From Inception to Invasion: Modeling Pathways to Pancreatic Cancer

  • Sunil R. Hingorani
Part of the M. D. Anderson Solid Tumor Oncology Series book series (MDA)

Despite a relatively modest incidence, pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related deaths in the Western hemisphere (1). The reason is straightforward and sobering: with rare exception, pancreas cancer kills every patient it afflicts. The disease is not only uniformly but also rapidly lethal, largely because of delayed detection. Most patients are diagnosed too late in the course of disease progression to permit surgical intervention. Symptoms, when they occur at all, are typically vague and nonlocalizing, and there are currently no biomarkers for early detection. Radiographically evident lesions have already crossed the threshold of curability. Nevertheless, it is difficult to escape the conclusion that the improved survival seen in the first few years after surgery in the fortuitous few results from lead-time bias (2); all of these patients also eventually succumb to recurrent and/or metastatic disease. Despite increasingly aggressive surgical procedures and the use of adjuvant chemotherapies and radiation, the result is the same (3–5). Anatomy and biology conspire not only to elude early detection but also to hinder scientific inquiry. The pancreas is difficult to access and hazardous to biopsy: the organ does not forgive violation and biopsy can be fraught with the potentially dire consequences of pancreatitis.

These ineluctable truths of pancreas cancer beg the development of animal models that faithfully mimic the disease from its very inception to invasion and metastasis. In fact, driven by the ubiquity and sequelae of diabetes, genetic manipulation of the murine pancreas has a long and rich history that dates to the earliest experiments in transgenesis. Those early years formed the foundation for continuing refinements that have recently achieved notable success. These most recent attempts, specifically employing conditional activation of oncogenic K-ras, to genetically engineer pancreatic ductal adenocarcinoma in the mouse are the prescribed purview of this chapter.


Pancreatic Cancer Pancreatic Ductal Adenocarcinoma Intraductal Papillary Mucinous Neoplasm Pancreas Cancer Noonan Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Jemal A, Siegel R, Ward E, 2007, Cancer statistics, 2007. CA Cancer J Clin 57: 43–66.CrossRefPubMedGoogle Scholar
  2. 2.
    Hingorani SR, Tuveson D. A. 2003, In search of an early warning system for pancreatic cancer. Cancer Biol Ther 2:84–86.PubMedGoogle Scholar
  3. 3.
    Allison DC, Piantadosi S, Hruban RH, 1998, DNA content and other factors associated with ten-year survival after resection of pancreatic carcinoma. J Surg Oncol 67:151–159.CrossRefPubMedGoogle Scholar
  4. 4.
    Farnell MB, Pearson RK, Sarr MG, 2005, A prospective randomized trial comparing standard pancreatoduodenectomy with pancreatoduodenectomy with extended lymphadenectomy in resectable pancreatic head adenocarcinoma. Surgery 138: 618–628; discussion 628-630.CrossRefPubMedGoogle Scholar
  5. 5.
    Oettle H, Post S, Neuhaus P, 2007, Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 297:267–277.CrossRefPubMedGoogle Scholar
  6. 6.
    Hruban RH, Adsay NV, Albores-Saavedra J, 2001, Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol 25:579–586.CrossRefPubMedGoogle Scholar
  7. 7.
    Hruban RH, Takaori K, Klimstra DS, 2004, An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol 28:977–987.CrossRefPubMedGoogle Scholar
  8. 8.
    Cubilla AL, Fitzgerald PJ. 1976, Morphological lesions associated with human primary inva-sive nonendocrine pancreas cancer. Cancer Res 36:2690–2698.PubMedGoogle Scholar
  9. 9.
    Klimstra DS, Longnecker DS. 1994, K-ras mutations in pancreatic ductal proliferative lesions. Am J Pathol 145:1547–1550.PubMedGoogle Scholar
  10. 10.
    Adsay NV. 2005, Pathological classification of cystic neoplasms of the pancreas. In: Hoff DD, Von Evans DB, Hruban RH (eds.) Pancreatic cancer. Sudbury, Jones and Bartlett, MA, 716–756.Google Scholar
  11. 11. Hruban RH. 2006 Tumors of the pancreas. In: Hruban RH, Klimstra DS, Pitman MB (eds.) Atlas of tumor pathology, 4 Armed Forces Institute of Pathology, Washington, DC, th series ed.Google Scholar
  12. 12.
    Tanaka M, Chari S, Adsay V, 2006, International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 6:17–32.CrossRefPubMedGoogle Scholar
  13. 13.
    Maitra A, Fukushima N, Takaori K, 2005, Precursors to invasive pancreatic cancer. Adv Anat Pathol 12:81–91.CrossRefPubMedGoogle Scholar
  14. 14.
    Sugiyama M, Atomi Y. 2003, Recent topics in mucinous cystic tumor and intraductal papil-lary mucinous tumor of the pancreas. J Hepatobiliary Pancreat Surg 10:123–124.CrossRefPubMedGoogle Scholar
  15. 15.
    Goh BK, Tan YM, Cheow PC, 2005, Cystic neoplasms of the pancreas with mucin-produc-tion. Eur J Surg Oncol 31:282–287.CrossRefPubMedGoogle Scholar
  16. 16.
    Goh BK, Tan YM, Chung YF, 2006, A review of mucinous cystic neoplasms of the pancreas defined by ovarian-type stroma: clinicopathological features of 344 patients. World J Surg 30:2236–2245.CrossRefPubMedGoogle Scholar
  17. 17.
    Hruban RH, Goggins M, Parsons J, 2000, Progression model for pancreatic cancer. Clin Cancer Res 6:2969–2972.PubMedGoogle Scholar
  18. 18.
    Iacobuzio-Donahue CA, Wilentz RE, Argani P, 2000, Dpc4 protein in mucinous cystic neo-plasms of the pancreas: frequent loss of expression in invasive carcinomas suggests a role in genetic progression. Am J Surg Pathol 24:1544–1548.CrossRefPubMedGoogle Scholar
  19. 19.
    Schonleben F, Qiu W, Ciau NT, 2006, PIK3CA mutations in intraductal papillary mucinous neoplasm/carcinoma of the pancreas. Clin Cancer Res 12:3851–3855.CrossRefPubMedGoogle Scholar
  20. 20.
    Sato N, Rosty C, Jansen M, 2001, STK11/LKB1 Peutz-Jeghers gene inactivation in intraduc-tal papillary-mucinous neoplasms of the pancreas. Am J Pathol 159:2017–2022.PubMedGoogle Scholar
  21. 21.
    Iacobuzio-Donahue CA, Klimstra DS, Adsay NV, 2000, Dpc-4 protein is expressed in virtu-ally all human intraductal papillary mucinous neoplasms of the pancreas: comparison with conventional ductal adenocarcinomas. Am J Pathol 157:755–761.PubMedGoogle Scholar
  22. 22.
    Osvaldt AB, Wendt LR, Bersch VP, 2006, Pancreatic intraepithelial neoplasia and ductal ade-nocarcinoma induced by DMBA in mice. Surgery 140:803–809.CrossRefPubMedGoogle Scholar
  23. 23.
    Kimura K, Satoh K, Kanno A, 2007, Activation of Notch signaling in tumorigenesis of experi-mental pancreatic cancer induced by dimethylbenzanthracene in mice. Cancer Sci 98:155–162.CrossRefPubMedGoogle Scholar
  24. 24.
    Leach SD. 2004, Mouse models of pancreatic cancer: the fur is finally flying! Cancer Cell 5:7–11.CrossRefPubMedGoogle Scholar
  25. 25.
    Grippo PJ, Sandgren EP. 2005, Modeling pancreatic cancer in animals to address specific hypotheses. Methods Mol Med 103:217–243.PubMedGoogle Scholar
  26. 26.
    Hingorani SR. 2005, Modeling pancreatic ductal adenocarcinoma in the mouse. In: Gress TM, Neoptolemos JP, Lemoine (eds.) NR, Exocrine pancreas cancer. Felsenstein CCCP Publishing, Hannover, 152–171.Google Scholar
  27. 27.
    Lowy AM. 2003, Transgenic models of pancreatic cancer. Int J Gastrointest Cancer 33:71–78.CrossRefPubMedGoogle Scholar
  28. 28.
    Sandgren EP, Quaife CJ, Paulovich AG, 1991, Pancreatic tumor pathogenesis reflects the causative genetic lesion. Proc Natl Acad Sci U S A, 88:93–97.CrossRefPubMedGoogle Scholar
  29. 29.
    Hanahan D. 1985, Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 315:115–122.CrossRefPubMedGoogle Scholar
  30. 30.
    Ornitz DM, Hammer RE, Messing A, 1987, Pancreatic neoplasia induced by SV40 T-antigen expression in acinar cells of transgenic mice. Science 238:188–193.CrossRefPubMedGoogle Scholar
  31. 31.
    Quaife CJ, Pinkert CA, Ornitz DM, 1987, Pancreatic neoplasia induced by ras expression in acinar cells of transgenic mice. Cell 48:1023–1034.CrossRefPubMedGoogle Scholar
  32. 32.
    Hanahan D, Folkman J. 1996, Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364.CrossRefPubMedGoogle Scholar
  33. 33.
    Sandgren EP, Luetteke NC, Palmiter RD, 1990, Overexpression of TGF alpha in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell 61:1121–1135.CrossRefPubMedGoogle Scholar
  34. 34.
    Wagner M, Luhrs H, Kloppel G, 1998, Malignant transformation of duct-like cells originating from acini in transforming growth factor transgenic mice. Gastroenterology 115:1254–1262.CrossRefPubMedGoogle Scholar
  35. 35.
    Wagner M, Greten FR, Weber CK, 2001, A murine tumor progression model for pancreatic cancer recapitulating the genetic alterations of the human disease. Genes Dev 15:286–293.CrossRefPubMedGoogle Scholar
  36. 36.
    Grippo PJ, Nowlin PS, Demeure MJ, 2003, Preinvasive pancreatic neoplasia of ductal pheno-type induced by acinar cell targeting of mutant Kras in transgenic mice. Cancer Res 63:2016–2019.PubMedGoogle Scholar
  37. 37.
    Brembeck FH, Schreiber FS, Deramaudt TB, 2003, The mutant K-ras oncogene causes pan-creatic periductal lymphocytic infiltration and gastric mucous neck cell hyperplasia in trans-genic mice. Cancer Res 63:2005–2009.PubMedGoogle Scholar
  38. 38.
    Jonkers J, Berns A. 2002, Conditional mouse models of sporadic cancer. Nat Rev Cancer 2:251–265.CrossRefPubMedGoogle Scholar
  39. 39.
    Dyke T, Van Jacks T. 2002, Cancer modeling in the modern era: progress and challenges. Cell 108:135–144.CrossRefPubMedGoogle Scholar
  40. 40.
    Rangarajan A, Weinberg RA. 2003, Opinion: comparative biology of mouse versus human cells: modelling human cancer in mice. Nat Rev Cancer 3:952–959.CrossRefPubMedGoogle Scholar
  41. 41.
    Donehower LA, Harvey M, Slagle BL, 1992, Mice deficient for p53 are developmentally nor-mal but susceptible to spontaneous tumours. Nature 356:215–221.CrossRefPubMedGoogle Scholar
  42. 42.
    Jacks T, Remington L, Williams BO, 1994, Tumor spectrum analysis in p53-mutant mice. Curr Biol 4:1–7.CrossRefPubMedGoogle Scholar
  43. 43.
    Serrano M, Lee H, Chin L, 1996, Role of the INK4a locus in tumor suppression and cell mor-tality. Cell 85:27–37.CrossRefPubMedGoogle Scholar
  44. 44.
    Sirard C, Pompa JL, de la Elia A, 1998, The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo. Genes Dev 12:107–119.CrossRefPubMedGoogle Scholar
  45. 45.
    Takaku K, Oshima M, Miyoshi H, 1998, Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes. Cell 92:645–656.CrossRefPubMedGoogle Scholar
  46. 46.
    Takaku K, Miyoshi H, Matsunaga A, 1999, Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice. Cancer Res 59:6113–6117.PubMedGoogle Scholar
  47. 47.
    Xu X, Brodie SG, Yang X, 2000, Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric polyposis and cancer in mice. Oncogene 19:1868–1874.CrossRefPubMedGoogle Scholar
  48. 48.
    Tuveson DA, Shaw AT, Willis NA, 2004, Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5:375–387.CrossRefPubMedGoogle Scholar
  49. 49.
    Sauer B. 1998, I nducible gene targeting in mice using the Cre/lox system. Methods 14:381–392.CrossRefPubMedGoogle Scholar
  50. 50.
    Branda CS, Dymecki SM. 2004, Talking about a revolution: The impact of site-specific recombinases on genetic analyses in mice. Dev Cell 6:7–28.CrossRefPubMedGoogle Scholar
  51. 51.
    Hingorani SR, Petricoin EF, Maitra A, 2003, Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4:437–450.CrossRefPubMedGoogle Scholar
  52. 52.
    Hansel DE, Kern SE, Hruban RH. 2003, Molecular pathogenesis of pancreatic cancer. Annu Rev Genomics Hum Genet 4:237–256.CrossRefPubMedGoogle Scholar
  53. 53.
    Hingorani SR, Wang L, Multani AS, 2005, Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7:469–483.CrossRefPubMedGoogle Scholar
  54. 54.
    Aguirre AJ, Bardeesy N, Sinha M, 2003, Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev 17:3112–3126.CrossRefPubMedGoogle Scholar
  55. 55.
    Hruban RH, Adsay NV, Albores-Saavedra J, 2006, A. Pathology of genetically engineered mouse models of pancreatic exocrine cancer. consensus report and recommendations. Cancer Res 66:95–106.CrossRefPubMedGoogle Scholar
  56. 56.
    Bardeesy N, Aguirre AJ, Chu GC, 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.CrossRefPubMedGoogle Scholar
  57. 57.
    Izeradjene K, Combs C, Best M, 2007, Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. Cancer Cell 11:229–243.CrossRefPubMedGoogle Scholar
  58. 58.
    Bardeesy N, Cheng KH, Berger JH, 2006, Smad4 is dispensable for normal pancreas develop-ment yet critical in progression and tumor biology of pancreas cancer. Genes Dev 20:3130–3146.CrossRefPubMedGoogle Scholar
  59. 59.
    Gorelik L, Flavell RA. 2002, Transforming growth factor-beta in T-cell biology. Nat Rev Immunol 2:46–53.CrossRefPubMedGoogle Scholar
  60. 60.
    Siegel PM, Massague J. 2003, Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer 3:807–821.CrossRefPubMedGoogle Scholar
  61. 61.
    Bhowmick NA, Neilson EG, Moses HL. 2004, Stromal fibroblasts in cancer initiation and progression. Nature 432:332–337.CrossRefPubMedGoogle Scholar
  62. 62.
    Ijichi H, Chytil A, Gorska AE, 2006, Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooper-ation with active Kras expression. Genes Dev 20:3147–3160.CrossRefPubMedGoogle Scholar
  63. 63.
    Kelly OG, Melton DA. 2000, Development of the pancreas in Xenopus laevis. Dev Dyn 218:615–627.CrossRefPubMedGoogle Scholar
  64. 64.
    Kim SK, Hebrok M, Melton DA. 1997, Pancreas development in the chick embryo. Cold Spring Harb Symp Quant Biol 62:377–383.PubMedGoogle Scholar
  65. 65.
    Slack JM. 1995, Developmental biology of the pancreas. Development 121:1569–1580.PubMedGoogle Scholar
  66. 66.
    Niihori T, Aoki Y, Narumi Y, 2006, Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet 38:294–296.CrossRefPubMedGoogle Scholar
  67. 67.
    Schubbert S, Zenker M, Rowe SL, 2006, Germline KRAS mutations cause Noonan syndrome. Nat Genet 38:331–336.CrossRefPubMedGoogle Scholar
  68. 68.
    Apelqvist A, Li H, Sommer L, 1999, Notch signalling controls pancreatic cell differentiation. Nature 400:877–881.CrossRefPubMedGoogle Scholar
  69. 69.
    Jensen J, Pedersen EE, Galante P, 2000, Control of endodermal endocrine development by Hes-1. Nat Genet 24:36–44.CrossRefPubMedGoogle Scholar
  70. 70.
    Miyamoto Y, Maitra A, Ghosh B, 2003, Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell 3:565–576.CrossRefPubMedGoogle Scholar
  71. 71.
    Hebrok M. 2003, Hedgehog signaling in pancreas development. Mech Dev 120:45–57.CrossRefPubMedGoogle Scholar
  72. 72.
    Berman DM, Karhadkar SS, Maitra A, 2003, Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425:846–851.CrossRefPubMedGoogle Scholar
  73. 73.
    Thayer SP, di Magliano MP, Heiser PW, 2003, Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425:851–856.CrossRefPubMedGoogle Scholar
  74. 74.
    Apelqvist A, Ahlgren U, Edlund H. 1997, Sonic hedgehog directs specialised mesoderm dif-ferentiation in the intestine and pancreas. Curr Biol 7:801–804.CrossRefPubMedGoogle Scholar
  75. 75.
    Pasca di Magliano M, Sekine S, Ermilov A, 2006, Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Genes Dev 20:3161–3173.CrossRefPubMedGoogle Scholar
  76. 76.
    Land H, Parada LF, Weinberg RA. 1983, Tumorigenic conversion of primary embryo fibrob-lasts requires at least two cooperating oncogenes. Nature 304:596–602.CrossRefPubMedGoogle Scholar
  77. 77.
    Ruley HE. 1983, Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture. Nature 304:602–606.CrossRefPubMedGoogle Scholar
  78. 78.
    Serrano M, Lin AW, McCurrach ME, 1997, Oncogenic ras provokes premature cell senes-cence associated with accumulation of p53 and p16INK4a. Cell 88:593–602.CrossRefPubMedGoogle Scholar
  79. 79.
    Malumbres M, Barbacid M. 2003, RAS oncogenes: the first 30 years. Nat Rev Cancer 3:459–465.CrossRefPubMedGoogle Scholar
  80. 80.
    Almoguera C, Shibata D, Forrester K, 1988, Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53:549–554.CrossRefPubMedGoogle Scholar
  81. 81.
    Guerra C, Mijimolle N, Dhawahir A, 2003, Tumor induction by an endogenous K-ras onco-gene is highly dependent on cellular context. Cancer Cell 4:111–120.CrossRefPubMedGoogle Scholar
  82. 82.
    Hamad NM, Elconin JH, Karnoub AE, 2002, Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev 16:2045–2057.CrossRefPubMedGoogle Scholar
  83. 83.
    Rangarajan A, Hong SJ, Gifford A, 2004, Species- and cell type-specific requirements for cellular transformation. Cancer Cell 6:171–183.CrossRefPubMedGoogle Scholar
  84. 84.
    Hingorani SR, Tuveson DA. 2003, Ras redux: rethinking how and where Ras acts. Curr Opin Genet Dev 13:6–13.CrossRefPubMedGoogle Scholar
  85. 85.
    Burris HA 3rdMoore MJ, Andersen J, 1997, Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a rand-omized trial. J Clin Oncol 15:2403–2413.PubMedGoogle Scholar
  86. 86.
    Ko AH, Tempero MA. 2005, Treatment of metastatic pancreatic cancer. J Natl Compr Canc Netw 3:627–636.PubMedGoogle Scholar
  87. 87.
    Cardenes HR, Chiorean EG, Dewitt J, 2006, Locally advanced pancreatic cancer: current therapeutic approach. Oncologist 11:612–623.CrossRefPubMedGoogle Scholar
  88. 88.
    Xiong HQ, Carr K, Abbruzzese JL. 2006, Cytotoxic chemotherapy for pancreatic cancer: Advances to date and future directions. Drugs 66:1059–1072.CrossRefPubMedGoogle Scholar
  89. 89.
    Tang PA, Tsao MS, Moore MJ. 2006, A review of erlotinib and its clinical use. Expert Opin Pharmacother 7:177–193.CrossRefPubMedGoogle Scholar
  90. 90.
    Canto MI, Goggins M, Hruban RH, 2006, Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study. Clin Gastroenterol Hepatol 4:766–781; quiz 665.CrossRefPubMedGoogle Scholar
  91. 91.
    Rulyak SJ, Brentnall TA. 2001, Inherited pancreatic cancer: surveillance and treatment strategies for affected families. Pancreatology 1:477–485.CrossRefPubMedGoogle Scholar
  92. 92.
    Archer H, Jura N, Keller J, 2006, A mouse model of hereditary pancreatitis generated by transgenic expression of R122H trypsinogen. Gastroenterology 131:1844–1855.CrossRefPubMedGoogle Scholar
  93. 93.
    Cano DA, Sekine S, Hebrok M. 2006, Primary cilia deletion in pancreatic epithelial cells results in cyst formation and pancreatitis. Gastroenterology 131:1856–1869.CrossRefPubMedGoogle Scholar
  94. 94.
    Lowenfels AB, Maisonneuve P, Cavallini G, 1993, Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med 328:1433–437.CrossRefPubMedGoogle Scholar
  95. 95.
    Lowenfels AB, Maisonneuve P, DiMagno EP, 1997, Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J Natl Cancer Inst 89:442–446.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2008

Authors and Affiliations

  • Sunil R. Hingorani
    • 1
  1. 1.Fred Hutchinson Cancer Research CenterUniversity of Washington School of MedicineSeattleUSA

Personalised recommendations