Acral melanoma commonly occurs in areas that are not exposed to much sunlight, such as the sole of the foot. Little is known about risk factors and mutational processes of plantar acral melanoma. Nuclear envelope rupture during interphase contributes to genome instability in cancer. Here, we show that the nuclear and micronuclear membranes of melanoma cells are frequently ruptured by macroscopic mechanical stress on the plantar surface due to weight-bearing activities. The marginal region of plantar melanoma nodules exhibits increased nuclear morphological abnormalities and collagen accumulations, and is more susceptible to mechanical stress than the tumor center. An increase in DNA damage coincides with nuclear membrane rupture in the tumor margin. Nuclear envelope integrity is compromised by the mechanosensitive transcriptional cofactor YAP activated in the tumor margin. Our results suggest a mutagenesis mechanism in melanoma and explain why plantar acral melanoma is frequent at higher mechanical stress points.
|Publication status||Published - 2022 Dec|
Bibliographical noteFunding Information:
We thank the members of the J.K. lab for critical discussions. We would also like to thank M.Y.K. for schematic drawings and Dr. Yongsuk Hur of the KAIST BioMedical Research Center for helping with the preparation and acquisition of TEM images. Funding: This study was supported by the National Research Foundation of Korea Grant funded by the Korean Ministry of Science and ICT: 2020R1A2C3007748 to J.K., 2020R1A2C1102987 to K.Y.C., and 2021R1A4A1032094 to J.K.
© 2022, The Author(s).
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)