Background
Metastasis is associated with, and likely initiated by, diffuse changes of tumor cell phenotype, resulting from genomic heterogeneity and clonal selection, as well as modification of the tumor-prone stroma. Myeloid neoplasms (MyNe) are hematopoietic stem cell-derived neoplasms that typically face progressive worsening to more aggressive diseases and acute leukemia and may undergo systemic spreading.
Hypothesis
We hypothesize that MyNe represent a model of multistep tumor progression and systemic diffusion that reflect the stepwise acquisition of genomic abnormalities, sustaining clonal selection within the population of neoplastic hematopoietic stem cells, as well as the disruption of bone marrow niches supporting normal hematopoiesis. As such, MyNe mimic the events occurring in the cells of a primary tumor that, by acquiring additional genetic alterations, undergo clonal progression and clonal selection, and generate metastasis; in particular, clonal evolution in MyNe is herein meant to epitomize the metastatic process.
Aims
This project (acronym, MYNERVA) aims at understanding the mechanisms that are responsible of the clonal progression of MyNe cancer cells, resulting in the transformation of a chronic disease to an accelerated form or acute leukemia, as well as the role of modifications of the hematopoietic niche that facilitate escape and systemic spreading of the neoplastic cells. We also seek to discover clinically meaningful biomarkers of disease progression and disease' systemic diffusion to be used in the setting of retrospective and prospective clinical studies. Finally, we aim at identifying potentially promising molecules for intervention trials.
Experimental Design
To reach those aims, we gathered together six operative units (OUs) that will be jointly involved in four Working Parties. The most up-to-date molecular, cellular and biochemical approaches will be used to dissect the phenotypic characteristics and the molecular landscape of MyNe cells and of the MyNe-associated microenvironment. Findings generated in vitro will be validated in animal models and huge cohorts of patients that are already available in the four clinical OUs, and will be shared among them. Clinical studies will be designed to describe the natural history and molecular profile of MyNe and to validate biomarkers of disease progression and systemic spreading, based on the results generated along the experimental researches. We will focus on novel potentially actionable targets we succeeded to identify, with the aim to perform pilot intervention studies.
Expected Results
Results produced by MYNERVA scientists will increase the knowledge of pathophysiology of these still incurable hematologic neoplasms, help to describe and validate novel biomarkers of disease progression and systemic spreading, and lead to identifying novel actionable targets, in the spirit of personalized medicine.
Impact On Cancer
MyNe are prototype metastatic diseases that, along their intrinsic evolution, recapitulate the events of clonal emergence, clonal selection and systemic dissemination of cancer cells that are well described in solid tumor metastasis. Therefore, we argue that in-depth analysis of MyNe model might contribute to generate a thorough understanding of molecular, biochemical and cellular events involved in tumor progression and metastasis more in general.