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The adult healthy human pancreas has been poorly studied given the lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors, thus avoiding any warm ischemia time. The 30 donors were diverse in age and race and had no known pancreas disease. Histopathologic analysis of the samples revealed pancreatic intraepithelial neoplasia (PanIN) lesions in most individuals irrespective of age. Using a combination of multiplex IHC, single-cell RNA sequencing, and spatial transcriptomics, we provide the first-ever characterization of the unique microenvironment of the adult human pancreas and of sporadic PanIN lesions. We compared healthy pancreata to pancreatic cancer and peritumoral tissue and observed distinct transcriptomic signatures in fibroblasts and, to a lesser extent, macrophages. PanIN epithelial cells from healthy pancreata were remarkably transcriptionally similar to cancer cells, suggesting that neoplastic pathways are initiated early in tumorigenesis. Significance: Precursor lesions to pancreatic cancer are poorly characterized. We analyzed donor pancreata and discovered that precursor lesions are detected at a much higher rate than the incidence of pancreatic cancer, setting the stage for efforts to elucidate the microenvironmental and cell-intrinsic factors that restrain or, conversely, promote malignant progression.

Supplementary Figures 1-10 and associated legends

The adult healthy human pancreas has been poorly studied given the lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors, thus avoiding any warm ischemia time. The 30 donors were diverse in age and race and had no known pancreas disease. Histopathologic analysis of the samples revealed pancreatic intraepithelial neoplasia (PanIN) lesions in most individuals irrespective of age. Using a combination of multiplex IHC, single-cell RNA sequencing, and spatial transcriptomics, we provide the first-ever characterization of the unique microenvironment of the adult human pancreas and of sporadic PanIN lesions. We compared healthy pancreata to pancreatic cancer and peritumoral tissue and observed distinct transcriptomic signatures in fibroblasts and, to a lesser extent, macrophages. PanIN epithelial cells from healthy pancreata were remarkably transcriptionally similar to cancer cells, suggesting that neoplastic pathways are initiated early in tumorigenesis.Significance:Precursor lesions to pancreatic cancer are poorly characterized. We analyzed donor pancreata and discovered that precursor lesions are detected at a much higher rate than the incidence of pancreatic cancer, setting the stage for efforts to elucidate the microenvironmental and cell-intrinsic factors that restrain or, conversely, promote malignant progression.

Supplementary Figures 11-14 and associated legends.

Supplemental Table 1: Demographics and clinical data for donor Gife of Life Samples Supplemental Table 2: Putative Ligand-Receptor pairs comparing all cell types from single cell sequencing of tumor samples compared to healthy samples. Supplemental Table 3: Differential gene expression using linear mixed model analysis of cell types from spatial transcriptomic ROIs. Supplemental Table 4: Kras mutational profiling on select donor samples Supplemental Table 5: Antibodies used for multiplex immunofluoresence. Supplemental Table 6: Antibodies and RNAScope probe used for co-IF/ISH.

The adult healthy human pancreas has been poorly studied given lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors thus avoiding any warm ischemia time. The 30 donors were diverse in age and race and had no known pancreas disease. Histopathological analysis of the samples revealed PanIN lesions in most individuals irrespective of age. Using a combination of multiplex immunohistochemistry, single cell RNA sequencing, and spatial transcriptomics, we provide the first ever characterization of the unique microenvironment of the adult human pancreas and of sporadic PanIN lesions. We compared healthy pancreata to pancreatic cancer and peritumoral tissue and observed distinct transcriptomic signatures in fibroblasts, and, to a lesser extent, macrophages. PanIN epithelial cells from healthy pancreata were remarkably transcriptionally similar to cancer cells, suggesting that neoplastic pathways are initiated early in tumorigenesis.Statement of significanceThe causes underlying the onset of pancreatic cancer remain largely unknown, hampering early detection and prevention strategies. Here, we show that PanIN are abundant in healthy individuals and present at a much higher rate than the incidence of pancreatic cancer, setting the stage for efforts to elucidate the microenvironmental and cell intrinsic factors that restrain, or, conversely, promote, malignant progression.

It is well-recognized that cigarette smoking is a primary risk factor in the development of non-small cell lung cancer (NSCLC), known to account for ~80% of all lung cancers with nicotine recognized as the major addictive component. In investigating the effect of nicotine, brain-derived neurotrophic factor (BDNF), and the β-adrenergic receptor blocker, propranolol, on sensitivity of NSCLC cell lines, A549 and H1299, to cisplatin, we found increased cell viability, and enhanced cisplatin resistance with nicotine and/or BDNF treatment while opposite effects were found upon treatment with propranolol. Cell treatment with epinephrine or nicotine led to EGFR and IGF-1R activation, effects opposite to those found with propranolol. Blocking EGFR and IGF-1R activation increased cell sensitivity to cisplatin in both cell lines. PI3K and AKT activities were upregulated by nicotine or BDNF and downregulated by cell treatment with inhibitors against EGFR and IGF-1R and by propranolol. Apoptosis and cell sensitivity to cisplatin increased upon co-treatment of cells with cisplatin and inhibitors against PI3K or AKT. Our findings shed light on an interplay between nicotine, BDNF, and β-Adrenergic receptor signaling in regulating survival of lung cancer cells and chemoresistance which can likely expand therapeutic opportunities that target this regulatory network in the future.