Nerves are a notable feature of the tumor microenvironment in some epithelial tumors, but their role in the malignant progression of pancreatic ductal adenocarcinoma (PDAC) is uncertain. Here we identify dense innervation in the microenvironment of precancerous pancreatic lesions, known as pancreatic intraepithelial neoplasms (PanIN), and describe a unique subpopulation of neuroendocrine PanIN cells that express the neuropeptide substance P (SP) receptor Neurokinin 1-R (NK1-R). Using organoid culture, we demonstrated that sensory neurons promoted the proliferation of PanIN organoids via SP-NK1-R signaling and Stat3 activation. Nerve-responsive neuroendocrine cells exerted trophic influences and potentiated global PanIN organoid growth. Sensory denervation of a genetically engineered mouse model of PDAC led to loss of Stat3 activation, a decrease in the neoplastic neuroendocrine cell population, and impaired PanIN progression to tumor. Overall, our data provide evidence that nerves of the PanIN microenvironment promote oncogenesis, likely via direct signaling to neoplastic neuroendocrine cells capable of trophic influences. These findings identify neuroepithelial crosstalk as a potential novel target in PDAC treatment.

Nerves are a notable feature of the tumor microenvironment in some epithelial tumors, but their role in the malignant progression of pancreatic ductal adenocarcinoma (PDAC) is uncertain. Here we identify dense innervation in the microenvironment of precancerous pancreatic lesions, known as pancreatic intraepithelial neoplasms (PanIN), and describe a unique subpopulation of neuroendocrine PanIN cells that express the neuropeptide substance P (SP) receptor Neurokinin 1-R (NK1-R). Using organoid culture, we demonstrated that sensory neurons promoted the proliferation of PanIN organoids via SP-NK1-R signaling and Stat3 activation. Nerve-responsive neuroendocrine cells exerted trophic influences and potentiated global PanIN organoid growth. Sensory denervation of a genetically engineered mouse model of PDAC led to loss of Stat3 activation, a decrease in the neoplastic neuroendocrine cell population, and impaired PanIN progression to tumor. Overall, our data provide evidence that nerves of the PanIN microenvironment promote oncogenesis, likely via direct signaling to neoplastic neuroendocrine cells capable of trophic influences. These findings identify neuroepithelial crosstalk as a potential novel target in PDAC treatment.

Purpose of review The review intends to describe recent studies on the development of pancreatic cancer from a genetic, molecular, and microenvironment perspective. Recent findings Pancreatic cancer has been discovered to have distinct molecular subtypes based on transcriptome analyses that may have implications for treatment. Recent studies are also mapping the complex molecular biology of this cancer as it relates to the core signaling abnormalities inherent to this disease. There have been discoveries of novel modes of regulation of pancreatic cancer development, including alterations in key transcription factors, epigenetic modifiers, and metabolic pathways. Studies of the tumor-associated microenvironment continue to reveal its complex role in tumor development. Summary Pancreatic cancer development appears to depend on a multifaceted network of signals that are dynamic, involve multiple cell types, and are linked to spatiotemporal factors in tumor evolution. Understanding the development of pancreatic cancer in this context is key to identifying novel and effective targets for treatment.

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Personalized therapy is the future of cancer care. Almost half of the cancer patients do not respond to chemotherapy. For instance, pancreatic ductal adenocarcinoma (PDAC) patients with the limited local disease and with no detectable metastasis typically have their primary tumor surgically resected, but the disease recurs in approximately 50% of cases within 1 year of surgery, in spite of adjuvant chemotherapy. Although gene expression signatures correlating prognosis have been described in PDAC, the therapeutic utility of these signatures has been limited based in part on a large number of genes displaying an altered expression. On the other hand, regulatory regions common to these genes might be amenable to collective epigenetic reprogramming using epigenetic drugs. We interrogated genome-wide chromatin accessibility using Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) on EpCAM+ PDAC malignant cells sorted from a cohort of 54 treatment-naïve resected tumors, in hopes of defining a tumor-intrinsic chromatin signature associated with recurrence. We discovered a signature of 1092 loci that were differentially accessible between recurrent (disease-free survival (DFS) < 1 year) and non-recurrent patients (DFS > 1 year). Through transcription factor (TF) binding motif analysis, we identified candidate TFs whose accessible motifs were differentially associated with recurrence. Nuclear localization of two such TFs, ZKSCAN1 and HNF1b, were assessed by immunostaining on tissue microarrays (TMA) representing 40 out of 54 patients. Nuclear staining of HNF1b was strong in tumor tissue from non-recurrent patients and weak or absent in recurrent patients, but ZKSCAN1 staining patterns were not significantly associated with recurrence. In a TMA representing an independent PDAC cohort (n=97) preselected for 52 long (OS 6 years)- and 45 short (OS 6 months)- term survivors, the number of nuclear positive cells for HNF1b was 52-fold higher in the long-term compared to the short-term survivors and that for ZKSCAN1 was 5.3-fold higher in the short-term compared to the long-term survivors. We further validated the 1092 chromatin accessibility signature by a novel microarray-based platform technology that we termed “ATAC-Array”, where the differentially accessible regions from the signatures were probed on a glass slide and then hybridized with fluorescent-labeled ATAC-libraries. This is a cost-effective, easy-to-use platform technology avoiding the time and cost of next-generation ATAC library sequencing. ATAC-array is the only microarray that reads chromatin accessibility. We have compared ATAC-array side-by-side with ATAC-seq (n=30) and found significant correlation (Pearson's median r= 0.64, range= 0.50- 0.77). By performing ATAC-array on the PDAC cohort (n=38), we have independently re-classified the patients who recurred early and the ones who did not (Gehan-Breslow-Wilcoxon test p=0.0076). ATAC-array, as the technology itself, has enormous potential for a wide range of applications, and we propose to develop it as a clinically validated theragnostic tool to predict and stratify cancer patients for epigenetic therapy. Citation Format: Surajit Dhara, Sagar Chhangawala, Himanshu Chintalapudi, Alexandra L. Massa, Victoria Aveson, Gokce Askan, Liguo Zhang, Remy Nicolle, Alvin P. Makohon-Moore, Smrita Sinha, Jiang Gui, Richard Moffitt, Kenneth H. Yu, Vinod Balachandran, Rohit Chandwani, Christina Leslie, Steven D. Leach. Pancreatic cancer prognosis is predicted by chromatin accessibility microarray [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-263.

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