Lactate accumulation promotes immunosuppression and fibrotic transformation of bone marrow microenvironment in myelofibrosis
Abstract Background Clonal myeloproliferation and fibrotic transformation of the bone marrow (BM) are the pathogenetic events most commonly occurring in myelofibrosis (MF). There is great evidence indicating that tumor microenvironment is characterized by high lactate levels, acting not only as an e...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-01-01
|
| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-025-06083-4 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832594507856609280 |
|---|---|
| author | Mariarita Spampinato Cesarina Giallongo Sebastiano Giallongo Enrico La Spina Andrea Duminuco Lucia Longhitano Rosario Caltabiano Lucia Salvatorelli Giuseppe Broggi Elisabetta P. Pricoco Vittorio Del Fabro Ilaria Dulcamare Antonio Massimo DI Mauro Alessandra Romano Francesco Di Raimondo Giovanni Li Volti Giuseppe A. Palumbo Daniele Tibullo |
| author_facet | Mariarita Spampinato Cesarina Giallongo Sebastiano Giallongo Enrico La Spina Andrea Duminuco Lucia Longhitano Rosario Caltabiano Lucia Salvatorelli Giuseppe Broggi Elisabetta P. Pricoco Vittorio Del Fabro Ilaria Dulcamare Antonio Massimo DI Mauro Alessandra Romano Francesco Di Raimondo Giovanni Li Volti Giuseppe A. Palumbo Daniele Tibullo |
| author_sort | Mariarita Spampinato |
| collection | DOAJ |
| description | Abstract Background Clonal myeloproliferation and fibrotic transformation of the bone marrow (BM) are the pathogenetic events most commonly occurring in myelofibrosis (MF). There is great evidence indicating that tumor microenvironment is characterized by high lactate levels, acting not only as an energetic source, but also as a signaling molecule. Methods To test the involvement of lactate in MF milieu transformation, we measured its levels in MF patients’ sera, eventually finding a massive accumulation of this metabolite, which we showed to promote the expansion of immunosuppressive subsets. Therefore, to assess the significance of its trafficking, we inhibited monocarboxylate transporter 1 (MCT1) by its selective antagonist, AZD3965, eventually finding a mitigation of lactate-mediated immunosuppressive subsets expansion. To further dig into the impact of lactate in tumor microenvironment, we evaluated the effect of this metabolite on mesenchymal stromal cells (MSCs) reprogramming. Results Our results show an activation of a cancer-associated phenotype (CAF) related to mineralized matrix formation and early fibrosis development. Strikingly, MF serum, enriched in lactate, causes a strong deposition of collagen in healthy stromal cells, which was restrained by AZD3965. To corroborate these outcomes, we therefore generated for the first time a TPOhigh zebrafish model for the establishment of experimental fibrosis. By adopting this model, we were able to unveil a remarkable increase in lactate concentration and monocarboxylate transporter 1 (MCT1) expression in the site of hematopoiesis, associated with a strong downregulation of lactate export channel MCT4. Notably, exploiting MCTs expression in biopsy specimens from patients with myeloproliferative neoplasms, we found a loss of MCT4 expression in PMF, corroborating changes in MCT expression during BM fibrosis establishment. Conclusions In conclusion, our results unveil lactate as a key regulator of immune escape and BM fibrotic transformation in MF patients, suggesting MCT1 blocking as a novel antifibrotic strategy. |
| format | Article |
| id | doaj-art-c48c841c55ee4e84995c1ae7ca6d53a3 |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-c48c841c55ee4e84995c1ae7ca6d53a32025-01-19T12:37:15ZengBMCJournal of Translational Medicine1479-58762025-01-0123111510.1186/s12967-025-06083-4Lactate accumulation promotes immunosuppression and fibrotic transformation of bone marrow microenvironment in myelofibrosisMariarita Spampinato0Cesarina Giallongo1Sebastiano Giallongo2Enrico La Spina3Andrea Duminuco4Lucia Longhitano5Rosario Caltabiano6Lucia Salvatorelli7Giuseppe Broggi8Elisabetta P. Pricoco9Vittorio Del Fabro10Ilaria Dulcamare11Antonio Massimo DI Mauro12Alessandra Romano13Francesco Di Raimondo14Giovanni Li Volti15Giuseppe A. Palumbo16Daniele Tibullo17Department of Biomedical and Biotechnological Sciences, Division of Medical Biochemistry, University of CataniaDepartment of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, Division of Hematology, University of CataniaDepartment of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, Division of Hematology, University of CataniaDepartment of Biomedical and Biotechnological Sciences, Division of Medical Biochemistry, University of CataniaHematology Unit with BMT, A.O.U. Policlinico “G. Rodolico-San Marco”Department of Biomedical and Biotechnological Sciences, Division of Medical Biochemistry, University of CataniaDepartment of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, Division of Anatomic Pathology, University of CataniaDepartment of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, Division of Anatomic Pathology, University of CataniaDepartment of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, Division of Anatomic Pathology, University of CataniaAnatomic Pathology, A.O.U. Policlinico “G. Rodolico-San Marco”Hematology Unit with BMT, A.O.U. Policlinico “G. Rodolico-San Marco”Department of Clinical and Experimental Medicine, University of CataniaOspedale CannizzaroDepartment of General Surgery and Medical-Surgical Specialties, University of CataniaDepartment of General Surgery and Medical-Surgical Specialties, University of CataniaDepartment of Biomedical and Biotechnological Sciences, Division of Medical Biochemistry, University of CataniaDepartment of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, Division of Hematology, University of CataniaDepartment of Biomedical and Biotechnological Sciences, Division of Medical Biochemistry, University of CataniaAbstract Background Clonal myeloproliferation and fibrotic transformation of the bone marrow (BM) are the pathogenetic events most commonly occurring in myelofibrosis (MF). There is great evidence indicating that tumor microenvironment is characterized by high lactate levels, acting not only as an energetic source, but also as a signaling molecule. Methods To test the involvement of lactate in MF milieu transformation, we measured its levels in MF patients’ sera, eventually finding a massive accumulation of this metabolite, which we showed to promote the expansion of immunosuppressive subsets. Therefore, to assess the significance of its trafficking, we inhibited monocarboxylate transporter 1 (MCT1) by its selective antagonist, AZD3965, eventually finding a mitigation of lactate-mediated immunosuppressive subsets expansion. To further dig into the impact of lactate in tumor microenvironment, we evaluated the effect of this metabolite on mesenchymal stromal cells (MSCs) reprogramming. Results Our results show an activation of a cancer-associated phenotype (CAF) related to mineralized matrix formation and early fibrosis development. Strikingly, MF serum, enriched in lactate, causes a strong deposition of collagen in healthy stromal cells, which was restrained by AZD3965. To corroborate these outcomes, we therefore generated for the first time a TPOhigh zebrafish model for the establishment of experimental fibrosis. By adopting this model, we were able to unveil a remarkable increase in lactate concentration and monocarboxylate transporter 1 (MCT1) expression in the site of hematopoiesis, associated with a strong downregulation of lactate export channel MCT4. Notably, exploiting MCTs expression in biopsy specimens from patients with myeloproliferative neoplasms, we found a loss of MCT4 expression in PMF, corroborating changes in MCT expression during BM fibrosis establishment. Conclusions In conclusion, our results unveil lactate as a key regulator of immune escape and BM fibrotic transformation in MF patients, suggesting MCT1 blocking as a novel antifibrotic strategy.https://doi.org/10.1186/s12967-025-06083-4LactateMyelofibrosisTumor microenvironmentMonocarboxylate transporters |
| spellingShingle | Mariarita Spampinato Cesarina Giallongo Sebastiano Giallongo Enrico La Spina Andrea Duminuco Lucia Longhitano Rosario Caltabiano Lucia Salvatorelli Giuseppe Broggi Elisabetta P. Pricoco Vittorio Del Fabro Ilaria Dulcamare Antonio Massimo DI Mauro Alessandra Romano Francesco Di Raimondo Giovanni Li Volti Giuseppe A. Palumbo Daniele Tibullo Lactate accumulation promotes immunosuppression and fibrotic transformation of bone marrow microenvironment in myelofibrosis Journal of Translational Medicine Lactate Myelofibrosis Tumor microenvironment Monocarboxylate transporters |
| title | Lactate accumulation promotes immunosuppression and fibrotic transformation of bone marrow microenvironment in myelofibrosis |
| title_full | Lactate accumulation promotes immunosuppression and fibrotic transformation of bone marrow microenvironment in myelofibrosis |
| title_fullStr | Lactate accumulation promotes immunosuppression and fibrotic transformation of bone marrow microenvironment in myelofibrosis |
| title_full_unstemmed | Lactate accumulation promotes immunosuppression and fibrotic transformation of bone marrow microenvironment in myelofibrosis |
| title_short | Lactate accumulation promotes immunosuppression and fibrotic transformation of bone marrow microenvironment in myelofibrosis |
| title_sort | lactate accumulation promotes immunosuppression and fibrotic transformation of bone marrow microenvironment in myelofibrosis |
| topic | Lactate Myelofibrosis Tumor microenvironment Monocarboxylate transporters |
| url | https://doi.org/10.1186/s12967-025-06083-4 |
| work_keys_str_mv | AT mariaritaspampinato lactateaccumulationpromotesimmunosuppressionandfibrotictransformationofbonemarrowmicroenvironmentinmyelofibrosis AT cesarinagiallongo lactateaccumulationpromotesimmunosuppressionandfibrotictransformationofbonemarrowmicroenvironmentinmyelofibrosis AT sebastianogiallongo lactateaccumulationpromotesimmunosuppressionandfibrotictransformationofbonemarrowmicroenvironmentinmyelofibrosis AT enricolaspina lactateaccumulationpromotesimmunosuppressionandfibrotictransformationofbonemarrowmicroenvironmentinmyelofibrosis AT andreaduminuco lactateaccumulationpromotesimmunosuppressionandfibrotictransformationofbonemarrowmicroenvironmentinmyelofibrosis AT lucialonghitano lactateaccumulationpromotesimmunosuppressionandfibrotictransformationofbonemarrowmicroenvironmentinmyelofibrosis AT rosariocaltabiano lactateaccumulationpromotesimmunosuppressionandfibrotictransformationofbonemarrowmicroenvironmentinmyelofibrosis AT luciasalvatorelli lactateaccumulationpromotesimmunosuppressionandfibrotictransformationofbonemarrowmicroenvironmentinmyelofibrosis AT giuseppebroggi lactateaccumulationpromotesimmunosuppressionandfibrotictransformationofbonemarrowmicroenvironmentinmyelofibrosis AT elisabettappricoco lactateaccumulationpromotesimmunosuppressionandfibrotictransformationofbonemarrowmicroenvironmentinmyelofibrosis AT vittoriodelfabro lactateaccumulationpromotesimmunosuppressionandfibrotictransformationofbonemarrowmicroenvironmentinmyelofibrosis AT ilariadulcamare lactateaccumulationpromotesimmunosuppressionandfibrotictransformationofbonemarrowmicroenvironmentinmyelofibrosis AT antoniomassimodimauro lactateaccumulationpromotesimmunosuppressionandfibrotictransformationofbonemarrowmicroenvironmentinmyelofibrosis AT alessandraromano lactateaccumulationpromotesimmunosuppressionandfibrotictransformationofbonemarrowmicroenvironmentinmyelofibrosis AT francescodiraimondo lactateaccumulationpromotesimmunosuppressionandfibrotictransformationofbonemarrowmicroenvironmentinmyelofibrosis AT giovannilivolti lactateaccumulationpromotesimmunosuppressionandfibrotictransformationofbonemarrowmicroenvironmentinmyelofibrosis AT giuseppeapalumbo lactateaccumulationpromotesimmunosuppressionandfibrotictransformationofbonemarrowmicroenvironmentinmyelofibrosis AT danieletibullo lactateaccumulationpromotesimmunosuppressionandfibrotictransformationofbonemarrowmicroenvironmentinmyelofibrosis |