SyLeNCe · Synapses between Leukaemia and its Neighbouring Cells
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-07-01 → 2022-06-30
- EU contribution
- €160,932
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Synapses between Leukaemia and its Neighbouring Cells
Our project tries to understand how the bone marrow (BM) microenvironment participates in the regulation of hematopoiesis during neoplastic transformation and how we can use this knowledge to improve the treatment of these patients. Hematopoiesis is the process by which blood lineages are formed from a common and undifferentiated cellular precursor, the hematopoietic stem cell (HSC). Alterations in the molecular mechanisms that control hematopoiesis lead to abnormal differentiation and to the development of various hematological disorders. Their prevalence is almost exclusive to older patients (median of 70 years old), suggesting that aged-related alterations predispose to an abnormal differentiation with different clinical manifestations. Such alterations have started to be elucidated and involve both extrinsic and HSC-intrinsic alterations. HSCs reside in a perivascular microenvironment that integrates local and systemic inputs. BM microenvironment is the micro-anatomical location where stem cells reside and contribute to tissue generation, maintenance, and repair. Fortunately, in recent decades, the technology has evolved: single-cell profiling, computer, and systems-biology analytical tools. With that “toolkit” we can investigate biological mechanisms such as hematopoiesis and their impact on many immune-related diseases such as Acute myeloid leukemia (AML). Information gathered from these experiments provides a list of molecular candidates for therapeutic intervention. We validate those candidate cell populations by means of gain and loss-of-function assays in vitro and in vivo using murine models and primary human AML samples. Completion of our interdisciplinary project provides, for the first time a complete transcriptional and cellular map of a tissue, revealing the heterotypic interactions that define the real nature of tissue. Moreover, our results may be of interest in order to modulate stem cell output in individuals with AML as a therapeutic strategy.
Data: CORDIS, © European Union
Project objective
Our understanding of the different layers of organization in tissues remains limited. Stem cell niches offer a tightly controlled environment and a unique opportunity to look into this question. Reductionist approaches have been proven highly efficient dissecting the complexity of stem cell niches in a unidirectional fashion. However, this approach fails to recognize the tri-dimensional complexity of tissue organization. Hence we propose a systems biology approach based on low input and single cell RNA sequencing of bone marrow niche populations in order to establish not only the molecular landscape of cells that comprise the stem cell niche in homeostasis and disease but also the lineage relationships that may exist between cells in the stroma. Using the mouse bone marrow niche during neoplastic transformation to acute myeloid leukemia (AML), we will first unravel the cellular and molecular interactions that constitute the tumor microenvironment during disease development and progression using multi parametric flow cytometry and RNA-sequencing. Information gathered from these experiments will also provide a list of molecular candidates for therapeutic intervention in AML. We will validate those candidate cell populations and genetic pathways by means of gain and loss-of-function assays in vitro and in vivo using murine models and primary human AML samples. Completion of our interdisciplinary project will provide, for the first time a complete transcriptional and cellular map of a tissue, revealing the heterotypic interactions that define the real nature of a tissue. Perhaps then we could start to appreciate the elegant complexity of the ecosystem that the stem cell and its niche share. I hope SyLeNCe will facilitate the description of novel vulnerabilities that could be explored therapeutically for the treatment of acute myeloid leukaemia having an impact on the quality of life and long-term survival of AML patients.
Original text from CORDIS.
Participants
- FUNDACION PARA LA INVESTIGACION MEDICA APLICADA FIMA · PamplonaCoordinatorSpain
Links
- View on CORDIS
- DOI: 10.3030/837491
- https://www.sciencedirect.com/science/article/pii/S2589004222004953
Data: CORDIS, © European Union