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Transportome Malfunctions and the Hallmarks of Pancreatic Cancer

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Transportome Malfunction in the Cancer Spectrum

Part of the book series: Reviews of Physiology, Biochemistry and Pharmacology ((REVIEWS,volume 181))

Abstract

Ion channels and transporters (ICT) play important roles in almost all basic cellular processes. During last decades, abundant evidences have been provided that ICT (e.g., Ca2+ and K+ channels) are notable for regulating physiological pancreatic duct cellular function and deregulation of ICT is closely associated with the widely accepted hallmarks of pancreatic ductal adenocarcinoma (PDAC) such as proliferation, apoptosis resistance, invasion, and metastasis. Hence this review focuses on the role of ICT malfunctions in context with the hallmarks of PDAC. After briefly introducing epidemiology and history of molecular oncology of PDAC and summarizing the recent studies on molecular classification systems, we focus then on the exocrine pancreas as a very active secretory gland which considerably impacts the changes in the ion transport system (the transportome) upon malignant transformation. We highlight multiplicity of ICT members (H+ transporters, Ca2+, K+, Na+ and Cl− channels) and their functional impact in PDAC. We also present some selective therapeutic options to interfere with transportome functions and thereby with key mechanisms of malignant progression. This will hopefully contribute to a better clinical outcome based on improved therapeutic strategies for this still extremely deadly disease.

Qi Ling wrote the draft.

Holger Kalthoff revised the manuscript.

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Abbreviations

ASIC:

Acid-sensing ion channel

CAF:

Cancer-associated fibroblast

CaSR:

Calcium-sensing receptor

CFTR:

Cystic fibrosis transmembrane conductance regulator

DOG-1:

Gastrointestinal stromal tumor 1

ECM:

Extracellular matrix

EGF:

Epidermal growth factor

FXYD3:

Ion transport regulator 3

GIRK1:

G protein inwardly rectifying K+ channel 1

GPCR:

G protein-coupled receptor

hERG1:

Human ether-a-go-go-related potassium channel 1

ICT:

Ion channels and transporter

IPMN:

Intraductal papillary mucinous neoplasm

KCMF1:

Potassium channel modulatory factor 1

MCT:

Monocarboxylate transporters

MCN:

Mucinous cystic neoplasm

NHE1:

Na+/H+ exchanger

PanIN:

Pancreatic intraepithelial neoplasia

PDAC:

Pancreatic ductal adenocarcinoma

PSC:

Pancreatic stellate cell

ROS:

Reactive oxygen species

SOC:

Store-operated Ca2+ channel

TAM:

Tumor-associated macrophage

TRP:

Transient receptor potential

TRPM:

Transient receptor potential melastatin

TTCC:

T-type Ca2+

VGCC:

Voltage-gated Ca2+ channel

References

  • Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M (1988) Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53:549–554

    Article  CAS  PubMed  Google Scholar 

  • Arnes L, Liu Z, Wang J, Maurer C, Sagalovskiy I, Sanchez-Martin M, Bommakanti N, Garofalo DC, Balderes DA, Sussel L et al (2018) Comprehensive characterisation of compartment-specific long non-coding RNAs associated with pancreatic ductal adenocarcinoma. Gut 68:499–511

    Article  PubMed  CAS  Google Scholar 

  • Awaji M, Singh RK (2019) Cancer-associated fibroblasts’ functional heterogeneity in pancreatic ductal adenocarcinoma. Cancers (Basel) 11

    Google Scholar 

  • Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, Miller DK, Christ AN, Bruxner TJ, Quinn MC et al (2016) Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531:47–52

    Article  CAS  PubMed  Google Scholar 

  • Bardeesy N, Aguirre AJ, Chu GC, Cheng KH, Lopez LV, Hezel AF, Feng B, Brennan C, Weissleder R, Mahmood U et al (2006) Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc Natl Acad Sci U S A 103:5947–5952

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bauer I, Grozio A, Lasiglie D, Basile G, Sturla L, Magnone M, Sociali G, Soncini D, Caffa I, Poggi A et al (2012) The NAD+-dependent histone deacetylase SIRT6 promotes cytokine production and migration in pancreatic cancer cells by regulating Ca2+ responses. J Biol Chem 287:40924–40937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Begenisich T, Nakamoto T, Ovitt CE, Nehrke K, Brugnara C, Alper SL, Melvin JE (2004) Physiological roles of the intermediate conductance, Ca2+-activated potassium channel Kcnn4. J Biol Chem 279:47681–47687

    Article  CAS  PubMed  Google Scholar 

  • Beilke S, Oswald F, Genze F, Wirth T, Adler G, Wagner M (2010) The zinc-finger protein KCMF1 is overexpressed during pancreatic cancer development and downregulation of KCMF1 inhibits pancreatic cancer development in mice. Oncogene 29:4058–4067

    Article  CAS  PubMed  Google Scholar 

  • Bergmann F, Andrulis M, Hartwig W, Penzel R, Gaida MM, Herpel E, Schirmacher P, Mechtersheimer G (2011) Discovered on gastrointestinal stromal tumor 1 (DOG1) is expressed in pancreatic centroacinar cells and in solid-pseudopapillary neoplasms--novel evidence for a histogenetic relationship. Hum Pathol 42:817–823

    Article  CAS  PubMed  Google Scholar 

  • Birnbaum DJ, Bertucci F, Finetti P, Adelaide J, Giovannini M, Turrini O, Delpero JR, Raoul JL, Chaffanet M, Moutardier V et al (2016) Expression of genes with copy number alterations and survival of patients with pancreatic adenocarcinoma. Cancer Genomics Proteomics 13:191–200

    CAS  PubMed  Google Scholar 

  • Bonito B, Sauter DR, Schwab A, Djamgoz MB, Novak I (2016) KCa3.1 (IK) modulates pancreatic cancer cell migration, invasion and proliferation: anomalous effects on TRAM-34. Pflugers Arch 468:1865–1875

    Article  CAS  PubMed  Google Scholar 

  • Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424

    Article  PubMed  Google Scholar 

  • Brevet M, Fucks D, Chatelain D, Regimbeau JM, Delcenserie R, Sevestre H, Ouadid-Ahidouch H (2009) Deregulation of 2 potassium channels in pancreas adenocarcinomas: implication of KV1.3 gene promoter methylation. Pancreas 38:649–654

    Article  CAS  PubMed  Google Scholar 

  • Buchholz M, Schatz A, Wagner M, Michl P, Linhart T, Adler G, Gress TM, Ellenrieder V (2006) Overexpression of c-myc in pancreatic cancer caused by ectopic activation of NFATc1 and the Ca2+/calcineurin signaling pathway. EMBO J 25:3714–3724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cancer Genome Atlas Research Network (2017) Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 32:185–203.e13

    Google Scholar 

  • Cardone RA, Greco MR, Zeeberg K, Zaccagnino A, Saccomano M, Bellizzi A, Bruns P, Menga M, Pilarsky C, Schwab A et al (2015) A novel NHE1-centered signaling cassette drives epidermal growth factor receptor-dependent pancreatic tumor metastasis and is a target for combination therapy. Neoplasia 17:155–166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J (2016) Cancer statistics in China, 2015. CA Cancer J Clin 66:115–132

    Article  PubMed  Google Scholar 

  • Collins MA, Bednar F, Zhang Y, Brisset JC, Galban S, Galban CJ, Rakshit S, Flannagan KS, Adsay NV, Pasca di Magliano M (2012) Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest 122:639–653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Collisson EA, Sadanandam A, Olson P, Gibb WJ, Truitt M, Gu S, Cooc J, Weinkle J, Kim GE, Jakkula L et al (2011) Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med 17:500–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Collisson EA, Bailey P, Chang DK, Biankin AV (2019) Molecular subtypes of pancreatic cancer. Nat Rev Gastroenterol Hepatol 16:207–220

    Article  PubMed  Google Scholar 

  • Connor AA, Denroche RE, Jang GH, Timms L, Kalimuthu SN, Selander I, McPherson T, Wilson GW, Chan-Seng-Yue MA, Borozan I et al (2017) Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma. JAMA Oncol 3:774–783

    Article  PubMed  Google Scholar 

  • Daemen A, Peterson D, Sahu N, McCord R, Du X, Liu B, Kowanetz K, Hong R, Moffat J, Gao M et al (2015) Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors. Proc Natl Acad Sci U S A 112:E4410–E4417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dong H, Shim KN, Li JM, Estrema C, Ornelas TA, Nguyen F, Liu S, Ramamoorthy SL, Ho S, Carethers JM et al (2010) Molecular mechanisms underlying Ca2+-mediated motility of human pancreatic duct cells. Am J Physiol Cell Physiol 299:C1493–C1503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dou D, Yang S, Lin Y, Zhang J (2018) An eight-miRNA signature expression-based risk scoring system for prediction of survival in pancreatic adenocarcinoma. Cancer Biomark 23:79–93

    Article  CAS  PubMed  Google Scholar 

  • Dovmark TH, Hulikova A, Niederer SA, Vaughan-Jones RD, Swietach P (2018) Normoxic cells remotely regulate the acid-base balance of cells at the hypoxic core of connexin-coupled tumor growths. FASEB J 32:83–96

    Article  CAS  PubMed  Google Scholar 

  • Earl J, Galindo-Pumarino C, Encinas J, Barreto E, Castillo ME, Pachon V, Ferreiro R, Rodriguez-Garrote M, Gonzalez-Martinez S, Ramon YCT et al (2020) A comprehensive analysis of candidate genes in familial pancreatic cancer families reveals a high frequency of potentially pathogenic germline variants. EBio Med 53:102675

    Google Scholar 

  • Feng J, Yu J, Pan X, Li Z, Chen Z, Zhang W, Wang B, Yang L, Xu H, Zhang G et al (2014) HERG1 functions as an oncogene in pancreatic cancer and is downregulated by miR-96. Oncotarget 5:5832–5844

    Article  PubMed  PubMed Central  Google Scholar 

  • Fischer CG, Wood LD (2018) From somatic mutation to early detection: insights from molecular characterization of pancreatic cancer precursor lesions. J Pathol 246:395–404

    Article  PubMed  PubMed Central  Google Scholar 

  • Follia L, Ferrero G, Mandili G, Beccuti M, Giordano D, Spadi R, Satolli MA, Evangelista A, Katayama H, Hong W et al (2019) Integrative analysis of novel metabolic subtypes in pancreatic cancer fosters new prognostic biomarkers. Front Oncol 9:115

    Article  PubMed  PubMed Central  Google Scholar 

  • Fu S, Hirte H, Welch S, Ilenchuk TT, Lutes T, Rice C, Fields N, Nemet A, Dugourd D, Piha-Paul S et al (2017) First-in-human phase I study of SOR-C13, a TRPV6 calcium channel inhibitor, in patients with advanced solid tumors. Investig New Drugs 35:324–333

    Article  CAS  Google Scholar 

  • Giannuzzo A, Pedersen SF, Novak I (2015) The P2X7 receptor regulates cell survival, migration and invasion of pancreatic ductal adenocarcinoma cells. Mol Cancer 14:203

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Giannuzzo A, Saccomano M, Napp J, Ellegaard M, Alves F, Novak I (2016) Targeting of the P2X7 receptor in pancreatic cancer and stellate cells. Int J Cancer 139:2540–2552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gong H, Wu TT, Clarke EM (2014) Pathway-gene identification for pancreatic cancer survival via doubly regularized cox regression. BMC Syst Biol 8(Suppl 1):S3

    Article  PubMed  PubMed Central  Google Scholar 

  • Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH et al (1996) DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271:350–353

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  • Hayashi M, Wang J, Hede SE, Novak I (2012) An intermediate-conductance Ca2+−activated K+ channel is important for secretion in pancreatic duct cells. Am J Physiol Cell Physiol 303:C151–C159

    Article  CAS  PubMed  Google Scholar 

  • Helm O, Held-Feindt J, Grage-Griebenow E, Reiling N, Ungefroren H, Vogel I, Kruger U, Becker T, Ebsen M, Rocken C et al (2014) Tumor-associated macrophages exhibit pro- and anti-inflammatory properties by which they impact on pancreatic tumorigenesis. Int J Cancer 135:843–861

    Article  CAS  PubMed  Google Scholar 

  • Hennig A, Wolf L, Jahnke B, Polster H, Seidlitz T, Werner K, Aust DE, Hampe J, Distler M, Weitz J et al (2019) CFTR expression analysis for subtyping of human pancreatic cancer organoids. Stem Cells Int 2019:1024614

    PubMed  PubMed Central  Google Scholar 

  • Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, Ross S, Conrads TP, Veenstra TD, Hitt BA et al (2003) Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4:437–450

    Article  CAS  PubMed  Google Scholar 

  • Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, Rustgi AK, Chang S, Tuveson DA (2005) Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7:469–483

    Article  CAS  PubMed  Google Scholar 

  • Hou Y, Guan X, Yang Z, Li C (2016) Emerging role of cystic fibrosis transmembrane conductance regulator - an epithelial chloride channel in gastrointestinal cancers. World J Gastrointest Oncol 8:282–288

    Article  PubMed  PubMed Central  Google Scholar 

  • Jager H, Dreker T, Buck A, Giehl K, Gress T, Grissmer S (2004) Blockage of intermediate-conductance Ca2+−activated K+ channels inhibit human pancreatic cancer cell growth in vitro. Mol Pharmacol 65:630–638

    Article  PubMed  Google Scholar 

  • Jiang S, Zhu L, Yang J, Hu L, Gu J, Xing X, Sun Y, Zhang Z (2017) Integrated expression profiling of potassium channels identifys KCNN4 as a prognostic biomarker of pancreatic cancer. Biochem Biophys Res Commun 494:113–119

    Article  CAS  PubMed  Google Scholar 

  • Kamel D, Gray C, Walia JS, Kumar V (2018) PARP inhibitor drugs in the treatment of breast, ovarian, prostate and pancreatic cancers: an update of clinical trials. Curr Drug Targets 19:21–37

    Article  CAS  PubMed  Google Scholar 

  • Kanda M, Matthaei H, Wu J, Hong SM, Yu J, Borges M, Hruban RH, Maitra A, Kinzler K, Vogelstein B et al (2012) Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology 142:730–733.e739

    Article  CAS  PubMed  Google Scholar 

  • Kayed H, Kleeff J, Kolb A, Ketterer K, Keleg S, Felix K, Giese T, Penzel R, Zentgraf H, Buchler MW et al (2006) FXYD3 is overexpressed in pancreatic ductal adenocarcinoma and influences pancreatic cancer cell growth. Int J Cancer 118:43–54

    Article  CAS  PubMed  Google Scholar 

  • Kendrick AA, Schafer J, Dzieciatkowska M, Nemkov T, D'Alessandro A, Neelakantan D, Ford HL, Pearson CG, Weekes CD, Hansen KC et al (2017) CD147: a small molecule transporter ancillary protein at the crossroad of multiple hallmarks of cancer and metabolic reprogramming. Oncotarget 8:6742–6762

    Article  PubMed  Google Scholar 

  • Kim S, Kang M, Lee S, Bae S, Han S, Jang JY, Park T (2014) Identifying molecular subtypes related to clinicopathologic factors in pancreatic cancer. Biomed Eng Online 13(Suppl 2):S5

    Article  PubMed  PubMed Central  Google Scholar 

  • Knudsen ES, Vail P, Balaji U, Ngo H, Botros IW, Makarov V, Riaz N, Balachandran V, Leach S, Thompson DM et al (2017) Stratification of pancreatic ductal adenocarcinoma: combinatorial genetic, stromal, and immunologic markers. Clin Cancer Res 23:4429–4440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kojima K, Vickers SM, Adsay NV, Jhala NC, Kim HG, Schoeb TR, Grizzle WE, Klug CA (2007) Inactivation of Smad4 accelerates Kras(G12D)-mediated pancreatic neoplasia. Cancer Res 67:8121–8130

    Article  CAS  PubMed  Google Scholar 

  • Kondratska K, Kondratskyi A, Yassine M, Lemonnier L, Lepage G, Morabito A, Skryma R, Prevarskaya N (2014) Orai1 and STIM1 mediate SOCE and contribute to apoptotic resistance of pancreatic adenocarcinoma. Biochim Biophys Acta 1843:2263–2269

    Article  CAS  PubMed  Google Scholar 

  • Kong SC, Giannuzzo A, Novak I, Pedersen SF (2014) Acid-base transport in pancreatic cancer: molecular mechanisms and clinical potential. Biochem Cell Biol 92:449–459

    Article  CAS  PubMed  Google Scholar 

  • Kong SC, Nohr-Nielsen A, Zeeberg K, Reshkin SJ, Hoffmann EK, Novak I, Pedersen SF (2016) Monocarboxylate transporters MCT1 and MCT4 regulate migration and invasion of pancreatic ductal adenocarcinoma cells. Pancreas 45:1036–1047

    Article  CAS  PubMed  Google Scholar 

  • Kovalenko I, Glasauer A, Schockel L, Sauter DR, Ehrmann A, Sohler F, Hagebarth A, Novak I, Christian S (2016) Identification of KCa3.1 channel as a novel regulator of oxidative phosphorylation in a subset of pancreatic carcinoma cell lines. PLoS One 11:e0160658

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lankadasari MB, Mukhopadhyay P, Mohammed S, Harikumar KB (2019) TAMing pancreatic cancer: combat with a double edged sword. Mol Cancer 18:48

    Article  PubMed  PubMed Central  Google Scholar 

  • Lastraioli E, Perrone G, Sette A, Fiore A, Crociani O, Manoli S, D’Amico M, Masselli M, Iorio J, Callea M et al (2015) hERG1 channels drive tumour malignancy and may serve as prognostic factor in pancreatic ductal adenocarcinoma. Br J Cancer 112:1076–1087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leanza L, Romio M, Becker KA, Azzolini M, Trentin L, Manago A, Venturini E, Zaccagnino A, Mattarei A, Carraretto L et al (2017) Direct pharmacological targeting of a mitochondrial ion channel selectively kills tumor cells in vivo. Cancer Cell 31:516–531.e510

    Article  CAS  PubMed  Google Scholar 

  • Ligorio M, Sil S, Malagon-Lopez J, Nieman LT, Misale S, Di Pilato M, Ebright RY, Karabacak MN, Kulkarni AS, Liu A et al (2019) Stromal microenvironment shapes the intratumoral architecture of pancreatic cancer. Cell 178:160–175.e127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin QJ, Yang F, Jin C, Fu DL (2015) Current status and progress of pancreatic cancer in China. World J Gastroenterol 21:7988–8003

    Article  PubMed  PubMed Central  Google Scholar 

  • Lin R, Wang Y, Chen Q, Liu Z, Xiao S, Wang B, Shi B (2018) TRPM2 promotes the proliferation and invasion of pancreatic ductal adenocarcinoma. Mol Med Rep 17:7537–7544

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu J, Hu G, Gong Y, Yu Q, He B, Li W, He Z, Hao W, Liu Y (2018) Silencing of TRPM8 inhibits aggressive tumor phenotypes and enhances gemcitabine sensitivity in pancreatic cancer. Pancreatology 18:935–944

    Article  CAS  PubMed  Google Scholar 

  • Long J, Zhang ZB, Liu Z, Xu YH, Ge CL (2015) Loss of heterozygosity at the calcium regulation gene locus on chromosome 10q in human pancreatic cancer. Asian Pac J Cancer Prev 16:2489–2493

    Article  PubMed  Google Scholar 

  • Luo G, Zhang Y, Guo P, Ji H, Xiao Y, Li K (2019) Global patterns and trends in pancreatic cancer incidence: age, period, and birth cohort analysis. Pancreas 48:199–208

    Article  PubMed  Google Scholar 

  • Mahmmoud YA, Vorum H, Cornelius F (2005) Interaction of FXYD10 (PLMS) with Na,K-ATPase from shark rectal glands. Close proximity of Cys74 of FXYD10 to Cys254 in the a domain of the alpha-subunit revealed by intermolecular thiol cross-linking. J Biol Chem 280:27776–27782

    Article  CAS  PubMed  Google Scholar 

  • Maisonneuve P (2019) Epidemiology and burden of pancreatic cancer. Presse Med 48:e113–e123

    Article  PubMed  Google Scholar 

  • Manoli S, Coppola S, Duranti C, Lulli M, Magni L, Kuppalu N, Nielsen N, Schmidt T, Schwab A, Becchetti A et al (2019) The activity of Kv 11.1 potassium channel modulates F-actin organization during cell migration of pancreatic ductal adenocarcinoma cells. Cancers (Basel) 11

    Google Scholar 

  • Martens S, Lefesvre P, Nicolle R, Biankin AV, Puleo F, Van Laethem JL, Rooman I (2019) Different shades of pancreatic ductal adenocarcinoma, different paths towards precision therapeutic applications. Ann Oncol 30:1428–1436

    Article  CAS  PubMed  Google Scholar 

  • Maruthappu M, Watkins J, Noor AM, Williams C, Ali R, Sullivan R, Zeltner T, Atun R (2016) Economic downturns, universal health coverage, and cancer mortality in high-income and middle-income countries, 1990-2010: a longitudinal analysis. Lancet 388:684–695

    Article  PubMed  Google Scholar 

  • Mattarei A, Romio M, Manago A, Zoratti M, Paradisi C, Szabo I, Leanza L, Biasutto L (2018) Novel mitochondria-targeted furocoumarin derivatives as possible anti-cancer agents. Front Oncol 8:122

    Article  PubMed  PubMed Central  Google Scholar 

  • Mayerle J, Kalthoff H, Reszka R, Kamlage B, Peter E, Schniewind B, Gonzalez Maldonado S, Pilarsky C, Heidecke CD, Schatz P et al (2018) Metabolic biomarker signature to differentiate pancreatic ductal adenocarcinoma from chronic pancreatitis. Gut 67:128–137

    Article  CAS  PubMed  Google Scholar 

  • Miller BA (2019) TRPM2 in cancer. Cell Calcium 80:8–17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moffitt RA, Marayati R, Flate EL, Volmar KE, Loeza SG, Hoadley KA, Rashid NU, Williams LA, Eaton SC, Chung AH et al (2015) Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet 47:1168–1178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moskaluk CA, Hruban RH, Kern SE (1997) p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res 57:2140–2143

    CAS  PubMed  Google Scholar 

  • Pedersen SF, Novak I, Alves F, Schwab A, Pardo LA (2017) Alternating pH landscapes shape epithelial cancer initiation and progression: focus on pancreatic cancer. BioEssays 39

    Google Scholar 

  • Peppicelli S, Bianchini F, Toti A, Laurenzana A, Fibbi G, Calorini L (2015) Extracellular acidity strengthens mesenchymal stem cells to promote melanoma progression. Cell Cycle 14:3088–3100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peruzzo R, Mattarei A, Romio M, Paradisi C, Zoratti M, Szabo I, Leanza L (2017) Regulation of proliferation by a mitochondrial potassium channel in pancreatic ductal adenocarcinoma cells. Front Oncol 7:239

    Article  PubMed  PubMed Central  Google Scholar 

  • Puleo F, Nicolle R, Blum Y, Cros J, Marisa L, Demetter P, Quertinmont E, Svrcek M, Elarouci N, Iovanna J et al (2018) Stratification of pancreatic ductal adenocarcinomas based on tumor and microenvironment features. Gastroenterology 155:1999–2013.e1993

    Article  PubMed  Google Scholar 

  • Raphael BJ et al (2017) Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 32:185–203.e113

    Article  CAS  Google Scholar 

  • Reddy RP, Smyrk TC, Zapiach M, Levy MJ, Pearson RK, Clain JE, Farnell MB, Sarr MG, Chari ST (2004) Pancreatic mucinous cystic neoplasm defined by ovarian stroma: demographics, clinical features, and prevalence of cancer. Clin Gastroenterol Hepatol 2:1026–1031

    Article  PubMed  Google Scholar 

  • Redston MS, Caldas C, Seymour AB, Hruban RH, da Costa L, Yeo CJ, Kern SE (1994) p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res 54:3025–3033

    CAS  PubMed  Google Scholar 

  • Ren B, Liu X, Suriawinata AA (2019) Pancreatic ductal adenocarcinoma and its precursor lesions: histopathology, cytopathology, and molecular pathology. Am J Pathol 189:9–21

    Article  PubMed  Google Scholar 

  • Ryder NM, Guha S, Hines OJ, Reber HA, Rozengurt E (2001) G protein-coupled receptor signaling in human ductal pancreatic cancer cells: neurotensin responsiveness and mitogenic stimulation. J Cell Physiol 186:53–64

    Article  CAS  PubMed  Google Scholar 

  • Sallan MC, Visa A, Shaikh S, Nager M, Herreros J, Canti C (2018) T-type Ca(2+) channels: T for targetable. Cancer Res 78:603–609

    Article  CAS  PubMed  Google Scholar 

  • Sauter DRP, Novak I, Pedersen SF, Larsen EH, Hoffmann EK (2015) ANO1 (TMEM16A) in pancreatic ductal adenocarcinoma (PDAC). Pflugers Arch 467:1495–1508

    Article  CAS  PubMed  Google Scholar 

  • Sauter DR, Sorensen CE, Rapedius M, Bruggemann A, Novak I (2016) pH-sensitive K(+) channel TREK-1 is a novel target in pancreatic cancer. Biochim Biophys Acta 1862:1994–2003

    Article  CAS  PubMed  Google Scholar 

  • Schnittert J, Bansal R, Prakash J (2019) Targeting pancreatic stellate cells in cancer. Trends Cancer 5:128–142

    Article  CAS  PubMed  Google Scholar 

  • Sica A, Schioppa T, Mantovani A, Allavena P (2006) Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 42:717–727

    Article  CAS  PubMed  Google Scholar 

  • Singhi AD, George B, Greenbowe JR, Chung J, Suh J, Maitra A, Klempner SJ, Hendifar A, Milind JM, Golan T et al (2019a) Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers. Gastroenterology 156:2242–2253.e2244

    Article  CAS  PubMed  Google Scholar 

  • Singhi AD, Wood LD, Parks E, Torbenson MS, Felsenstein M, Hruban RH, Nikiforova MN, Wald AI, Kaya C, Nikiforov YE et al (2019b) Recurrent rearrangements in PRKACA and PRKACB in intraductal oncocytic papillary neoplasms of the pancreas and bile duct. Gastroenterology 158:573–582

    Article  PubMed  CAS  Google Scholar 

  • Stock C, Pedersen SF (2017) Roles of pH and the Na(+)/H(+) exchanger NHE1 in cancer: from cell biology and animal models to an emerging translational perspective? Semin Cancer Biol 43:5–16

    Article  CAS  PubMed  Google Scholar 

  • Storck H, Hild B, Schimmelpfennig S, Sargin S, Nielsen N, Zaccagnino A, Budde T, Novak I, Kalthoff H, Schwab A (2017) Ion channels in control of pancreatic stellate cell migration. Oncotarget 8:769–784

    Article  PubMed  Google Scholar 

  • Tang B, Chow JY, Dong TX, Yang SM, Lu DS, Carethers JM, Dong H (2016) Calcium sensing receptor suppresses human pancreatic tumorigenesis through a novel NCX1/Ca(2+)/beta-catenin signaling pathway. Cancer Lett 377:44–54

    Article  CAS  PubMed  Google Scholar 

  • Ueki T, Toyota M, Sohn T, Yeo CJ, Issa JP, Hruban RH, Goggins M (2000) Hypermethylation of multiple genes in pancreatic adenocarcinoma. Cancer Res 60:1835–1839

    CAS  PubMed  Google Scholar 

  • Venkatachalam K, Montell C (2007) TRP channels. Annu Rev Biochem 76:387–417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, Johns AL, Miller D, Nones K, Quek K et al (2015) Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518:495–501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wartenberg M, Cibin S, Zlobec I, Vassella E, Eppenberger-Castori S, Terracciano L, Eichmann MD, Worni M, Gloor B, Perren A et al (2018) Integrated genomic and immunophenotypic classification of pancreatic cancer reveals three distinct subtypes with prognostic/predictive significance. Clin Cancer Res 24:4444–4454

    Article  CAS  PubMed  Google Scholar 

  • Whittle MC, Hingorani SR (2019) Fibroblasts in pancreatic ductal adenocarcinoma: biological mechanisms and therapeutic targets. Gastroenterology 156:2085–2096

    Article  CAS  PubMed  Google Scholar 

  • Williams S, Bateman A, O'Kelly I (2013) Altered expression of two-pore domain potassium (K2P) channels in cancer. PLoS One 8:e74589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yee NS, Zhou W, Lee M (2010) Transient receptor potential channel TRPM8 is over-expressed and required for cellular proliferation in pancreatic adenocarcinoma. Cancer Lett 297:49–55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yee NS, Chan AS, Yee JD, Yee RK (2012a) TRPM7 and TRPM8 ion channels in pancreatic adenocarcinoma: potential roles as cancer biomarkers and targets. Scientifica (Cairo) 2012:415158

    Google Scholar 

  • Yee NS, Zhou W, Lee M, Yee RK (2012b) Targeted silencing of TRPM7 ion channel induces replicative senescence and produces enhanced cytotoxicity with gemcitabine in pancreatic adenocarcinoma. Cancer Lett 318:99–105

    Article  CAS  PubMed  Google Scholar 

  • Yee NS, Li Q, Kazi AA, Yang Z, Berg A, Yee RK (2014) Aberrantly over-expressed TRPM8 channels in pancreatic adenocarcinoma: correlation with tumor size/stage and requirement for cancer cells invasion. Cell 3:500–516

    Article  CAS  Google Scholar 

  • Young SH, Rozengurt E (2010) Crosstalk between insulin receptor and G protein-coupled receptor signaling systems leads to Ca(2)+ oscillations in pancreatic cancer PANC-1 cells. Biochem Biophys Res Commun 401:154–158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zaccagnino A, Pilarsky C, Tawfik D, Sebens S, Trauzold A, Novak I, Schwab A, Kalthoff H (2016) In silico analysis of the transportome in human pancreatic ductal adenocarcinoma. Eur Biophys J 45:749–763

    Article  CAS  PubMed  Google Scholar 

  • Zaccagnino A, Manago A, Leanza L, Gontarewitz A, Linder B, Azzolini M, Biasutto L, Zoratti M, Peruzzo R, Legler K et al (2017) Tumor-reducing effect of the clinically used drug clofazimine in a SCID mouse model of pancreatic ductal adenocarcinoma. Oncotarget 8:38276–38293

    Article  PubMed  Google Scholar 

  • Zhan W, Shelton CA, Greer PJ, Brand RE, Whitcomb DC (2018) Germline variants and risk for pancreatic cancer: a systematic review and emerging concepts. Pancreas 47:924–936

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhao L, Zhao H, Yan H (2018) Gene expression profiling of 1200 pancreatic ductal adenocarcinoma reveals novel subtypes. BMC Cancer 18:603

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhi D, Zhao X, Dong M, Yan C (2017) miR-493 inhibits proliferation and invasion in pancreatic cancer cells and inversely regulated hERG1 expression. Oncol Lett 14:7398–7404

    PubMed  PubMed Central  Google Scholar 

  • Zhu S, Zhou HY, Deng SC, Deng SJ, He C, Li X, Chen JY, Jin Y, Hu ZL, Wang F et al (2017) ASIC1 and ASIC3 contribute to acidity-induced EMT of pancreatic cancer through activating Ca(2+)/RhoA pathway. Cell Death Dis 8:e2806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors like to thank Dr. Xueyou Zhang, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, for valuable support in drawing the figures and in silico analysis.

This study was supported by Zhejiang Provincial Natural Science Foundation of China (LR18H030001) and National Natural Science Foundation of China (81771713).

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Authors and Affiliations

  1. Department of Surgery, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Qi Ling

  2. Institute for Experimental Cancer Research, Comprehensive Cancer Center North, CAU, Kiel, Germany

    Holger Kalthoff

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  1. Qi Ling
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  2. Holger Kalthoff
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Correspondence to Qi Ling or Holger Kalthoff .

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Editors and Affiliations

  1. Medizinische Hochschule Hannover, Zentrum für Innere Medizin, Hannover, Germany

    Christian Stock

  2. Max-Planck-Institut für Experimentelle Medizin, Göttingen, Germany

    Luis A. Pardo

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Ling, Q., Kalthoff, H. (2020). Transportome Malfunctions and the Hallmarks of Pancreatic Cancer. In: Stock, C., Pardo, L.A. (eds) Transportome Malfunction in the Cancer Spectrum. Reviews of Physiology, Biochemistry and Pharmacology, vol 181. Springer, Cham. https://doi.org/10.1007/112_2020_20

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