Schwann cells induce cancer cell dispersion and invasion
Sylvie Deborde, Tatiana Omelchenko, Anna Lyubchik, Yi Zhou, Shizhi He, William F. McNamara, Natalya Chernichenko, Sei-Young Lee, Fernando Barajas, Chun-Hao Chen, Richard L. Bakst, Efsevia Vakiani, Shuangba He, Alan Hall, Richard J. Wong
Sylvie Deborde, Tatiana Omelchenko, Anna Lyubchik, Yi Zhou, Shizhi He, William F. McNamara, Natalya Chernichenko, Sei-Young Lee, Fernando Barajas, Chun-Hao Chen, Richard L. Bakst, Efsevia Vakiani, Shuangba He, Alan Hall, Richard J. Wong
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Research Article Cell biology Oncology

Schwann cells induce cancer cell dispersion and invasion

Abstract

Nerves enable cancer progression, as cancers have been shown to extend along nerves through the process of perineural invasion, which carries a poor prognosis. Furthermore, the innervation of some cancers promotes growth and metastases. It remains unclear, however, how nerves mechanistically contribute to cancer progression. Here, we demonstrated that Schwann cells promote cancer invasion through direct cancer cell contact. Histological evaluation of murine and human cancer specimens with perineural invasion uncovered a subpopulation of Schwann cells that associates with cancer cells. Coculture of cancer cells with dorsal root ganglion extracts revealed that Schwann cells direct cancer cells to migrate toward nerves and promote invasion in a contact-dependent manner. Upon contact, Schwann cells induced the formation of cancer cell protrusions in their direction and intercalated between the cancer cells, leading to cancer cell dispersion. The formation of these processes was dependent on Schwann cell expression of neural cell adhesion molecule 1 (NCAM1) and ultimately promoted perineural invasion. Moreover, NCAM1-deficient mice showed decreased neural invasion and less paralysis. Such Schwann cell behavior reflects normal Schwann cell programs that are typically activated in nerve repair but are instead exploited by cancer cells to promote perineural invasion and cancer progression.

Authors

Sylvie Deborde, Tatiana Omelchenko, Anna Lyubchik, Yi Zhou, Shizhi He, William F. McNamara, Natalya Chernichenko, Sei-Young Lee, Fernando Barajas, Chun-Hao Chen, Richard L. Bakst, Efsevia Vakiani, Shuangba He, Alan Hall, Richard J. Wong

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Figure 9

NCAM1 expression by Schwann cells promotes cancer cell invasion in vitro.

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NCAM1 expression by Schwann cells promotes cancer cell invasion in vitro...
(A) NCAM1 depletion in Schwann cells (HEI-286). Western blot analysis in control (shC) and NCAM1 shRNA–expressing cells. NCAM1 was strongly depleted in cell lines infected with sh 1 and sh 2 constructs and mildly depleted with sh 3. (B and C) NCAM1 depletion reduced cancer cell invasion. Representative Z-stacks of confocal images and quantification showing cancer cell invasion in control shRNA– and NCAM1 shRNA1–expressing Schwann cells. n = 16 (shC), n = 8 (sh 1), n = 20 (sh 2), n = 8 (sh 3). Scale bar: 200 μm. (D and E) Cancer cell invasion rescue in NCAM1-depleted cells with chicken NCAM1-GFP expression. Western blot analysis in control cells (shC), NCAM1-depleted cells (sh 1, sh 2), and NCAM1-depleted cells plus chicken GFP-NCAM1 (Rsh 1, Rsh 2). Quantification of cancer cell invasion in presence of control Schwann cells (shC), NCAM1-depleted Schwann cells (sh 2), and NCAM1-depleted Schwann cells expressing chicken NCAM1 (Rsh 2). n = 16 (shC), n = 20 (sh 2), n = 8 (Rsh 2). (F) NCAM1-depleted Schwann cells are less efficient than control Schwann cells in reorganizing circular cancer cell cluster. Quantification of reorganization of cancer cell clusters contacting control Schwann cells or NCAM1-depleted Schwann cells (sh 2) or in absence of Schwann cells (no HEI) using shape factor index. n = 15 (shC), n = 16 (sh 2). (G) NCAM1-depleted Schwann cells are less efficient than control Schwann cells in inducing cancer cell protrusions. n = 4 experiments with >45 contacts/experiment/condition. (H) Upon contact with NCAM1-depleted Schwann cells, cancer cells develop protrusions with a defect in their directionality. Images from time-lapse videos and Rose diagrams showing quantification of directionality of cancer protrusions (arrows) after contact with Schwann cell as done in Figure 5 (n = 9 cells). Times are shown as hours and minutes. Scale bar: 20 μm. Data represent mean ± SEM. *P < 0.05,***P < 0.0001, ****P < 0.0001, t test (G) or 1-way ANOVA with Holm-Sidak’s multiple comparisons test (C, E, and F).