Compromised nuclear envelope integrity drives TREX1-dependent DNA damage and tumor cell invasion

Nader, Guilherme Pedreira de Freitas; Agüera-González, Sonia; Routet, Fiona; Gratia, Matthieu; Maurin, Mathieu; Cancila, Valeria; Cadart, Clotilde; Palamidessi, Andrea; Ramos, Rodrigo Nalio; Roman, Mabel San; Gentili, Matteo; Yamada, Ayako; Williart, Alice; Lodillinsky, Catalina; Lagoutte, Emilie; Villard, Catherine; Viovy, Jean‐Louis; Tripodo, Claudio; Galon, Jérôme; Scita, Giorgio; Manel, Nicolas; Chavrier, Philippe; Piel, Matthieu

doi:10.1016/j.cell.2021.08.035

Cited by 152 publications

(130 citation statements)

References 64 publications

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“…It is worth noting that while the cell height ceased to further decrease from 400 to 600 Pa, the nuclear area kept increasing when the compression load increased. These data indicate that the compression indeed squeezed the cells and nuclei, which was most likely to alter the membrane tension, impact SACs activity, and thus change the invasion capacity of the cells [ 29 ]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Compression enhances invasive phenotype and matrix degradation of breast cancer cells via Piezo1 activation

Luo

Cai

et al. 2022

BMC Mol and Cell Biol

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Background Uncontrolled growth in solid breast cancer generates mechanical compression that may drive the cancer cells into a more invasive phenotype, but little is known about how such compression affects the key events and corresponding regulatory mechanisms associated with invasion of breast cancer cells including cellular behaviors and matrix degradation. Results Here we show that compression enhanced invasion and matrix degradation of breast cancer cells. We also identified Piezo1 as the putative mechanosensitive cellular component that transmitted compression to not only enhance the invasive phenotype, but also induce calcium influx and downstream Src signaling. Furthermore, we demonstrated that Piezo1 was mainly localized in caveolae, and both Piezo1 expression and compression-enhanced invasive phenotype of the breast cancer cells were reduced when caveolar integrity was compromised by either knocking down caveolin1 expression or depleting cholesterol content. Conclusions Taken together, our data indicate that mechanical compression activates Piezo1 channels to mediate enhanced breast cancer cell invasion, which involves both cellular events and matrix degradation. This may be a critical mechanotransduction pathway during breast cancer metastasis, and thus potentially a novel therapeutic target for the disease.

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Section: Resultsmentioning

confidence: 99%

Compression enhances invasive phenotype and matrix degradation of breast cancer cells via Piezo1 activation

Luo

Cai

et al. 2022

BMC Mol and Cell Biol

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“…This mechanical dysregulation increases the susceptibility of BROX-silenced cells to suffer NERDI and impairs the efficient repair of these ruptures, ultimately compromising genome stability. Intriguingly, haploinsufficiency of BROX is associated with familial non-medullary thyroid cancer ( Pasquali et al., 2021 ); thus, it is conceivable that NE instability associated with BROX deficiencies may contribute to tumor cell invasion ( Nader et al., 2021 ).…”

Section: Discussionmentioning

confidence: 99%

The ESCRT machinery counteracts Nesprin-2G-mediated mechanical forces during nuclear envelope repair

et al. 2021

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Summary Transient nuclear envelope ruptures during interphase (NERDI) occur due to cytoskeletal compressive forces at sites of weakened lamina, and delayed NERDI repair results in genomic instability. Nuclear envelope (NE) sealing is completed by endosomal sorting complex required for transport (ESCRT) machinery. A key unanswered question is how local compressive forces are counteracted to allow efficient membrane resealing. Here, we identify the ESCRT-associated protein BROX as a crucial factor required to accelerate repair of the NE. Critically, BROX binds Nesprin-2G, a component of the linker of nucleoskeleton and cytoskeleton complex (LINC). This interaction promotes Nesprin-2G ubiquitination and facilitates the relaxation of mechanical stress imposed by compressive actin fibers at the rupture site. Thus, BROX rebalances excessive cytoskeletal forces in cells experiencing NE instability to promote effective NERDI repair. Our results demonstrate that BROX coordinates mechanoregulation with membrane remodeling to ensure the maintenance of nuclear-cytoplasmic compartmentalization and genomic stability.

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“…Importantly, NER has been associated with cancer. Recent studies from Nader and coworkers showed the increase in NER at the invasive foci of human breast cancer and colorectal adenocarcinoma [ 50 ]. Moreover, NER has also been observed in vivo in invasive cells and CTC in mice models [ 46 , 47 , 50 ].…”

Section: Mechanical Stress During Metastasismentioning

confidence: 99%

“…The loss of proper nuclear compartmentalization can have drastic consequences in terms of genome evolution. During NER, the unprotected DNA in contact with the cytoplasm can result in DNA breaks [ 46 , 47 , 50 , 51 ] ( Figure 3 ). Indeed, the use of DNA damage markers such as γH2AX and 53BP1 foci revealed important double strand DNA (ds-DNA) breaks in the constricted nuclei during migration through narrow areas [ 46 , 47 , 50 , 51 , 52 ].…”

Section: Consequences Of Nuclear Envelope Rupture On Tumor Genomic Heterogeneitymentioning

confidence: 99%

“…During NER, the unprotected DNA in contact with the cytoplasm can result in DNA breaks [ 46 , 47 , 50 , 51 ] ( Figure 3 ). Indeed, the use of DNA damage markers such as γH2AX and 53BP1 foci revealed important double strand DNA (ds-DNA) breaks in the constricted nuclei during migration through narrow areas [ 46 , 47 , 50 , 51 , 52 ]. Importantly, nuclear compression and deformation, even in the absence of NER, leads to increased replication stress in the S/G2 phase and provokes DNA breaks [ 51 ].…”

Section: Consequences Of Nuclear Envelope Rupture On Tumor Genomic Heterogeneitymentioning

confidence: 99%

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Physical Forces and Transient Nuclear Envelope Rupture during Metastasis: The Key for Success?

Gauthier

Lorenzo

Comaills

2021

Cancers

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During metastasis, invading tumor cells and circulating tumor cells (CTC) face multiple mechanical challenges during migration through narrow pores and cell squeezing. However, little is known on the importance and consequences of mechanical stress for tumor progression and success in invading a new organ. Recently, several studies have shown that cell constriction can lead to nuclear envelope rupture (NER) during interphase. This loss of proper nuclear compartmentalization has a profound effect on the genome, being a key driver for the genome evolution needed for tumor progression. More than just being a source of genomic alterations, the transient nuclear envelope collapse can also support metastatic growth by several mechanisms involving the innate immune response cGAS/STING pathway. In this review we will describe the importance of the underestimated role of cellular squeezing in the progression of tumorigenesis. We will describe the complexity and difficulty for tumor cells to reach the metastatic site, detail the genomic aberration diversity due to NER, and highlight the importance of the activation of the innate immune pathway on cell survival. Cellular adaptation and nuclear deformation can be the key to the metastasis success in many unsuspected aspects.

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Compromised nuclear envelope integrity drives TREX1-dependent DNA damage and tumor cell invasion

Cited by 152 publications

References 64 publications

Compression enhances invasive phenotype and matrix degradation of breast cancer cells via Piezo1 activation

Compression enhances invasive phenotype and matrix degradation of breast cancer cells via Piezo1 activation

The ESCRT machinery counteracts Nesprin-2G-mediated mechanical forces during nuclear envelope repair

Physical Forces and Transient Nuclear Envelope Rupture during Metastasis: The Key for Success?

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