Coy Shannon, Cheng Brian, Lee Jong Suk, Rashid Rumana, Browning Lindsay, Xu Yilin, Chakrabarty Sankha S, Yapp Clarence, Chan Sabrina, Tefft Juliann B, Scott Emily, Spektor Alexander, Ligon Keith L, Baker Gregory J, Pellman David, Sorger Peter K, Santagata Sandro
Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.
Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
bioRxiv. 2023 Nov 11:2023.11.07.566063. doi: 10.1101/2023.11.07.566063.
Nuclear atypia, including altered nuclear size, contour, and chromatin organization, is ubiquitous in cancer cells. Atypical primary nuclei and micronuclei can rupture during interphase; however, the frequency, causes, and consequences of nuclear rupture are unknown in most cancers. We demonstrate that nuclear envelope rupture is surprisingly common in many human cancers, particularly glioblastoma. Using highly-multiplexed 2D and super-resolution 3D-imaging of glioblastoma tissues and patient-derived xenografts and cells, we link primary nuclear rupture with reduced lamin A/C and micronuclear rupture with reduced lamin B1. Moreover, ruptured glioblastoma cells activate cGAS-STING-signaling involved in innate immunity. We observe that local patterning of cell states influences tumor spatial organization and is linked to both lamin expression and rupture frequency, with neural-progenitor-cell-like states exhibiting the lowest lamin A/C levels and greatest susceptibility to primary nuclear rupture. Our study reveals that nuclear instability is a core feature of cancer, and links nuclear integrity, cell state, and immune signaling.
核异型性，包括核大小、轮廓和染色质组织的改变，在癌细胞中普遍存在。非典型的初级细胞核和微核在间期可能破裂；然而，在大多数癌症中，核破裂的频率、原因和后果尚不清楚。我们证明核膜破裂在许多人类癌症中惊人地常见，尤其是胶质母细胞瘤。通过对胶质母细胞瘤组织、患者来源的异种移植瘤和细胞进行高度多重的二维和超分辨率三维成像，我们将初级核破裂与核纤层蛋白A/C减少联系起来，将微核破裂与核纤层蛋白B1减少联系起来。此外，破裂的胶质母细胞瘤细胞激活参与先天免疫的cGAS-STING信号通路。我们观察到细胞状态的局部模式影响肿瘤的空间组织，并与核纤层蛋白表达和破裂频率相关，神经祖细胞样状态表现出最低的核纤层蛋白A/C水平和对初级核破裂的最大易感性。我们的研究表明，核不稳定性是癌症的核心特征，并将核完整性、细胞状态和免疫信号联系起来。
