vivo, thereby enabling the study of cellular interactions, niche-vulnerabilities, and dependencies in a relevant setting. Besides its immediate use for modeling MDS/AML in their “natural” milieu, these engineered models are also being exploited to support other research question, related to other bone home homing tumor cells, such as disseminated tumor cells from solid cancer (i.e. bone metastasis). Although yet unpublished, this model has been widely presented at several international meetings (ESH; ASH; EHA; etc.) and the expertise shared with colleagues to promote its exploitation for a wide range of research questions/applications. On our end, we initiated a collaborative effort to enhance the scalability and standardization of these models, to enable medium throughput drug screenings and their exploitation as potential patient avatar systems. In doing so we hope to accelerate and facilitate the application of precision medicine approaches to these hard to model diseases.