Gong Xiangyu, Ogino Noriyoshi, Leite M Fátima, Zhang Dingyao, Chen Zehua, Nguyen Ryan Y, Liu Raymond, Kruglov Emma, Flores Kaitlin, Cabral Aidan T, Moreira de M Mendes Gabriel, Ehrlich Barbara E, Mak Michael
Yale University, New Haven, Connecticut, United States.
Yale University, United States.
Cancer Res. 2025 May 19. doi: 10.1158/0008-5472.CAN-24-0859.
Physical constraints like compression influence cancer cell invasion and transcriptional dynamics in various tumors. Liver cancer is characterized by the rapid proliferation of tumor cells within a densely packed tissue matrix, subjecting the cancer cells to crowding and compression. The highly dysregulated mechanical environment highlights the need to elucidate the broader impact of compression on liver cancer development and evolution. In this study, we investigated and described a unique adaptive response of liver cells to prolonged compression. Liver cells presented significant transcriptional changes due to compression, including the loss of liver-specific markers and enrichment of epithelial-to-mesenchymal transition genes. Compression elevated Rac1 activity, which promoted cellular protrusions and YAP nuclear translocation and maintained cell viability under mechanical stress. Furthermore, compression disrupted intracellular calcium signaling, leading to resistance to apoptosis. Counteracting the effects of compression by inhibiting Rac1 or manipulating intracellular calcium facilitated death of compression-adapted cells. This study highlights compression as a critical biophysical signal in the tissue microenvironment that can induce cell state transitions and disease-driving phenotypes in the liver.
诸如压缩等物理限制会影响各种肿瘤中的癌细胞侵袭和转录动态。肝癌的特征是肿瘤细胞在密集堆积的组织基质中快速增殖，使癌细胞受到拥挤和压缩。这种高度失调的力学环境凸显了阐明压缩对肝癌发展和演变的更广泛影响的必要性。在本研究中，我们调查并描述了肝细胞对长期压缩的独特适应性反应。由于压缩，肝细胞呈现出显著的转录变化，包括肝特异性标志物的丧失和上皮-间质转化基因的富集。压缩提高了Rac1活性，促进了细胞突起和YAP核转位，并在机械应力下维持细胞活力。此外，压缩破坏了细胞内钙信号传导，导致对凋亡的抵抗。通过抑制Rac1或操纵细胞内钙来抵消压缩的影响，促进了适应压缩的细胞死亡。这项研究强调压缩是组织微环境中的一个关键生物物理信号，可诱导肝脏中的细胞状态转变和疾病驱动表型。
