Department of Oncology, University of Wisconsin-Madison, Madison, WI.
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI.
Blood Adv. 2023 Nov 28;7(22):6859-6872. doi: 10.1182/bloodadvances.2023010139.
The bone marrow (BM) microenvironment is critical for dissemination, growth, and survival of multiple myeloma (MM) cells. Homing of myeloma cells to the BM niche is a crucial step in MM dissemination, but the mechanisms involved are incompletely understood. In particular, any role of matrikines, neofunctional peptides derived from extracellular matrix proteins, remains unknown. Here, we report that a matrikine derived from hyaluronan and proteoglycan link protein 1 (HAPLN1) induces MM cell adhesion to the BM stromal components, such as fibronectin, endothelial cells, and stromal cells and, furthermore, induces their chemotactic and chemokinetic migration. In a mouse xenograft model, we show that MM cells preferentially home to HAPLN1 matrikine-conditioned BM. The transcription factor STAT1 is activated by HAPLN1 matrikine and is necessary to induce MM cell adhesion, migration, migration-related genes, and BM homing. STAT1 activation is mediated by interferon beta (IFN-β), which is induced by NF-κB after stimulation by HAPLN1 matrikine. Finally, we also provide evidence that higher levels of HAPLN1 in BM samples correlate with poorer progression-free survival of patients with newly diagnosed MM. These data reveal that a matrikine present in the BM microenvironment acts as a chemoattractant, plays an important role in BM homing of MM cells via NF-κB-IFN-β-STAT1 signaling, and may help identify patients with poor outcomes. This study also provides a mechanistic rationale for targeting HAPLN1 matrikine in MM therapy.
骨髓（BM）微环境对多发性骨髓瘤（MM）细胞的扩散、生长和存活至关重要。骨髓瘤细胞向 BM 龛位的归巢是 MM 扩散的关键步骤，但其中涉及的机制尚不完全清楚。特别是，细胞外基质蛋白衍生的新功能肽——基质细胞衍生因子，其作用仍不清楚。在这里，我们报告了一种源自透明质酸和蛋白聚糖连接蛋白 1（HAPLN1）的基质细胞衍生因子可诱导骨髓瘤细胞与 BM 基质成分（如纤维连接蛋白、内皮细胞和基质细胞）的黏附，并且还诱导它们的趋化和趋动迁移。在小鼠异种移植模型中，我们表明 MM 细胞优先归巢到 HAPLN1 基质细胞衍生因子条件化的 BM 中。转录因子 STAT1 被 HAPLN1 基质细胞衍生因子激活，是诱导 MM 细胞黏附、迁移、迁移相关基因和 BM 归巢所必需的。STAT1 的激活是由 NF-κB 介导的，NF-κB 可在受到 HAPLN1 基质细胞衍生因子刺激后诱导干扰素 β（IFN-β）的产生。最后，我们还提供了证据表明，BM 样本中 HAPLN1 的水平较高与新诊断的 MM 患者无进展生存期较差相关。这些数据表明，BM 微环境中存在的一种基质细胞衍生因子可作为趋化因子，通过 NF-κB-IFN-β-STAT1 信号通路在 MM 细胞向 BM 的归巢中发挥重要作用，并且可能有助于识别预后不良的患者。该研究还为 MM 治疗中靶向 HAPLN1 基质细胞衍生因子提供了机制上的依据。
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