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Introduction: Osteosarcoma (OS) is the most common primary malignant bone tumor in adolescents and young adults. Intensive multimodal treatment cures almost 75% of patients who present with localized disease; however, only 25% of patients who present with metastases become long term survivors, and those who suffer a metastatic relapse are almost never cured. Polyamine metabolism and signaling play important roles in multiple cancers but have not previously been studied in osteosarcoma. D, L-alpha-difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC), the initial, rate-limiting enzyme within the polyamine biosynthetic pathway, and has been studied in a number of different cancers as either a therapeutic or a chemopreventive agent. We investigated the role of polyamines in OS proliferation and metastasis and whether blocking the polyamine synthetic pathway with DFMO had therapeutic potential in the treatment of OS. Methods: We evaluated proliferation, apoptosis, clonogenic growth and the ability to grow under nonadherent conditions in vitro using established OS lines. To investigate the effect of DFMO on tumor growth in vivo, we implanted fragments of patient derived xenograft into the tibias of NOD/SCID/IL-2Rγ null mice. Upon confirmation of tumor growth, mice were randomized to either receive drinking water or drinking water supplemented with 2% DFMO. A third cohort of mice received water supplemented with 2% DFMO only after hindlimb amputation. Results: DFMO has a profound effect on the proliferation of OS cell lines in vitro. Utilizing caspase assays, we determined that DFMO does not induce apoptosis, but is cytostatic and inhibits proliferation. We found that DFMO prevents the clonogenic growth of 3 different OS cell lines in soft agar and prevents spheroid formation under non-adherent conditions. Interestingly, once established, spheroidss were not disrupted by the addition of DFMO. In vivo, administration of 2% DFMO after hindlimb amputation decreased local recurrence and limited metastasis (p=0.02). Conclusion: DFMO inhibits proliferation and clonogenic growth in vitro, and decreases distant metastasis in vivo. Since pediatric dosing and safety data are already established, our findings are readily translatable to clinical trials. Citation Format: Rachel Offenbacher, Paul Ciero, David Loeb. Targeting urea cycle dysfunction to prevent and treat osteosarcoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6725.

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. Strikingly, supplementation of a sympathomimetic acting selectively on adrenoreceptor β3 to old mice significantly rejuvenated the in vivo function of aged HSCs, suggesting that the preservation or restitution of bone marrow SNS innervation during aging may hold the potential for new HSC rejuvenation strategies.

In the version of this article originally published, the key for Fig. 4c was incorrect. The symbols for 'Sham' and 'Den' were reversed. The error has been corrected in the PDF and HTML versions of the manuscript.

How HSCs populate the fetal liver Hematopoietic stem cells (HSCs) undergo dramatic expansion in the fetal liver before migrating to their definitive site in the bone marrow. Khan et al. identify portal vessel–associated Nestin + NG2 + pericytes as critical HSC niche components (see the Perspective by Cabezas-Wallscheid and Trumpp). The portal vessel niche and HSCs expand according to fractal geometries, suggesting that niche cells—rather than factors expressed by the niche—drive HSC proliferation. After birth, arterial portal vessels transform into portal veins, and lose Nestin + NG2 + pericytes. When this happens, the niche is lost and HSCs migrate away from the neonatal liver. Science , this issue p. 176 ; see also p. 126