Subtypes of Pancreatic Ductal Adenocarcinoma and Their Differing Responses to Therapy

Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA.
Nature medicine (Impact Factor: 27.36). 04/2011; 17(4):500-3. DOI: 10.1038/nm.2344
Source: PubMed


Pancreatic ductal adenocarcinoma (PDA) is a lethal disease. Overall survival is typically 6 months from diagnosis. Numerous phase 3 trials of agents effective in other malignancies have failed to benefit unselected PDA populations, although patients do occasionally respond. Studies in other solid tumors have shown that heterogeneity in response is determined, in part, by molecular differences between tumors. Furthermore, treatment outcomes are improved by targeting drugs to tumor subtypes in which they are selectively effective, with breast and lung cancers providing recent examples. Identification of PDA molecular subtypes has been frustrated by a paucity of tumor specimens available for study. We have overcome this problem by combined analysis of transcriptional profiles of primary PDA samples from several studies, along with human and mouse PDA cell lines. We define three PDA subtypes: classical, quasimesenchymal and exocrine-like, and we present evidence for clinical outcome and therapeutic response differences between them. We further define gene signatures for these subtypes that may have utility in stratifying patients for treatment and present preclinical model systems that may be used to identify new subtype specific therapies.

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Available from: Anguraj Sadanandam, Jan 29, 2014
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    • "In a small fraction of human PanINs, low levels of PTF1A were observed in a subset of epithelial cells (Figure 1—figure supplement 1). Residual PTF1A expression is consistent with the finding that approximately one-third of human PDAC samples express low levels of acinar-specific genes (Collisson et al., 2011). "
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    ABSTRACT: Understanding the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) may provide therapeutic strategies for this deadly disease. Recently, we and others made the surprising finding that PDAC and its preinvasive precursors, pancreatic intraepithelial neoplasia (PanIN), arise via reprogramming of mature acinar cells. We therefore hypothesized that the master regulator of acinar differentiation, PTF1A, could play a central role in suppressing PDAC initiation. Here, we demonstrate that PTF1A expression is lost in both mouse and human PanINs, and that this downregulation is functionally imperative in mice for acinar reprogramming by oncogenic KRAS. Loss of Ptf1a alone is sufficient to induce acinar-to-ductal metaplasia, potentiate inflammation, and induce a KRAS-permissive, PDAC-like gene expression profile. As a result, Ptf1a-deficient acinar cells are dramatically sensitized to KRAS transformation, and reduced Ptf1a greatly accelerates development of invasive PDAC. Together, these data indicate that cell differentiation regulators constitute a new tumor suppressive mechanism in the pancreas.
    eLife Sciences 07/2015; 4. DOI:10.7554/eLife.07125 · 9.32 Impact Factor
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    • "To analyze the ability of cells to grow in an anchorage-independent manner in 3D semisolid media (ECM scaffolds) [25], we dispersed cells of each cell line into drops of 7% Matrigel in the presence or absence of EGF and/or cariporide. As shown in Figure 2A, the different cell lines had quite different basal and EGF-stimulated colony formation dynamics and shapes consistent with their reported malignant potential and subtype gene signatures [9]. The classical subtypes, CAPAN-2 and BXPC3, were the slowest to form colonies (Figure 2, A and B), and they formed the most regular, spherical Figure 1. "
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers principally because of early invasion and metastasis. The epidermal growth factor receptor (EGFR) is essential for PDAC development even in the presence of Kras, but its inhibition with erlotinib gives only a modest clinical response, making the discovery of novel EGFR targets of critical interest. Here, we revealed by mining a human pancreatic gene expression database that the metastasis promoter Na(+)/H(+) exchanger (NHE1) associates with the EGFR in PDAC. In human PDAC cell lines, we confirmed that NHE1 drives both basal and EGF-stimulated three-dimensional growth and early invasion via invadopodial extracellular matrix digestion. EGF promoted the complexing of EGFR with NHE1 via the scaffolding protein Na+/H+ exchanger regulatory factor 1, engaging EGFR in a negative transregulatory loop that controls the extent and duration of EGFR oncogenic signaling and stimulates NHE1. The specificity of NHE1 for growth or invasion depends on the segregation of the transient EGFR/Na+/H+ exchanger regulatory factor 1/NHE1 signaling complex into dimeric subcomplexes in different lipid raftlike membrane domains. This signaling complex was also found in tumors developed in orthotopic mice. Importantly, the specific NHE1 inhibitor cariporide reduced both three-dimensional growth and invasion independently of PDAC subtype and synergistically sensitized these behaviors to low doses of erlotinib. Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.
    Neoplasia 02/2015; 17(2):155. DOI:10.1016/j.neo.2014.12.003 · 4.25 Impact Factor
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    • "For example, in a K-ras LSL-G12D/+ ; p53 Flox/Flox mouse model of PDAC, EMT and invasiveness precede the detection of tumors in situ[39]. Interestingly, a molecular classification of human PDAC was performed recently, where three subtypes were defined: classical, exocrine-like, and quasi-mesenchymal (which has the worst prognosis of all three) [40]; SLC2A3 was one of a 20-gene signature of the quasi-mesenchymal subtype. This observation, together with our findings of a connection between GLUT3 and EMT in human liver cells from HCC, indicates that the regulation of GLUT3 by EMT extends beyond lung cancer. "
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    ABSTRACT: Background Alterations in glucose metabolism and epithelial-mesenchymal transition (EMT) constitute two important characteristics of carcinoma progression toward invasive cancer. Despite an extensive characterization of each of them separately, the links between EMT and glucose metabolism of tumor cells remain elusive. Here we show that the neuronal glucose transporter GLUT3 contributes to glucose uptake and proliferation of lung tumor cells that have undergone an EMT. Results Using a panel of human non-small cell lung cancer (NSCLC) cell lines, we demonstrate that GLUT3 is strongly expressed in mesenchymal, but not epithelial cells, a finding corroborated in hepatoma cells. Furthermore, we identify that ZEB1 binds to the GLUT3 gene to activate transcription. Importantly, inhibiting GLUT3 expression reduces glucose import and the proliferation of mesenchymal lung tumor cells, whereas ectopic expression in epithelial cells sustains proliferation in low glucose. Using a large microarray data collection of human NSCLCs, we determine that GLUT3 expression correlates with EMT markers and is prognostic of poor overall survival. Conclusions Altogether, our results reveal that GLUT3 is a transcriptional target of ZEB1 and that this glucose transporter plays an important role in lung cancer, when tumor cells loose their epithelial characteristics to become more invasive. Moreover, these findings emphasize the development of GLUT3 inhibitory drugs as a targeted therapy for the treatment of patients with poorly differentiated tumors.
    07/2014; 2(1):11. DOI:10.1186/2049-3002-2-11
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