{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T06:27:39Z","timestamp":1787120859085,"version":"build-2736575974"},"reference-count":88,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, characterized by early metastasis, profound therapy resistance, and the highest prevalence of perineural invasion (PNI) among solid tumors. PNI fosters neuropathic pain and recurrence, ultimately correlating with poor survival. Sensory neurons promote PNI via neuropeptidergic signaling, including substance P (SP), while Schwann cells undergo injury-like reprogramming (GFAP\n                      <jats:sup>+<\/jats:sup>\n                      \/p75NTR\n                      <jats:sup>high<\/jats:sup>\n                      ), 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To elucidate the role of the SP\/NK-1R axis in perineural invasion, we employed a series of complementary\n                      <jats:italic>in vitro<\/jats:italic>\n                      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\u00ae 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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\u00ae 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1876023","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T05:45:54Z","timestamp":1787118354000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The substance P\/ Neurokinin-1 receptor signaling drives perineural invasion in pancreatic ductal adenocarcinoma (PDAC)"],"prefix":"10.3389","volume":"14","author":[{"given":"Katja","family":"Schiedlauske","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University D\u00fcsseldorf","place":["D\u00fcsseldorf, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Biskup","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital and Heinrich-Heine-University","place":["D\u00fcsseldorf, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Hofer","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University D\u00fcsseldorf","place":["D\u00fcsseldorf, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Deipenbrock","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University D\u00fcsseldorf","place":["D\u00fcsseldorf, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaan","family":"\u00c7ifciba\u015f\u0131","sequence":"additional","affiliation":[{"name":"Department of Medicine III, TUM University Hospital, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich","place":["Munich, Germany"]},{"name":"Department of Surgery, TUM University Hospital, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ihsan Ekin","family":"Demir","sequence":"additional","affiliation":[{"name":"Department of Medicine III, TUM University Hospital, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Esposito","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital and Heinrich-Heine-University","place":["D\u00fcsseldorf, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Weyhe","sequence":"additional","affiliation":[{"name":"Carl von Ossietzky Universit\u00e4t Oldenburg, University Hospital for Visceral Surgery, PIUS-Hospital Oldenburg","place":["Oldenburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole Elisabeth","family":"Teusch","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University D\u00fcsseldorf","place":["D\u00fcsseldorf, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1186\/s12885-023-10633-8","article-title":"Expression of substance P, neurokinin 1 receptor, Ki-67 and pyruvate kinase M2 in hormone receptor negative breast cancer and evaluation of impact on overall survival","volume":"23","author":"Al-Keilani","year":"2023","journal-title":"BMC Cancer"},{"key":"B2","doi-asserted-by":"publisher","first-page":"8082608","DOI":"10.1155\/2022\/8082608","article-title":"The potential in vitro inhibitory effects of Neurokinin-1 receptor (NK-1R) antagonist, aprepitant, in osteosarcoma cell migration and metastasis","volume":"2022","author":"Alsaeed","year":"2022","journal-title":"Biomed. 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