Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA.
Sci Adv. 2020 Jan 22;6(4):eaax5611. doi: 10.1126/sciadv.aax5611. eCollection 2020 Jan.
Dysregulated physical stresses are generated during tumorigenesis that affect the surrounding compliant tissues including adipocytes. However, the effect of physical stressors on the behavior of adipocytes and their cross-talk with tumor cells remain elusive. Here, we demonstrate that compression of cells, resulting from various types of physical stresses, can induce dedifferentiation of adipocytes via mechanically activating Wnt/β-catenin signaling. The compression-induced dedifferentiated adipocytes (CiDAs) have a distinct transcriptome profile, long-term self-renewal, and serial clonogenicity, but do not form teratomas. We then show that CiDAs notably enhance human mammary adenocarcinoma proliferation both in vitro and in a xenograft model, owing to myofibrogenesis of CiDAs in the tumor-conditioned environment. Collectively, our results highlight unique physical interplay in the tumor ecosystem; tumor-induced physical stresses stimulate de novo generation of CiDAs, which feedback to tumor growth.
在肿瘤发生过程中会产生失调的物理应激，影响周围的顺应性组织，包括脂肪细胞。然而，物理应激对脂肪细胞行为的影响及其与肿瘤细胞的串扰仍然难以捉摸。在这里，我们证明，由于各种类型的物理应激导致的细胞压缩可以通过机械激活 Wnt/β-catenin 信号诱导脂肪细胞去分化。压缩诱导的去分化脂肪细胞（CiDAs）具有独特的转录组特征、长期自我更新和连续克隆性，但不会形成畸胎瘤。然后，我们发现 CiDAs 显著增强了体外和异种移植模型中人类乳腺腺癌的增殖，这归因于 CiDAs 在肿瘤条件性环境中的成肌纤维分化。总的来说，我们的结果强调了肿瘤生态系统中独特的物理相互作用；肿瘤诱导的物理应激刺激 CiDAs 的新生生成，这反过来又反馈到肿瘤生长。
