Portal de investigação
Nerve growth factor inducible (VGF) is a secreted mediator for metastatic breast cancer tropism to the brain
Autores da FMUP
Participantes de fora da FMUP
- Carvalho R.
- Santos L.
- Conde I.
- Leitão R.
- Ferreira H.R.S.
- Gomes C.
- Silva A.P.
- Carvalho-Maia C.
- Lobo J.
- Jerónimo C.
- Paredes J.
- Ribeiro A.S.
Unidades de investigação
Abstract
Brain metastases are one of the most serious clinical problems in breast cancer (BC) progression, associated with lower survival rates and a lack of effective therapies. Thus, to dissect the early stages of the brain metastatic process, we studied the impact of brain organotropic BC cells’ secretomes on the establishment of the brain pre-metastatic niche (PMN). We found that BC cells with specific tropism to the brain caused significant blood–brain barrier (BBB) disruption, as well as microglial activation, in both in vitro and in vivo models. Further, we searched for a brain-organotropic metastatic signature, as a promising source for the discovery of new biomarkers involved in brain metastatic progression. Of relevance, we identified VGF (nerve growth factor inducible) as a key mediator in this process, also impacting the BBB and microglial functions both in vitro and in vivo. In a series of human breast tumors, VGF was found to be expressed in both cancer cells and the adjacent stroma. Importantly, VGF-positive tumors showed a significantly worse prognosis and were associated with HER2 (human epidermal growth factor receptor 2) overexpression and triple-negative molecular signatures. Further clinical validation in primary tumors from metastatic BC cases showed a significant association between VGF and the brain metastatic location, clearly and significantly impacting on the prognosis of BC patients with brain metastasis. In conclusion, our study reveals a unique secretome signature for BC with a tropism for the brain, highlighting VGF as a crucial mediator in this process. Furthermore, its specific impact as a poor prognostic predictor for BC patients with brain metastasis opens new avenues to target VGF to control the progression of brain metastatic disease. © 2024 The Pathological Society of Great Britain and Ireland. © 2024 The Pathological Society of Great Britain and Ireland.
© 2024 The Pathological Society of Great Britain and Ireland.
Dados da publicação
- ISSN/ISSNe:
- 1096-9896, 0022-3417
- Tipo:
- Article
- Páginas:
- 132-147
- DOI:
- 10.1002/path.6319
- Link para outro recurso:
- www.scopus.com
Journal of Pathology John Wiley and Sons Ltd
Documentos
- Não há documentos
Filiações
Keywords
- Animals; Biomarkers, Tumor; Blood-Brain Barrier; Brain Neoplasms; Breast Neoplasms; Cell Line, Tumor; Female; Humans; Mice; Microglia; Tropism; epidermal growth factor receptor 2; messenger RNA; nerve growth factor; nerve growth factor inducible; unclassified drug; tumor marker; animal cell; animal experiment; animal model; animal tissue; Article; blood brain barrier; brain capillary endothelial cell; brain metastasis; cancer growth; cancer patient; cancer prognosis; cell activation; cell tropism; cohort analysis; controlled study; disease marker; female; gene overexpression; human; human cell; human tissue; in vitro study; in vivo study; major clinical study; MDA-MB-231 cell line; metastatic breast cancer; microglia; nonhuman; primary tumor; retrospective study; secretome; stroma; animal; blood brain barrier; brain tumor; breast tumor; genetics; metabolism; mouse; pathology; tropism; tumor cell line
Campos de estudo
Financiamento
Proyectos asociados
Parâmetros que demonstram ter influência na resposta à terapia neoadjuvante em pacientes com cancro da mama: Estado da arte e perspetivas futuras
Investigador Principal: Fernando Carlos de Landér Schmitt
Estudo Clínico Académico . 2021
Citar a publicação
Carvalho R,Santos L,Conde I,Leitão R,Ferreira HRS,Gomes C,Silva AP,Schmitt F,Carvalho C,Lobo J,Jerónimo C,Paredes J,Ribeiro AS. Nerve growth factor inducible (VGF) is a secreted mediator for metastatic breast cancer tropism to the brain. J. Pathol. 2024. 264. (2):p. 132-147. IF:7,300. (1).
