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Simulated microgravity increases polyploid giant cancer cells and nuclear localization of YAP.

ABSTRACT: Physical cues are vital in determining cellular fate in cancer. In vitro 3D culture do not replicate forces present in vivo. These forces including tumor interstitial fluid pressure and matrix stiffness behave as switches in differentiation and metastasis, which are intricate features of cancer stem cells (CSCs). Gravity determines the effect of these physical factors on cell fate and functions as evident from microgravity experiments on space and ground simulations. Here, we described the role of simulation of microgravity (SMG) using rotary cell culture system (RCCS) in increasing stemness in human colorectal cancer cell HCT116. We observed distinct features of cancer stem cells including CD133/CD44 dual positive cells and migration in SMG which was not altered by autophagy induction or inhibition. 3D and SMG increased autophagy, but the flux was staggered under SMG. Increased unique giant cancer cells housing complete nuclear localization of YAP were observed in SMG. This study highlights the role of microgravity in regulating stemness in CSC and importance of physical factors in determining the same.

SUBMITTER: Arun RP

PROVIDER: S-EPMC6650394 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Simulated microgravity increases polyploid giant cancer cells and nuclear localization of YAP.

Arun Raj Pranap RP Sivanesan Divya D Patra Bamadeb B Varadaraj Sudha S Verma Rama Shanker RS

Scientific reports 20190723 1

Physical cues are vital in determining cellular fate in cancer. In vitro 3D culture do not replicate forces present in vivo. These forces including tumor interstitial fluid pressure and matrix stiffness behave as switches in differentiation and metastasis, which are intricate features of cancer stem cells (CSCs). Gravity determines the effect of these physical factors on cell fate and functions as evident from microgravity experiments on space and ground simulations. Here, we described the role ...[more]

PMID: 31337825

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Project description:BackgroundPolyploid giant cancer cells (PGCCs), a specific type of cancer stem cells (CSCs), can be induced by hypoxic microenvironments, chemical reagents, radiotherapy, and Chinese herbal medicine. Moreover, PGCCs can produce daughter cells that undergo epithelial-mesenchymal transition, which leads to cancer recurrence and disseminated metastasis. Vimentin, a mesenchymal cell marker, is highly expressed in PGCCs and their daughter cells (PDCs) and drives migratory persistence. This study explored the molecular mechanisms by which vimentin synergistically regulates PGCCs to generate daughter cells with enhanced invasive and metastatic properties.MethodsArsenic trioxide (ATO) was used to induce the formation of PGCCs in Hct116 and LoVo cells. Immunocytochemical and immunohistochemical assays were performed to determine the subcellular localization of vimentin. Cell function assays were performed to compare the invasive metastatic abilities of the PDCs and control cells. The molecular mechanisms underlying vimentin expression and nuclear translocation were investigated by real-time polymerase chain reaction, western blotting, cell function assays, cell transfection, co-immunoprecipitation, and chromatin immunoprecipitation, followed by sequencing. Finally, animal xenograft experiments and clinical colorectal cancer samples were used to study vimentin expression in tumor tissues.ResultsDaughter cells derived from PGCCs showed strong proliferative, migratory, and invasive abilities, in which vimentin was highly expressed and located in both the cytoplasm and nucleus. Vimentin undergoes small ubiquitin-like modification (SUMOylation) by interacting with SUMO1 and SUMO2/3, which are associated with nuclear translocation. P62 regulates nuclear translocation of vimentin by controlling SUMO1 and SUMO2/3 expression. In the nucleus, vimentin acts as a transcription factor that regulates CDC42, cathepsin B, and cathepsin D to promote PDC invasion and migration. Furthermore, animal experiments and human colorectal cancer specimens have confirmed the nuclear translocation of vimentin.ConclusionP62-dependent SUMOylation of vimentin plays an important role in PDC migration and invasion. Vimentin nuclear translocation and overexpressed P62 of cancer cells may be used to predict patient prognosis, and targeting vimentin nuclear translocation may be a promising therapeutic strategy for metastatic cancers.

Project description:Our recent perplexing findings that polyploid giant cancer cells (PGCCs) acquired embryonic-like stemness and were capable of tumor initiation raised two important unanswered questions: how do PGCCs acquire such stemness, and to which stage of normal development do PGCCs correspond. Intriguingly, formation of giant cells due to failed mitosis/cytokinesis is common in the blastomere stage of the preimplantation embryo. However, the relationship between PGCCs and giant blastomeres has never been studied. Here, we tracked the fate of single PGCCs following paclitaxel-induced mitotic failure. Morphologically, early spheroids derived from PGCCs were indistinguishable from human embryos at the blastomere, polyploid blastomere, compaction, morula and blastocyst-like stages by light, scanning electron or three-dimensional confocal scanning microscopy. Formation of PGCCs was associated with activation of senescence, while budding of daughter cells was associated with senescence escape. PGCCs showed time- and space-dependent activation of expression of the embryonic stem cell markers OCT4, NANOG, SOX2 and SSEA1 and lacked expression of Xist. PGCCs acquired mesenchymal phenotype and were capable of differentiation into all three germ layers in vitro. The embryonic-like stemness of PGCCs was associated with nuclear accumulation of YAP, a key mediator of the Hippo pathway. Spheroids derived from single PGCCs grew into a wide spectrum of human neoplasms, including germ cell tumors, high-grade and low-grade carcinomas and benign tissues. Daughter cells derived from PGCCs showed attenuated capacity for invasion and increased resistance to paclitaxel. We also observed formation of PGCCs and dedifferentiation in ovarian cancer specimens from patients treated with chemotherapy. Taken together, our findings demonstrate that PGCCs represent somatic equivalents of blastomeres, the most primitive cancer stem cells reported to date. Thus, our studies reveal an evolutionarily conserved archaic embryonic program in somatic cells that can be de-repressed for oncogenesis. Our work offers a new paradigm for cancer origin and disease relapse.

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Simulated microgravity increases polyploid giant cancer cells and nuclear localization of YAP.

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Simulated microgravity increases polyploid giant cancer cells and nuclear localization of YAP.

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