Inhibition of DKK-1 by WAY262611 Inhibits Osteosarcoma Metastasis.

Osteosarcoma (OS) is the most common primary malignant bone tumor in childhood. Patients who present with metastatic disease at diagnosis or relapse have a very poor prognosis, and this has not changed over the past four decades. The Wnt signaling pathway plays a role in regulating osteogenesis and is implicated in OS pathogenesis.

Inhibition of DKK-1 by WAY262611 Inhibits Osteosarcoma Metastasis.

Osteosarcoma (OS) is the most common primary malignant bone tumor in childhood. Patients who present with metastatic disease at diagnosis or relapse have a very poor prognosis, and this has not changed over the past four decades. The Wnt signaling pathway plays a role in regulating osteogenesis and is implicated in OS pathogenesis.

Polyamine Depletion by D, L-alpha-difluoromethylornithine Inhibits Ewing Sarcoma Metastasis by Inducing Ferroptosis.

Polyamine metabolism and signaling play important roles in multiple cancers but have not previously been studied in Ewing sarcoma. Here, we show that blocking polyamine synthesis with D, L-alpha-difluoromethylornithine (DFMO) causes a G1 cell cycle arrest, dose-dependent decreases in sarcosphere formation from Ewing sarcoma cell lines growing in non-adherent conditions and a decrease in clonogenic growth in soft agar. Further, we utilized our orthotopic implantation/amputation model of Ewing sarcoma metastasis to demonstrate that DFMO slowed primary tumor growth in addition to limiting metastasis.

RNA helicase DDX3 regulates RAD51 localization and DNA damage repair in Ewing sarcoma.

We previously demonstrated that RNA helicase DDX3X (DDX3) can be a therapeutic target in Ewing sarcoma (EWS), but its role in EWS biology remains unclear. The present work demonstrates that DDX3 plays a unique role in DNA damage repair (DDR). We show that DDX3 interacts with several proteins involved in homologous recombination, including RAD51, RECQL1, RPA32, and XRCC2.

RNA Helicase DDX3 Regulates RAD51 Localization and DNA Damage Repair in Ewing Sarcoma.

We previously demonstrated that RNA helicase DDX3X (DDX3) can be a therapeutic target in Ewing sarcoma (EWS), but its role in EWS biology remains unclear. The present work demonstrates that DDX3 plays a unique role in DNA damage repair (DDR). We show that DDX3 interacts with several proteins involved in homologous recombination, including RAD51, RECQL1, RPA32, and XRCC2.

Author Correction: Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche.

In the version of this article originally published, the key for Fig. 4c was incorrect. The symbols for 'Sham' and 'Den' were reversed.

Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche.

Aging of hematopoietic stem cells (HSCs) is associated with a decline in their regenerative capacity and multilineage differentiation potential, contributing to the development of blood disorders. The bone marrow microenvironment has recently been suggested to influence HSC aging, but the underlying mechanisms remain largely unknown. Here we show that HSC aging critically depends on bone marrow innervation by the sympathetic nervous system (SNS), as loss of SNS nerves or adrenoreceptor β3 signaling in the bone marrow microenvironment of young mice led to premature HSC aging, as evidenced by appearance of HSC phenotypes reminiscent of physiological aging.

Fetal liver hematopoietic stem cell niches associate with portal vessels.

Whereas the cellular basis of the hematopoietic stem cell (HSC) niche in the bone marrow has been characterized, the nature of the fetal liver niche is not yet elucidated. We show that Nestin(+)NG2(+) pericytes associate with portal vessels, forming a niche promoting HSC expansion. Nestin(+)NG2(+) cells and HSCs scale during development with the fractal branching patterns of portal vessels, tributaries of the umbilical vein.

The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss.

Aging is linked to greater susceptibility to chronic inflammatory diseases, several of which, including periodontitis, involve neutrophil-mediated tissue injury. Here we found that aging-associated periodontitis was accompanied by lower expression of Del-1, an endogenous inhibitor of neutrophil adhesion dependent on the integrin LFA-1, and by reciprocal higher expression of interleukin 17 (IL-17). Consistent with that, IL-17 inhibited gingival endothelial cell expression of Del-1, thereby promoting LFA-1-dependent recruitment of neutrophils.