Systemic brain dissemination of glioblastoma requires transdifferentiation into endothelial-like cells via TGF-β-ALK1-Smad1/5 signaling
Glioblastoma is the most aggressive type of brain cancer, but treatment improvements for glioblastoma patients remain stagnated for over 20 years. This is despite the large number of clinical trials that have attempted to replicate the success of therapeutics developed for other cancer types. This d...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558624001519 |
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| author | Thomas M.B. Ware Adilson Fonseca Teixeira Josephine Iaria Rodney B. Luwor Hong-Jian Zhu |
| author_facet | Thomas M.B. Ware Adilson Fonseca Teixeira Josephine Iaria Rodney B. Luwor Hong-Jian Zhu |
| author_sort | Thomas M.B. Ware |
| collection | DOAJ |
| description | Glioblastoma is the most aggressive type of brain cancer, but treatment improvements for glioblastoma patients remain stagnated for over 20 years. This is despite the large number of clinical trials that have attempted to replicate the success of therapeutics developed for other cancer types. This discrepancy highlights the urgent need to decipher the unique biology of glioblastomas. Here, we show that glioblastoma tumour cells are highly plastic, integrating into blood vessel walls to disseminate throughout the brain. This relies on the transdifferentiation of glioblastoma tumor cells into endothelial-like cells in a process we termed endothelialisation. Mechanistically, in addition to TGF-β-ALK5-Smad2/3 signaling, glioblastoma tumour cells also activate TGF-β-ALK1-Smad1/5 signaling – a mechanism previously thought to be limited to endothelial cells. Consequently, therapeutic targeting of TGF-β-ALK1-Smad1/5 activity impaired endothelialisation-driven glioblastoma progression. This study identifies a previously unknown component of glioblastoma biology and establishes a therapeutic approach to reduce the progression of this disease. |
| format | Article |
| id | doaj-art-05db3cf8e9a94b0c9ea3a598c9889630 |
| institution | Kabale University |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-05db3cf8e9a94b0c9ea3a598c98896302025-02-03T04:16:34ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-02-0160101110Systemic brain dissemination of glioblastoma requires transdifferentiation into endothelial-like cells via TGF-β-ALK1-Smad1/5 signalingThomas M.B. Ware0Adilson Fonseca Teixeira1Josephine Iaria2Rodney B. Luwor3Hong-Jian Zhu4Department of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Parkville 3050 Victoria, Australia; Huagene Institute, Kecheng Science and Technology Park, Pukou District, Nanjing 211806, Jiangsu, PR ChinaDepartment of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Parkville 3050 Victoria, Australia; Huagene Institute, Kecheng Science and Technology Park, Pukou District, Nanjing 211806, Jiangsu, PR ChinaDepartment of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Parkville 3050 Victoria, Australia; Huagene Institute, Kecheng Science and Technology Park, Pukou District, Nanjing 211806, Jiangsu, PR ChinaDepartment of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Parkville 3050 Victoria, Australia; Huagene Institute, Kecheng Science and Technology Park, Pukou District, Nanjing 211806, Jiangsu, PR China; Fiona Elsey Cancer Research Institute, Ballarat, Victoria 3350, Australia; Federation University, Ballarat, Victoria 3350, AustraliaDepartment of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Parkville 3050 Victoria, Australia; Huagene Institute, Kecheng Science and Technology Park, Pukou District, Nanjing 211806, Jiangsu, PR China; Lead contact; Correspondence author at Department of Surgery, The University of Melbourne, Level 5, Clinical Sciences Building, Royal Parade, Parkville 3050, Victoria, AustraliaGlioblastoma is the most aggressive type of brain cancer, but treatment improvements for glioblastoma patients remain stagnated for over 20 years. This is despite the large number of clinical trials that have attempted to replicate the success of therapeutics developed for other cancer types. This discrepancy highlights the urgent need to decipher the unique biology of glioblastomas. Here, we show that glioblastoma tumour cells are highly plastic, integrating into blood vessel walls to disseminate throughout the brain. This relies on the transdifferentiation of glioblastoma tumor cells into endothelial-like cells in a process we termed endothelialisation. Mechanistically, in addition to TGF-β-ALK5-Smad2/3 signaling, glioblastoma tumour cells also activate TGF-β-ALK1-Smad1/5 signaling – a mechanism previously thought to be limited to endothelial cells. Consequently, therapeutic targeting of TGF-β-ALK1-Smad1/5 activity impaired endothelialisation-driven glioblastoma progression. This study identifies a previously unknown component of glioblastoma biology and establishes a therapeutic approach to reduce the progression of this disease.http://www.sciencedirect.com/science/article/pii/S1476558624001519GlioblastomaAngiogenesisPhenotypic plasticityTGF-β signalingTargeted therapy |
| spellingShingle | Thomas M.B. Ware Adilson Fonseca Teixeira Josephine Iaria Rodney B. Luwor Hong-Jian Zhu Systemic brain dissemination of glioblastoma requires transdifferentiation into endothelial-like cells via TGF-β-ALK1-Smad1/5 signaling Neoplasia: An International Journal for Oncology Research Glioblastoma Angiogenesis Phenotypic plasticity TGF-β signaling Targeted therapy |
| title | Systemic brain dissemination of glioblastoma requires transdifferentiation into endothelial-like cells via TGF-β-ALK1-Smad1/5 signaling |
| title_full | Systemic brain dissemination of glioblastoma requires transdifferentiation into endothelial-like cells via TGF-β-ALK1-Smad1/5 signaling |
| title_fullStr | Systemic brain dissemination of glioblastoma requires transdifferentiation into endothelial-like cells via TGF-β-ALK1-Smad1/5 signaling |
| title_full_unstemmed | Systemic brain dissemination of glioblastoma requires transdifferentiation into endothelial-like cells via TGF-β-ALK1-Smad1/5 signaling |
| title_short | Systemic brain dissemination of glioblastoma requires transdifferentiation into endothelial-like cells via TGF-β-ALK1-Smad1/5 signaling |
| title_sort | systemic brain dissemination of glioblastoma requires transdifferentiation into endothelial like cells via tgf β alk1 smad1 5 signaling |
| topic | Glioblastoma Angiogenesis Phenotypic plasticity TGF-β signaling Targeted therapy |
| url | http://www.sciencedirect.com/science/article/pii/S1476558624001519 |
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