Gaete, D. | bioRxiv Science

bioRxiv2024

Endoglin regulates the integrity of the bone marrow vasculature

Endoglin (Eng) is an accessory receptor for transforming growth factor-{beta} (TGF-{beta}) that is critical for maintaining vascular integrity. Mutations in Eng cause hereditary hemorrhagic telangiectasia (HHT), resulting in arteriovenous malformations (AVMs) and blood abnormalities. Despite the known association between Eng deficiency and AVMs, the underlying mechanisms are unclear. In addition, the role of the bone marrow (BM), a major source of immune and blood cells, in endothelial Eng (EC-Eng) deficiency is unexplored. We show that BM blood vessels conditionally deficient in Eng (cKO) undergo a structured remodeling process over four weeks, with distinct proliferative and resolution phases. These phases involve angiogenic set points, the involvement of integrins, and the modulation of vascular integrity. In addition, we observe changes in hematopoietic stem and progenitor cells (HSPC) and circulating granulocytes, along with reduced red blood cells and platelets due to splenic sequestration. Using a conditional heterozygous EC-Eng deficient mouse model, reflecting the genetics of HHT patients, we identify vascular changes similar to those in the cKO model. Taken together, using multiple in vivo approaches, we suggest that reduced Eng expression in the endothelium drives significant BM vascular remodeling, sharing mechanisms with early vascular processes associated with AVM formation. Explanation of NoveltyOur findings reveal that BM blood vessels deficient in endoglin undergo an orchestrated remodeling process with distinct proliferative and resolution phases over several weeks. We identify specific angiogenic set points and profound alterations in vascular integrity, along with hematopoietic changes starting at the level of hematopoietic stem and progenitor cells. These findings advance our understanding of the role of Eng in vascular remodeling and may provide novel therapeutic targets for HHT. Key PointsO_LIConditional EC-Eng deficiency leads to vascular remodeling in the BM of mice in a temporally orchestrated manner. C_LIO_LIEC-Eng facilitates vascular integrity, hematopoietic homeostasis, and immune cell mobilization. C_LI

molecular biology↗

bioRxiv2021

The distinct role of ALDH1A1 and ALDH1A3 in the regulation of prostate cancer metastases

Cancer stem cells (CSC) are characterized by high self-renewal capacity, tumor-initiating potential, and therapy resistance. Aldehyde dehydrogenase (ALDH)+ cell population serves as an indicator of prostate CSCs with increased therapy resistance, enhanced DNA double-strand break repair, and activated epithelial-mesenchymal transition (EMT) and migration. Numerous ALDH genes contribute to ALDH enzymatic activity; however, only some of them showed clinical relevance. We found that ALDH1A1 and ALDH1A3 genes functionally regulate CSC properties and radiation sensitivity of PCa. We revealed a negative correlation between ALDH1A1 and ALDH1A3 expression in publicly available prostate cancer (PCa) datasets and demonstrated that ALDH1A1 and ALDH1A3 have opposing predictive value for biochemical recurrence-free survival. Our data suggest an association of ALDH1A1 with the metastatic burden, elucidating the role of ALDH genes in the metastatic spread and homing to the bone, which can be, at least partially, attributed to regulating the transforming growth factor beta 1 (TGFB1) and matrix metalloproteinases (MMPs). ALDH genes play a diverse role in PCa development under AR and {beta}-catenin-dependent regulation, with ALDH1A1 becoming dominant in later stages of tumor development when PCa cells gain androgen independence. Taken together, our results indicate that ALDH1A1 and ALDH1A3 modulate PCa radiosensitivity, regulate CSCs phenotype, and spread of PCa cells to the bone, therefore having clinical implication for identifying patients at high risk for progression to metastatic disease.

cancer biology↗