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 11

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

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NCAM1 expression by Schwann cells promotes cancer cell invasion in vivo....
(A) Histological analysis of injected murine sciatic nerves in WT and NCAM1 KO mice showing longer lengths of nerve invasion in WT mice. Representative samples of cancer cell invasion detected by analysis of H&E staining in WT and NCAM1 KO mice. White arrows indicate the site of injection and proximal side of spinal cord. The black arrows indicate the length of invasion with corresponding values (mm). Scale bar: 5 mm (top images) and 0.2 mm (bottom images). Quantification of nerve invasion, as measured by length and area of invasion. Data represent mean ± SD. **P < 0.005, ***P < 0.0005, t test, n = 8 (NCAM1 WT), n = 7 (NCAM1 KO). (B) GFAP immunofluorescence staining in WT and NCAM1 KO murine sciatic nerves injected with Panc02-H7 cells was similar. Scale bar: 100 μm. Quantification of the average intensity of GFAP fluorescence did not show a statistically significant difference between WT and NCAM1 KO sections. t test, n = 20 (WT), n = 11 (NCAM1 KO). Data represent mean ± SEM. (C) Reduction of perineural invasion in an in vivo assay. Representative images of mouse legs after Panc02-H7 cancer cell injection showing less paralysis in NCAM1 KO mice. In WT mice, injection induced paralysis compared with noninjected leg. Injected NCAM1 KO mice show a reduced paralysis compared with WT mice. Quantification of sciatic nerve function in WT noninjected (WT PBS), WT injected (WT Panc02-H7), and NCAM1 KO injected (NCAM1 KO Panc02-H7) mice. Data represent mean ± SEM. **P < 0.01, ****P < 0.0001, 1-way ANOVA with Holm-Sidak’s multiple comparisons test, n = 10 per condition.