Trick or treat? Does cancer fool Schwann cells by mimicking axons to promote metastasis into nerves?

Abstract

The Schwann cell reaction to nerve injury, termed the repair program, is crucial to successful nerve regeneration. Over the last decade, substantial advances have been made in elucidating the underlying molecular mechanisms in Schwann cells that lead to functional nerve repair. Moreover, the field has identified situations, such as aging and chronic denervation where these mechanisms go awry, paving the way for the development of therapeutic interventions (Arthur-Farraj and Coleman, 2021; Cattin and Lloyd, 2016; Jessen and Mirsky, 2019). A recent article by Deborde et al. (2022) has demonstrated that unfortunately there is a downside to Schwann cells having such an efficient regeneration-promoting program; the promotion of tumor invasion of peripheral nerves. Pancreatic cancer has a very poor prognosis, largely due to its ability to locally metastasize, very often via invasion of peripheral nerves, termed perineural invasion (Bapat et al., 2011). The study by Deborde et al. (2022) builds on previous findings that Schwann cells associate with and induce cancer cell protrusions, leading to enhanced cancer cell invasion in an in vitro model (Deborde et al., 2016). In their most recent publication, they mined sequencing data from 178 patients with pancreatic adenocarcinoma from the cancer genome atlas. They generated human Schwann cell gene signature profiles from two online databases, in addition to utilizing a single nuclei RNA-Seq study of the human pancreas, and then correlated these profiles with clinical outcomes, such as survival and progression-free survival. Not only is a non-myelinating Schwann cell profile correlated with a reduced survival rate in patients with pancreatic adenocarcinoma, but also, remarkably, that high expression of the transcription factor c-JUN, a key factor in regulating the Schwann cell repair program, was also associated with a worse patient prognosis (Arthur-Farraj et al., 2012; Deborde et al., 2022). The non-myelinating signature that Deborde et al. (2022) have used has many similarities with the gene signature of repair Schwann cells, and thus it is possible that many of the Schwann cells present in these tumors are similar to repair Schwann cells (Jessen and Mirsky, 2019). In support of this, immunolabelling in post-mortem specimens of human pancreatic adenocarcinoma demonstrated that Schwann cells near tumor cells expressed higher levels of phosphorylated c-JUN. In a mouse model of perineurial cancer invasion, where Schwann cells are green fluorescent protein labeled, they showed that Schwann cells closest to the tumor upregulate c-JUN, which is normally not expressed in myelinating cells and only lowly expressed in non-myelinating Schwann cells in the uninjured nerve (Jessen and Mirsky, 2019). Furthermore, the coculture of cancer cells with a human Schwann cell line demonstrated an upregulation of genes enriched for a previously identified set of Schwan cell-specific, c-JUN-dependent genes (Arthur-Farraj et al., 2012; Deborde et al., 2022). When Schwann cells interact with tumor cells, they display several fascinating cell behaviors such as wrapping, squeezing, pushing, and pulling of cancer cells to promote metastasis. In three-dimensional co-culture, Schwann cells form tracts, termed tumor activated Schwann cell tracts (TAST), that tumor cells migrate along. Interestingly, when c-JUN is deleted (c-JUN KO) from this human Schwann cell line these cellular behaviors are substantially reduced, and c-JUN KO Schwann cells are unable to form TASTs (Figure 1). Closer analysis of human c-JUN KO Schwann cells demonstrated that they were more rounded in a 3D culture, compared to the more elongated profile of wild-type (WT) Schwann cells. Using atomic force microscopy, the authors showed c-JUN KO Schwann cells were also stiffer and had cortical actin fibers, compared to WT Schwann cells that were more pliable and had typical actin stress fiber arrangements (Deborde et al., 2022). These findings closely resemble the abnormal shape of c-Jun KO Schwann cells in the mouse in vivo after nerve injury and also in cell culture (Arthur-Farraj et al., 2012).Figure 1: Tumor cells help transform Schwann cells into repair-like cells, termed, tumor activated Schwann cells.These Schwann cells wrap and push cancer cells, forming cellular tracts to promote tumor cell perineural invasion. Removal of the transcription factor, c-JUN in Schwann cells prevents the transformation of myelinating and non-myelinating Schwann cells into repair Schwann cells after nerve injury. c-JUN null Schwann cells often cluster together, interact with tumor cells infrequently compared to control cells, and lead to less perineural tumor invasion in an in vivo mouse model. In humans, reduced c-JUN expression in pancreatic adenocarcinoma is correlated with reduced perineural invasion and improved patient survival (Deborde et al., 2022). Created with BioRender.com.The authors then tested the hypothesis that Schwann cell c-JUN regulates the extent of perineural invasion by cancer cells in vivo, by injecting two different cancer cell lines into the sciatic nerve of a Schwann cell-specific KO of c-Jun in mice (P0Cre c-Junflox/flox). They showed that seven days after tumor cell injection, perineural invasion is substantially reduced in P0Cre c-Junflox/flox mice, which translated to improved hindlimb function compared to control animals. Finally, the authors showed that the JNK inhibitor SP600125, injected into mouse sciatic nerves, reproduced similar results in reducing perineural invasion as genetic deletion of c-Jun in Schwann cells. The role of the JNK pathway in the repair Schwann cell response in nerve injury remains unclear. While in vitro evidence is supportive there remains a critical lack of in vivo evidence to demonstrate its role (Jessen and Arthur-Farraj, 2019). However, these findings would suggest that the JNK pathway is likely to have a role in vivo in regulating c-JUN and the repair of Schwann cell transition (Deborde et al., 2022). This paper has wide-ranging implications for the fields of oncology and nerve regeneration. Perineural invasion is a common finding in a number of solid cancers such as pancreatic, stomach, head and neck, breast, biliary tract and prostate cancer, as well as also occurring with lymphoma (Bapat et al., 2011). From an oncological perspective, it now means that therapies directed to modify the Schwann cell repair phenotype could be used to reduce perineural invasion, cancer pain, which often stems from nerve invasion, and even potentially curb mortality (Amit and Maitra, 2022). Aside from the exciting possibility of a new approach to cancer treatment, this paper also sheds light on a new mechanism of how Schwann cells may promote nerve regeneration. Genes associated with axon regeneration were highly enriched in tumor-activated Schwann cells, raising the question if Schwann cells treat cancer cells in a similar way to a regenerating axon? The live imaging of cancer cell and Schwann cell interactions in coculture may suggest that the observed cellular behaviors of wrapping, squeezing, and pushing may resemble how Schwann cells encourage axon regeneration through the Bands of Büngner, in the distal stump of an injured nerve. Thus, this may be another piece in the puzzle of why the axon regeneration deficit, originally observed in the Schwann cell conditional knockout of c-Jun, was so severe (Arthur-Farraj et al., 2012; Fontana et al., 2012). PAF was funded by a Clinical Research Career Development Fellowship from the Wellcome Trust (UK), 206634/Z/17/Z. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. C-Editors: Zhao M, Liu WJ, Li CH; T-Editor: Jia Y