Bashtanova Uliana, Kuraite Agne, Rajan Rakesh, Duer Melinda
Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.
R Soc Open Sci. 2025 Aug 27;12(8):251036. doi: 10.1098/rsos.251036. eCollection 2025 Aug.
Extracellular hyaluronic acid (HA) has been shown to be important in cancer; low-molecular-weight HA typically correlates with cancer progression, high-molecular-weight HA with homeostasis. Here we show that even high-molecular-weight HA can induce cancer cell migration when it is highly diluted. HA-induced cell signalling is primarily through HA binding to the cell surface receptor, CD44. We show by NMR spectroscopy that at high dilution, high-molecular-weight HA molecules access the conformations needed for strong binding to CD44 on the tens of nanosecond time scale, the relevant time scale for induction of CD44 signalling. We further show that, by contrast, at higher concentrations, high-molecular-weight HA molecules have insufficient flexibility for strong CD44 binding. The high dilution HA condition correlates with profound changes in brain cancer cell morphology and proteome which supports cancer cell invasion. We hypothesize that the flexibility of HA molecules is central to HA-mediated cell signalling and that this concept can explain previous observations that the outcome of HA-mediated signalling depends on the HA molecular weight. HA dilution leading to stronger HA signalling may be important in understanding the role that oedema plays in cancer recurrence after primary surgery.
细胞外透明质酸（HA）已被证明在癌症中具有重要作用；低分子量HA通常与癌症进展相关，而高分子量HA与体内平衡相关。在此我们表明，即使是高分子量HA在高度稀释时也能诱导癌细胞迁移。HA诱导的细胞信号传导主要是通过HA与细胞表面受体CD44结合。我们通过核磁共振光谱表明，在高度稀释时，高分子量HA分子在数十纳秒的时间尺度上能够获得与CD44紧密结合所需的构象，这是诱导CD44信号传导的相关时间尺度。我们进一步表明，相比之下，在较高浓度下，高分子量HA分子缺乏足够的灵活性来与CD44紧密结合。高度稀释的HA条件与脑癌细胞形态和蛋白质组的深刻变化相关，这些变化支持癌细胞侵袭。我们推测，HA分子的灵活性是HA介导的细胞信号传导的核心，这一概念可以解释先前的观察结果，即HA介导的信号传导结果取决于HA分子量。HA稀释导致更强HA信号传导可能对于理解水肿在初次手术后癌症复发中所起的作用很重要。
