Abstract 5082: The selective bromodomain inhibitor, INCB054329 targets both cancer cells and the tumor microenvironment in the KC inflammatory preclinical model of ductal pancreatic cancer

Pancreatic cancer is the third leading cause of cancer-related deaths in the USA. Pancreatic tumors are characterized by enhanced glycolytic metabolism promoted by a hypoxic tumor microenvironment and a resultant acidic milieu. The metabolic reprogramming allows cancer cells to survive hostile microenvironments. Through the analysis of the principal metabolic pathways, we identified the specific metabolites that are altered during pancreatic cancer progression in the spontaneous progression (KPC) mouse model. Genetically engineered mice exhibited metabolic alterations during PanINs formation, even before the tumor development. To account for other cells in the tumor microenvironment and to focus on metabolic adaptations concerning tumorigenic cells only, we compared the metabolic profile of KPC and orthotopic tumors with those obtained from KPC-tumor derived cell lines. We observed significant upregulation of glycolysis and the pentose phosphate pathway metabolites even at the early stages of pathogenesis. Other biosynthetic pathways also demonstrated a few common perturbations. While some of the metabolic changes in tumor cells are not detectable in orthotopic and spontaneous tumors, a significant number of tumor cell-intrinsic metabolic alterations are readily detectable in the animal models. Overall, we identified that metabolic alterations in precancerous lesions are maintained during cancer development and are largely mirrored by cancer cells in culture conditions.

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G protein-coupled receptor signaling in human ductal pancreatic cancer cells: Neurotensin responsiveness and mitogenic stimulation

Journal of Cellular Physiology ◽

10.1002/1097-4652(200101)186:1<53::aid-jcp1004>3.0.co;2-q ◽

2000 ◽

Vol 186 (1) ◽

pp. 53-64 ◽

Cited By ~ 53

Author(s):

Nova M. Ryder ◽

Sushovan Guha ◽

Oscar J. Hines ◽

Howard A. Reber ◽

Enrique Rozengurt

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

G Protein ◽

Receptor Signaling ◽

G Protein Coupled Receptor ◽

Mitogenic Stimulation ◽

Pancreatic Cancer Cells ◽

Ductal Pancreatic Cancer ◽

G Protein Coupled

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PEPT1 is essential for the growth of pancreatic cancer cells: A viable drug target

Biochemical Journal ◽

10.1042/bcj20210377 ◽

2021 ◽

Author(s):

Bradley Schniers ◽

Devaraja Rajasekaran ◽

Ksenija Korac ◽

Tyler Sniegowski ◽

Vadivel Ganapathy ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Cell Lines ◽

Intracellular Localization ◽

Peptide Transporter ◽

Pdac Cell ◽

Functional Link ◽

Pancreatic Cancer Cells

PEPT1 is a proton-coupled peptide transporter that is upregulated in PDAC cell lines and PDXs, with little expression in normal pancreas. However, the relevance of this upregulation to cancer progression and the mechanism of upregulation have not been investigated. Herein, we show that PEPT1 is not just upregulated in a large panel of PDAC cell lines and PDXs but is also functional and transport-competent. PEPT2, another proton-coupled peptide transporter, is also overexpressed in PDAC cell lines and PDXs, but is not functional due to its intracellular localization. Using glibenclamide as a pharmacological inhibitor of PEPT1, we demonstrate in cell lines in vitro and mouse xenografts in vivothat inhibition of PEPT1 reduces the proliferation of the cancer cells. These findings are supported by genetic knockdown of PEPT1 with shRNA, wherein the absence of the transporter significantly attenuates the growth of cancer cells, both in vitro and in vivo, suggesting that PEPT1 is critical for the survival of cancer cells. We also establish that the tumor-derived lactic acid (Warburg effect) in the tumor microenvironment supports the transport function of PEPT1 in the maintenance of amino acid nutrition in cancer cells by inducing MMPs and DPPIV to generate peptide substrates for PEPT1 and by generating a H+ gradient across the plasma membrane to energize PEPT1. Taken collectively, these studies demonstrate a functional link between PEPT1 and extracellular protein breakdown in the tumor microenvironment as a key determinant of pancreatic cancer growth, thus identifying PEPT1 as a potential therapeutic target for PDAC.

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Neurotensin and EGF induce synergistic stimulation of DNA synthesis by increasing the duration of ERK signaling in ductal pancreatic cancer cells

Journal of Cellular Physiology ◽

10.1002/jcp.20187 ◽

2004 ◽

Vol 202 (3) ◽

pp. 880-890 ◽

Cited By ~ 41

Author(s):

Krisztina Kisfalvi ◽

Sushovan Guha ◽

Enrique Rozengurt

Keyword(s):

Pancreatic Cancer ◽

Dna Synthesis ◽

Cancer Cells ◽

Erk Signaling ◽

Pancreatic Cancer Cells ◽

Ductal Pancreatic Cancer ◽

Stimulation Of

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In vitro model of inflammatory, hypoxia, and cancer stem cell signaling in pancreatic cancer using heterocellular 3-dimensional spheroids

10.1101/454397 ◽

2018 ◽

Author(s):

Megha Suresh ◽

George Mattheolabakis ◽

Amit Singh ◽

Mansoor Amiji

Keyword(s):

Pancreatic Cancer ◽

Stem Cell ◽

Tumor Microenvironment ◽

Cancer Stem Cell ◽

Cancer Cells ◽

Cell Lines ◽

Pancreatic Tumor ◽

Stem Cell Markers ◽

3 Dimensional

AbstractIntroductionAs one of the most aggressive cancers worldwide, pancreatic cancer is associated with an extremely poor prognosis. The pancreatic tumor microenvironment consists of cancer cells and other tumor associated cells. Cross-talk between these different cell types through various signaling molecules results in the development of a more aggressive and malignant phenotype. Additionally, due to the highly dysregulated vasculature of tumors, the inner tumor core becomes hypoxic and eventually necrotic. Therefore, there is a need for the development of a physiologically relevant in vitro model that recapitulates these dynamic cell-cell interactions and the 3-dimensional (3D) structure of pancreatic tumors.MethodsFour different 3D co-culture spheroid models using different combinations of Panc-1 tumor cells, J774.A1 macrophages, and NIH-3T3 fibroblast cell lines were reproducibly developed using the hanging drop technique in order to mimic the tumor microenvironment and to evaluate the differences in expression of various inflammatory, hypoxia, and cancer stem cell markers, including IL-8, TNF-α, TGF-β, HIF-1α HIF-2α, SCF, and LDH-A. Additionally, immunofluorescence studies were employed to investigate whether these spheroids tested positive for a cancer stem cell population.ResultsPronounced differences in morphology as well as expression of signalling markers were observed using qPCR, indicative of strong influences of co-culturing different cell lines. These models also tested positive for cancer stem cell (CSCs) markers based on immunofluorescence and qPCR analysis.ConclusionOur results demonstrate the potential of 3D co-culture spheroid models to capture the inflammatory and hypoxic markers of pancreatic tumor microenvironment. We further demonstrate the presence of cancer cells with stem cell markers, similar to actual pancreatic cancer tumor. These spheroids present excellent in vitro system to study tumor-immune-stromal cell interactions as well as test deliverability of potential therapeutics in the tumor microenvironment with accurate physical and physiological barriers.

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