A New Therapeutic Strategy to Inhibit Blood Cancer Metastases
Myelofibrosis is a cancer affecting blood stem cells for which no definitive cure currently exists. The disease is primarily characterised by the development of fibrosis in the bone marrow, impairing its function. As a result, malignant stem cells leave the bone marrow, enter the bloodstream and colonise the spleen, causing a significant enlargement and clinical deterioration that, in severe cases, may require splenectomy.
Until now, the cellular and molecular mechanisms responsible for the colonisation of the spleen by malignant blood stem cells were unclear, and no therapies were available to inhibit the spread of malignant cells to the spleen and other tissues. A new strategy to block this process has now been developed by researchers at CIDSTEM.
The study, published in the Journal of Cellular and Molecular Medicine , a leading international journal in the field of precision medicine, demonstrated that the interaction between monocytes and malignant haematopoietic stem cells — which leads to their dissemination in patients with myelofibrosis — is mediated by the membrane protein CD44.
The research, supported by AIRC Foundation for Cancer Research, was coordinated by Professor Rossella Manfredini, head of the Genomics and Transcriptomics programme at the “Stefano Ferrari” Centre for Regenerative Medicine and leader of the research group on Multi-Omics and Functional Analysis of Haematopoietic Stem Cells in Myeloid Haematological Neoplasms at the Department of Biomedical, Metabolic and Neurosciences.
“Current therapies available for patients with myelofibrosis improve quality of life by acting only on symptoms,” explains Professor Rossella Manfredini . “Splenomegaly — the enlargement of the spleen — is one of the most evident and disabling symptoms, and can be reduced with targeted therapies such as ruxolitinib. However, these treatments do not prevent the dissemination of malignant stem cells. Colonisation of the spleen by malignant haematopoietic stem cells is a form of disease spread that leads to progression towards a more severe stage of myelofibrosis. It is therefore essential to identify therapies capable of counteracting this phenomenon.”
“In previous studies, we identified the protein osteopontin — significantly increased in the plasma of patients with myelofibrosis — as a key pro-fibrotic cytokine,” says Dr Margherita Mirabile. “Osteopontin also acts as a factor capable of stimulating monocyte migration. These monocytes, in turn, can remodel the splenic microenvironment and attract malignant blood stem cells. Our focus was therefore on identifying inhibitors of osteopontin to reduce extramedullary haematopoiesis in patients.”
“Among the various molecules analysed,” explains Dr Sebastiano Rontauroli , “the osteopontin receptor CD44 emerged as the main mediator of this process. We demonstrated that inhibiting CD44 blocks the migration of both monocytes and malignant blood stem cells from the bone marrow, which are recruited into the spleen by osteopontin produced by the monocytes themselves.”
“In summary,” concludes Professor Rossella Manfredini, “these results demonstrate that CD44 inhibition represents a novel targeted therapeutic approach that blocks the development of extramedullary haematopoiesis in patients with myelofibrosis — a step towards precision medicine that prevents the dissemination of neoplastic cells and disease progression to a more severe form.”
Rossella Manfredini
Graduated in 1988 with top marks and honours in Biological Sciences from the University of Modena, she obtained a PhD in Experimental Haematology in 1994 and a Specialisation in Biochemistry and Clinical Chemistry in 1996. Recipient of fellowships from AIRC and the Italian League for the Fight Against Cancer, she conducted postdoctoral research at Temple University in Philadelphia (USA), where she was granted a US patent in 1998 for the “Use of AS c-fes oligonucleotides and ATRA in M3-type leukaemias”. Since 2013, she has been Full Professor of Applied Biology in the Department of Life Sciences at UNIMORE. She is the author of 119 scientific publications in high-impact international journals. For over thirty years, her research has focused on the biology of normal and pathological stem cells, particularly the molecular mechanisms underlying self-renewal, proliferation, and differentiation processes. Her main research areas include: molecular and functional characterisation of normal and leukaemic haematopoietic stem cells; study of clonal heterogeneity in chronic myeloproliferative disorders; and investigation of cytotoxic T-cell exhaustion in myeloproliferative neoplasms.
Photo from left to right: Sebastiano Rontauroli, Camilla Tombari, Rossella Manfredini, Anita Neroni, Margherita Mirabile.
Categorie: International - english, Notizie_eng
Articolo pubblicato da: Ufficio Stampa Unimore - ufficiostampa@unimore.it