骨髓来源的髓样肿瘤融合细胞对前列腺癌骨转移进展的影响

前列腺癌（PCa）是男性中最常见的恶性肿瘤之一。肿瘤转移是造成前列腺癌患者死亡最主要的原因，其中骨是前列腺癌最好发的转移部位。目前针对前列腺癌晚期骨转移的患者仍然没有有效的治疗手段。散播肿瘤细胞（DTCs）可以在骨髓腔中保持休眠状态来对化疗和放疗产生逃逸，是造成治疗失败和癌症复发的主要原因之一。在形成骨转移的过程中，散播肿瘤细胞（DTCs）往往能获得新的特性。因此，进一步探究和了解骨髓腔中散播肿瘤细胞（DTCs）的性质和状态对于我们开发新的针对骨转移的治疗方案至关重要。

在本研究中，我们首先通过对GEO数据库中前列腺癌患者骨转移样本单细胞转录组测序数据进行分析，发现了一群特殊的高表达髓系细胞标志物的散播肿瘤细胞（DTCs），我们将它命名为髓样肿瘤细胞，并且在这群细胞中富集到了许多与免疫调节和肿瘤发展相关的信号通路。因此，我们推测这群髓样肿瘤细胞可能在前列腺癌的发展中发挥重要的作用。我们通过尾动脉注射小鼠前列腺癌细胞RM1的方式构建了小鼠骨转移模型，发现散播肿瘤细胞与骨髓细胞融合是这群髓样肿瘤细胞的来源之一。我们通过多组学分析的方法比较了髓样肿瘤融合细胞与亲本RM1细胞之间的差异，发现它在细胞增殖和细胞粘附方面与亲本细胞之间存在巨大的差异，并且通过体内动物实验也进一步证明了髓样肿瘤融合细胞具有更强的增殖能力和转移能力。我们还通过单细胞测序分析了髓样肿瘤融合细胞对免疫微环境的影响，发现髓样肿瘤融合细胞形成的肿瘤中含有更多的N2型肿瘤相关中性粒细胞（N2 TANs），并且肿瘤中的中性粒细胞、单核细胞和巨噬细胞呈现出更强的免疫抑制表型。我们通过质谱流式分析髓样肿瘤融合细胞对骨髓微环境的影响，发现髓样肿瘤融合细胞能诱导更多巨噬细胞的产生，并且可以诱导巨噬细胞中M2型巨噬细胞标志物Arg1的高表达。此外，我们发现髓样肿瘤融合细胞表现出更高的上皮间充质转化（EMT）的表型，在体内具有更好的成瘤能力。髓样肿瘤融合细胞还表现出对化疗药物多烯紫杉醇和铁死亡诱导剂的抗性，但是对放疗依然十分敏感。

综上所述，本研究发现骨髓来源的髓样肿瘤融合细胞具有更强的成瘤能力、转移能力，能够诱导更强的免疫抑制的肿瘤微环境，并且能对化疗产生抗性。因此，髓样肿瘤融合细胞在前列腺癌骨转移的进展中发挥重要的作用，有望成为前列腺癌临床治疗新的靶点。

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