title: Mutant p53 Together with TGFβ Signaling Influence Organ-Specific Hematogenous Colonization Patterns of Pancreatic Cancer.
abstract: Purpose:TP53 and the TGFβ pathway are major mediators of pancreatic cancer metastasis. The mechanisms by which they cause hematogenous metastasis have not been fully explored.Experimental Design:KPC(LSL-KRASG12D/+;LSL-Trp53R172H/+;Ptf1aCre/+) mice were generated, and the frequency and morphology of organ-specific hematogenous metastases compared with that seen inKPTCandKTClittermates (Tgfbr2+/-). Key findings were validated in primary cells from each genotype and samples of human pancreatic cancer liver metastases.Results:The frequency of hematogenous metastasis inKPTCmice was significantly lower than forKPCmice (41% vs. 68%,P< 0.05), largely due to a reduction in liver metastases. No differences were found betweenKPCandKPTClung metastases, whereas liver metastases inKPTCmice showed a profound extravasation deficiency characterized by sinusoidal growth and lack of desmoplastic stroma. Analogous findings were confirmed in liver samples from patients indicating their clinical relevance. Portal vein colonization as a direct mode of access to the liver was observed in both mice and humans. Secretome analyses ofKPCcells revealed an abundance of secreted prometastatic mediators including Col6A1 and Lcn2 that promoted early steps of metastatic colonization. These mediators were overexpressed in primary tumors but not metastases, suggesting that the ability to colonize is, in part, developed within the primary site, a phenomenon we refer to as the "Cinderella effect."Conclusions:These findings establish a novel paradigm for understanding pancreatic cancer metastasis and the observed clinical latencies of liver versus lung metastases specifically.Clin Cancer Res; 23(6); 1607-20. ©2016 AACR.
authors.affiliation: The David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.|Graduate Program in Pathobiology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Anne
authors.initials: A
authors.lastname: Macgregor-Das
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Tyler
authors.initials: T
authors.lastname: Saunders
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Whittle
authors.affiliation: The David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.|Graduate Program in Pathobiology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Alvin
authors.initials: A
authors.lastname: Makohon-Moore
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Kohutek
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Justin
authors.initials: J
authors.lastname: Poling
authors.affiliation: The David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Herbst
authors.affiliation: The David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Breanna M
authors.initials: BM
authors.lastname: Javier
authors.affiliation: Department of Oncology Biostatistics, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Leslie
authors.initials: L
authors.lastname: Cope
authors.affiliation: The David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Leach
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.|Division of Medical Oncology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Hingorani
authors.affiliation: The David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. iacobuzc@mskcc.org.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; C062602:transcription factor PTF1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)