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Early pancreatic cancer lesions suppress pain through CXCL12-mediated chemoattraction of Schwann cells

Significance Pancreatic ductal adenocarcinoma cancer (PDAC) cells have an exceptional propensity to invade nerves via pronounced crosstalk between nerves and cancer cells, but the mechanisms of this early neural invasion are yet unknown. By using genetically engineered mouse models, we show that in the precursor stage PDAC induces the generation of ready-to-use nerves for dissemination by secreting the chemokine CXCL12 that attracts glia (Schwann) cells of nerves. This migration of glia cells to cancerous cells at this very early stage intriguingly attenuates cancer-associated pain via downregulation of pain-associated targets in Schwann cells and via suppression of central glia. Hence, malignant transformed cells seem to disguise cancer-associated symptoms (such as pain) actively and thereby delay the early diagnosis of cancer. Pancreatic ductal adenocarcinoma (PDAC) cells (PCC) have an exceptional propensity to metastasize early into intratumoral, chemokine-secreting nerves. However, we hypothesized the opposite process, that precancerous pancreatic cells secrete chemokines that chemoattract Schwann cells (SC) of nerves and thus induce ready-to-use routes of dissemination in early carcinogenesis. Here we show a peculiar role for the chemokine CXCL12 secreted in early PDAC and for its receptors CXCR4/CXCR7 on SC in the initiation of neural invasion in the cancer precursor stage and the resulting delay in the onset of PDAC-associated pain. SC exhibited cancer- or hypoxia-induced CXCR4/CXCR7 expression in vivo and in vitro and migrated toward CXCL12-expressing PCC. Glia-specific depletion of CXCR4/CXCR7 in mice abrogated the chemoattraction of SC to PCC. PDAC mice with pancreas-specific CXCL12 depletion exhibited diminished SC chemoattraction to pancreatic intraepithelial neoplasia and increased abdominal hypersensitivity caused by augmented spinal astroglial and microglial activity. In PDAC patients, reduced CXCR4/CXCR7 expression in nerves correlated with increased pain. Mechanistically, upon CXCL12 exposure, SC down-regulated the expression of several pain-associated targets. Therefore, PDAC-derived CXCL12 seems to induce tumor infiltration by SC during early carcinogenesis and to attenuate pain, possibly resulting in delayed diagnosis in PDAC.