The Boring Schwann Cells: Tumor Me-TAST-asis along Nerves

Solid cancers mainly disseminate from their primary anatomic sites of origin in three ways: direct invasion into contiguous structures, lymphatic spread, and hematogenous spread (1). The overwhelming majority of patients with pancreatic ductal adenocarcinoma (PDAC) present with locally advanced and distant metastatic disease (2), with one or more of the three main avenues of dissemination accounting for the egress of cancer cells outside the pancreas. However, cancer can also spread via a fourth way that is frequently disregarded: dissemination along nerves. Cancer perineural invasion (CPNI) is commonly observed in neurotropic cancers, including PDAC and head and neck cancer; CPNI is an adverse pathologic feature that adversely affects survival, and, in many cases, its presence is an indication for treatment escalation. CPNI has been implicated both to have a role in the debilitating pain that many patients present with and to be a facile pathway for the migration of cancer cells (3). Thus far, the conventional assumption has been that CPNI results from “passive” cancer dissemination via the path of least resistance. However, recent studies have unveiled the mechanisms underlying this highly orchestrated process and shown that specific molecular signals in the perineural microenvironment can induce cancer dissemination along nerves (4, 5). In contrast, the physical interactions between cancer cells and neurons within a tumor's neural microenvironment are less well understood. Unlike blood and lymphatic vessels, peripheral nerves are dense and have no lumina. Therefore, substantial extracellular matrix rearrangements are required for cancer cells to propel along a nerve fiber. Deborde and colleagues revealed how tumors hijack supporting cells surrounding nerve fibers (i.e., Schwann cells) to carve their paths within the nerve matrix.

The interplay between cancer cells and neurons has negative clinical consequences for patients with solid cancers, including PDAC. For example, numerous studies have highlighted the relationship between the presence of CPNI in patients with PDAC and subsequent adverse outcomes (5–7). This is the basis for routine reporting of the presence or absence of CPNI in surgically resected samples of PDAC as well as other solid cancers. However, actionable targets for altering the neurobiology of cancer to inhibit CPNI or tumor progression have yet to be identified. Deborde and colleagues took on the challenge of identifying these targets by focusing on Schwann cells (8). The Schwann cell is the major glial cell type in the peripheral nervous system. These cells play essential roles in the development, maintenance, function, and regeneration of peripheral nerves. With nerve injury, such as that occurring in patients with cancer, Schwann cells become activated (i.e., nonmyelinating, GFAP⁺). By analyzing data on tumor samples from patients with PDAC, the authors found that patients with tumors with nonmyelinating Schwann cell signature enrichment had shorter survival than did those without tumors with this enrichment. Moreover, enrichment in the nonmyelinating Schwann cell signature correlated with multiple pathways related to cancer invasion, such as epithelial–mesenchymal transition.

Through analysis of human samples of PDAC and animal and in vitro 3D models of CPNI, Deborde and colleagues showed that nonmyelinating Schwann cells are closely associated with cancer cells within the perineural space and actually pave the way for cancer cells to propel within neurons (8). Activated Schwann cells enable this via (i) creation of tracks for migration within the nerve, which the authors named tumor-activated Schwann cell tracks (TAST), and (ii) reorganization of cancer cells into chains (Fig. 1). On the basis of their mechanistic studies as well as pathologic analysis of neural niches (invaded and noninvaded) within human samples of PDAC, the authors proposed that cancer cells migrate within microchannels lined by activated Schwann cells. Analogous to neoangiogenesis, in which cancer cells release factors that elicit the growth of blood vessels into a tumor, the interaction of PDAC cells with neighboring Schwann cells induces the reprogramming of Schwann cells into an “injury-like” state that promotes both TAST formation and CPNI.

Although a putative role for Schwann cells in enabling cancer progression is not entirely new (9), the formation of TASTs by reprogrammed Schwann cells has yet to be described. In this study, Deborde and colleagues not only identified TASTs but also unraveled the fascinating mechanobiology behind how these newly identified tracks facilitate cancer cell migration. Using time-lapse microscopy and particle image velocimetry, the authors discovered that activated Schwann cells within TASTs generate a propulsive wave that propagates toward its contact point with a static cancer cell. The wave then creates a Schwann cell protrusion at the site of contact, which propels cancer cells away from the Schwann cells. Moreover, particle image velocimetry analysis of both cancer and Schwann cells showed that Schwann cells also squeeze and pull cancer cells along the nerve fiber. In an effort to identify the regulators of this mechanical activation, the authors used lineage tracking with a mouse model of PDAC. This analysis revealed c-Jun activation specifically in Schwann cells in proximity to cancer cells. Physiologically, the transcription factor c-Jun is activated by N-terminal kinase–mediated phosphorylation, and both c-Jun and ATF3 are upregulated in neurons and Schwann cells after nerve injury. The authors demonstrated in ex vivo models that cancer cells can activate c-Jun and, through this process, reprogram Schwann cells. This reprogramming leads to enhanced motility and, moreover, changes in the physical properties of these active Schwann cells. Using atomic force microscopy, the authors showed that activated Schwann cells are softer than myelinating Schwann cells, with rearranged actin organization that facilitates improved passage of cancer cells. This is the first report demonstrating that Schwann cells, which have conventionally been attributed as having a trophic and protective function, are active participants in the formation of tunnels (i.e., TASTs) for cancer cells to move within nerves.

The formation of these intraneural tunnels, along with the discovery of the motor capacity of reprogrammed Schwann cells to serve as rear- or front-wheel drive for cancer cell propagation within the nerve, under the regulation of c-Jun, represents a highly innovative biophysical coupling concept in cancer progression. Of note, previous studies of CPNI focused on the endogenous motility of cancer cells. Deborde and colleagues raised the question of whether cancer migratory properties result from the ability of cancer to reprogram and harness cellular components in the tumor microenvironment (8). The authors’ findings are of particular interest because these insights may offer a way to combat tumor-driven Schwann cell activation and counteract the tumor-promoting effects of Schwann cells. An important step will be to establish whether the contribution of Schwann cells to tumor growth is limited to just PDAC or is a generalized feature of other solid cancers, as suggested by the prevalence of CPNI and nerve injury in patients with other tumors, such as head and neck and prostate cancers.

Three important caveats must be emphasized regarding the mechanistic and translational state of cancer neuroscience. First, whereas the role of c-Jun in enabling Schwann cell reprogramming and TAST formation was convincingly demonstrated in this study, notably, the authors and others have reported that additional mediators are implicated to have a role in the “PDAC–Schwann cell interactome,” including neural cell adhesion molecule 1, L1 cell adhesion molecule, and transforming growth factor beta (10–12). Whether any of these mediators also play a permissive role in TAST formation remains to be determined. Second, the paracrine mediator or mediators in neighboring PDAC cells that instigate Schwann cell reprogramming remain to be identified. Identifying these mediators is crucial, as they may be targets for intercepting Schwann cell reprogramming and TAST genesis. Third, because nonmyelinating Schwann cell signatures correlate with adverse prognosis in correlative data sets like The Cancer Genome Atlas, the next imperative step in translating the authors’ findings is to confirm whether the abrogation of TAST formation in biologically relevant in vivo models of CPNI is clinically actionable and results in improved survival—the “holy grail” of clinical efforts in PDAC research.

The discovery that c-Jun activation in Schwann cells by neighboring cancer cells influences the formation of intraneural tunnels for migration of cancer cells along nerve fibers may have relevance for interpreting reports that fluctuations in the levels of nerve injury are associated with the extent of CPNI observed in patients with neurotropic cancers. Thus, the findings reported by Deborde and colleagues may have repercussions that reach beyond cancer research to the burgeoning field of cancer neuroscience. Perhaps therapies that modulate the activity of Schwann cells in response to nerve injury will eventually have a role in aiding the repair or regeneration of neurons, an outcome that would make a profound positive difference in the lives of people who have neurodegenerative diseases or other types of nerve injury.

M. Amit reports grants from the NIH/NCI outside the submitted work. A. Maitra reports other support from Cosmos Wisdom Biotechnology and Thrive Earlier Detection (Exact Sciences), and personal fees from Freenome and Tezcat Biotech outside the submitted work.

This study was supported by the Khalifa bin Zayed Al Nahyan Foundation (to A. Maitra) and the NCI/NIH (R37 CA242006 award to M. Amit). We thank Mr. David Aten for the artistic work.