The substance P/ Neurokinin-1 receptor signaling drives perineural invasion in pancreatic ductal adenocarcinoma (PDAC)

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Background: ), facilitating tumor invasion through chemoattractant secretion. Although the activation of neurokinin-1 receptor (NK-1R) via SP is implicated in tumor invasion and pain signaling, its role in coordinating bidirectional crosstalk within the PDAC neural niche remains elusive. In this study, we investigated the SP/NK-1R axis as a mediator of bidirectional crosstalk between tumor cells, sensory neurons, and Schwann cells in pancreatic cancer. Methods: approaches. First, NK-1R expression was assessed by immunofluorescence in both primary PDAC tissue slices and PDAC tumor cell lines. To model the tumor-neural niche, MiaPaCa-2 cells were exposed to conditioned medium derived from iPSC-derived sensory neurons and primary human Schwann cells. Furthermore, to investigate the functional consequences of this signaling axis, we established a co-culture system composed of MiaPaCa-2 cells and Schwann cells, in which the number of invaded MiaPaCa-2 cells was quantified. Axon-guided tumor invasion was further examined using the OrganoPlate® Graft platform, where MiaPaCa-2 spheroids were co-cultured with sensory neurons. Moreover, NK-1R was pharmacologically inhibited using the FDA-approved antagonist aprepitant, and its effect on MiaPaCa-2 cell invasion was evaluated in both co-culture settings. Finally, the potential for therapeutic synergy was explored by combining aprepitant with the chemotherapeutic agent paclitaxel to assess potential synergy on cytotoxicity. Results: Immunofluorescence analysis of MiaPaCa-2, patient-derived tumor cells and primary PDAC tissue slices, revealed high NK-1R protein expression, establishing NK-1R as a putative clinically relevant target in PDAC. To model the bidirectional crosstalk within the PDAC niche, we examined NK-1R regulation under co-culture conditions. Conditioned media from sensory neurons and primary human Schwann cells significantly upregulated NK-1R expression in the MiaPaCa-2 cells. Reciprocally, exposure of both sensory neurons or Schwann cells to MiaPaCa-2 cells conditioned medium induced NK-1R upregulation, confirming bidirectional signaling. Consistent with this, supernatant from MiaPaCa-2/sensory neuron or MiaPaCa-2/Schwann cells co-cultures demonstrated a substantial increase in SP levels, indicating active neuropeptidergic communication within the tumor-neural niche. To assess the functional consequences of this crosstalk on tumor invasiveness, we employed our co-culture invasion models. Schwann cells significantly increased the number of invaded MiaPaCa-2 cells in co-culture. Furthermore, using the OrganoPlate® Graft platform, co-culture of MiaPaCa-2 spheroids and iPSC-derived sensory neurons demonstrated pronounced axon-guided tumor, validating the human 3D PNI model. Finally, to evaluate the therapeutic potential of NK-1R inhibition, we treated co-cultures with the FDA-approved NK-1R antagonist aprepitant. Pharmacological NK-1R blockade significantly reduced MiaPaCa-2 cell invasion in both sensory neuron and Schwann cell co-cultures. Moreover, combining aprepitant with paclitaxel synergistically enhanced cytotoxicity, revealing a dual role for NK-1R in driving both invasion and chemoresistance. Conclusion: Collectively, our findings confirm and extend previous work by implicating SP/NK-1R axis as a potential driver of perineural invasion in PDAC. By leveraging a human 3D microfluidic co-culture PNI model, we provide evidence that NK-1R signaling contributes to sustaining bidirectional tumor-neural crosstalk and promoting invasive progression. Critically, pharmacological inhibition of NK-1R using the FDA-approved antagonist aprepitant not only suppressed perineural invasion but also synergistically enhanced paclitaxel-induced cytotoxicity, highlighting dual vulnerability in both neural invasion and chemoresistance. Together, these findings position SP/NK-1R as a target, offering a novel and translationally relevant strategy to simultaneously disrupt tumor-nerve interactions and improve chemotherapy response in PDAC.

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