Stromal SLIT2 impacts on pancreatic cancer-associated neural remodeling

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a critical health issue in the field of cancer, with few therapeutic options. Evidence supports an implication of the intratumoral microenvironment (stroma) on PDA progression. However, its contribution to the role of neuroplastic changes within the pathophysiology and clinical course of PDA, through tumor recurrence and neuropathic pain, remains unknown, neglecting a putative, therapeutic window. Here, we report that the intratumoral microenvironment is a mediator of PDA-associated neural remodeling (PANR), and we highlight factors such as 'SLIT2' (an axon guidance molecule), which is expressed by cancer-associated fibroblasts (CAFs), that impact on neuroplastic changes in human PDA. We showed that 'CAF-secreted SLIT2' increases neurite outgrowth from dorsal root ganglia neurons as well as from Schwann cell migration/ proliferation by modulating N-cadherin/β-catenin signaling. Importantly, SLIT2/ROBO signaling inhibition disrupts this stromal/ neural connection. Finally, we revealed that SLIT2 expression and CAFs are correlated with neural remodeling within human and mouse PDA. All together, our data demonstrate the implication of CAFs, through the secretion of axon guidance molecule, in PANR. Furthermore, it provides rationale to investigate the disruption of the stromal/neural compartment connection with SLIT2/ROBO inhibitors for the treatment of pancreatic cancer recurrence and pain. Cell Death and Disease (2015) 6, e1592; doi:10.1038/cddis.2014.557; published online 15 January 2015Even after significant efforts from the scientific community in the past decade, pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal cancers with worrying predictions.1 Median survival stagnates around 5 months, together with a 5-year survival at 5%. For 5-20% of patients treated surgically, the 5-year survival reaches 20%, with a median survival of 16 months. Metastasis onset and high prevalence of local tumor recurrence after potential curative resection influence patient's survival. A recent study revealed that the overall survival of patients with tumor recurrence was 9.3, versus 26.3 months for patients without early relapse. 2,3 Although several causes are attributed to local recurrence, reports highlight intrapancreatic nerve invasion as a predictor for recurrence 4 by playing the role of a specific niche for scattered tumoral cells. In light of such epidemiologic data, there is a crucial need to develop optimal therapeutic strategies, taking into account the tumoral cellular composition, over the next decade.

LIF Drives Neural Remodeling in Pancreatic Cancer and Offers a New Candidate Biomarker

“…2G). Altogether, these data revealed that while numerous cell types within PDA potentially express LIF, the ability to secrete it seems restricted to the stromal compartment and in particular mostly to activated fibroblasts, a major cell component of PDA microenvironment that we have recently linked to PANR (12).…”

“…We previously showed that the stromal compartment can, through its secretory ability, impact nerve system reorganization within PDA tumors (12). Regarding recent studies revealing a role of inflammatory processes in PANR (11,22), we hypothesized that some genes/pathways, involved in the regulation of inflammatory processes, may be upregulated in the stromal compartment of pancreatic cancer and could impact PANR.…”

“…Regarding recent studies revealing a role of inflammatory processes in PANR (11,22), we hypothesized that some genes/pathways, involved in the regulation of inflammatory processes, may be upregulated in the stromal compartment of pancreatic cancer and could impact PANR. Using two sets of RNA microarray analysis previously published by our group (Gene Expression Omnibus (GEO): GSE50570 for human PDA, (12), and GSE61412 for mouse PDA, (27)), we revealed that numerous members of the gp130 "ligand/receptor" family, with some already associated with neuropathic disorders or regulation of the nervous system ( the two LIF receptors, LIFR and gp130 ( Fig. 1A and D).…”

“…Although several studies have reported the ability of cancer cells to attract nerve fibers (40,41), very few have reported the impact of stromal cells in this process (12), especially in PDA where stromal cells compose the vast majority of the tumor cell mass. Therefore, our goal was to identify molecular targets from the PDA microenvironment that are involved in PANR, which may lead to the discovery of potent future adjuvant therapies that could prolong survival and reduce morbidity by blocking PANR.…”

“…These alterations, called PDA associated neural remodeling (PANR), result in higher nerve densities in PDA due to peripheral nerve fibers infiltration and axonogenesis (10,11). Recently, we highlighted, in a previous study, that the intra-tumoral microenvironment could be a cause of those profound alterations (12). Thus, deciphering the specific connection between stromal compartment and nerve system in PDA could uncover potential therapeutic targets and clinical tools that would limit the nervous system-related impact on PDA evolution that alter patients' fate (13,14).…”