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Anastasis confers ovarian cancer cells increased malignancy through elevated p38 MAPK activation

Abstract

Activation of executioner caspases was once considered as a point of no return in apoptosis. However, in recent years, accumulating evidence has demonstrated that cells can survive executioner caspase activation in response to apoptotic stimuli through a process called anastasis. In this study, we developed a reporter system, mCasExpress, to track mammalian cells that survive executioner caspase activation. We demonstrate that anastatic ovarian cancer cells acquire enhanced migration following their transient exposure to apoptotic stimulus TRAIL or Paclitaxel. Moreover, anastatic cancer cells secrete more pro-angiogenic factors that enable tumor angiogenesis, growth and metastasis. Mechanistically, we demonstrate that activation of p38 MAPK, which occurs in a caspase-dependent manner in response to apoptotic stress to promote anastasis, persists at a higher level in anastatic cancer cells even after removal of apoptotic stimuli. Importantly, p38 is essential for the elevated migratory and angiogenic capacity in the anastatic cells. Our work unveils anastasis as a potential driver of tumor angiogenesis and metastasis.

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Fig. 1: HEY cells undergo anastasis after TRAIL or Paclitaxel (PTX) treatment.
Fig. 2: Anastasis enriches transcriptome in migration and angiogenesis and renders ovarian cancer cells more migratory.
Fig. 3: Anastatic HEY cells secrete more pro-angiogenic factors.
Fig. 4: Tumors formed by anastatic ovarian cancer cells exhibit enhanced growth and angiogenesis.
Fig. 5: Anastatic HEY cells exhibit elevated in vivo metastasis.
Fig. 6: The enhanced angiogenic capacity in the anastatic HEY cells depends on elevated p38 activity.
Fig. 7: p38 is activated by caspases during apoptosis induction and early recovery.
Fig. 8: p38 activation during apoptosis induction and recovery is required for anastasis.

Data availability

The raw data for RNAseq can be assessed at PRJNA798831. All the other raw data supporting the findings of this study are available from the corresponding author upon request. Original Western blots are provided with this paper.

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Acknowledgements

We thank Translational Medicine Core Facility of Shandong University for technical support.

Funding

This work was supported by National Natural Science Foundation of China (No. 31970781 and 81902837), Rongxiang Regenerative Medicine Foundation of Shandong University (No. 2019SDRX-06) and the Funds for Youth Interdisciplinary and Innovation Research Group of Shandong University (2020QNQT003) to GS.

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GS and LS designed the experiments. LS, YC, XL, YW, and RW carried out the experiments. GS, LS, DJM, CS, YG, MW, and QL prepared the manuscript.

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Correspondence to Gongping Sun.

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The research was approved by the Animal Care and Use Committee of Shandong University.

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Sun, L., Yao, C., Li, X. et al. Anastasis confers ovarian cancer cells increased malignancy through elevated p38 MAPK activation. Cell Death Differ (2022). https://doi.org/10.1038/s41418-022-01081-1

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