Mutant p53 together with tgfβ signaling influence organ-specific hematogenous colonization patterns of pancreatic cancer

Yi Zhong, Anne MacGregor-Das, Tyler Saunders, Martin C. Whittle, Alvin Makohon-Moore, Zachary A. Kohutek, Justin Poling, Brian T. Herbst, Breanna M. Javier, Leslie Cope, Steven D. Leach, Sunil R. Hingorani, Christine A. Iacobuzio-Donahue

Research output: Contribution to journalArticle

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 in KPTC and KTC littermates (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 in KPTC mice was significantly lower than for KPC mice (41% vs. 68%, P < 0.05), largely due to a reduction in liver metastases. No differences were found between KPC and KPTC lung metastases, whereas liver metastases in KPTC mice 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 of KPC cells 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.

Original languageEnglish (US)
Pages (from-to)1607-1620
Number of pages14
JournalClinical Cancer Research
Volume23
Issue number6
DOIs
StatePublished - Mar 15 2017

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Pancreatic Neoplasms
Neoplasm Metastasis
Liver
Lung
Liver Neoplasms
Portal Vein
Research Design
Genotype

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Zhong, Y., MacGregor-Das, A., Saunders, T., Whittle, M. C., Makohon-Moore, A., Kohutek, Z. A., ... Iacobuzio-Donahue, C. A. (2017). Mutant p53 together with tgfβ signaling influence organ-specific hematogenous colonization patterns of pancreatic cancer. Clinical Cancer Research, 23(6), 1607-1620. https://doi.org/10.1158/1078-0432.CCR-15-1615

Mutant p53 together with tgfβ signaling influence organ-specific hematogenous colonization patterns of pancreatic cancer. / Zhong, Yi; MacGregor-Das, Anne; Saunders, Tyler; Whittle, Martin C.; Makohon-Moore, Alvin; Kohutek, Zachary A.; Poling, Justin; Herbst, Brian T.; Javier, Breanna M.; Cope, Leslie; Leach, Steven D.; Hingorani, Sunil R.; Iacobuzio-Donahue, Christine A.

In: Clinical Cancer Research, Vol. 23, No. 6, 15.03.2017, p. 1607-1620.

Research output: Contribution to journalArticle

Zhong, Y, MacGregor-Das, A, Saunders, T, Whittle, MC, Makohon-Moore, A, Kohutek, ZA, Poling, J, Herbst, BT, Javier, BM, Cope, L, Leach, SD, Hingorani, SR & Iacobuzio-Donahue, CA 2017, 'Mutant p53 together with tgfβ signaling influence organ-specific hematogenous colonization patterns of pancreatic cancer', Clinical Cancer Research, vol. 23, no. 6, pp. 1607-1620. https://doi.org/10.1158/1078-0432.CCR-15-1615
Zhong, Yi ; MacGregor-Das, Anne ; Saunders, Tyler ; Whittle, Martin C. ; Makohon-Moore, Alvin ; Kohutek, Zachary A. ; Poling, Justin ; Herbst, Brian T. ; Javier, Breanna M. ; Cope, Leslie ; Leach, Steven D. ; Hingorani, Sunil R. ; Iacobuzio-Donahue, Christine A. / Mutant p53 together with tgfβ signaling influence organ-specific hematogenous colonization patterns of pancreatic cancer. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 6. pp. 1607-1620.
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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 in KPTC and KTC littermates (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 in KPTC mice was significantly lower than for KPC mice (41{\%} vs. 68{\%}, P < 0.05), largely due to a reduction in liver metastases. No differences were found between KPC and KPTC lung metastases, whereas liver metastases in KPTC mice 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 of KPC cells 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.",
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T1 - Mutant p53 together with tgfβ signaling influence organ-specific hematogenous colonization patterns of pancreatic cancer

AU - Zhong, Yi

AU - MacGregor-Das, Anne

AU - Saunders, Tyler

AU - Whittle, Martin C.

AU - Makohon-Moore, Alvin

AU - Kohutek, Zachary A.

AU - Poling, Justin

AU - Herbst, Brian T.

AU - Javier, Breanna M.

AU - Cope, Leslie

AU - Leach, Steven D.

AU - Hingorani, Sunil R.

AU - Iacobuzio-Donahue, Christine A.

PY - 2017/3/15

Y1 - 2017/3/15

N2 - 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 in KPTC and KTC littermates (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 in KPTC mice was significantly lower than for KPC mice (41% vs. 68%, P < 0.05), largely due to a reduction in liver metastases. No differences were found between KPC and KPTC lung metastases, whereas liver metastases in KPTC mice 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 of KPC cells 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.

AB - 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 in KPTC and KTC littermates (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 in KPTC mice was significantly lower than for KPC mice (41% vs. 68%, P < 0.05), largely due to a reduction in liver metastases. No differences were found between KPC and KPTC lung metastases, whereas liver metastases in KPTC mice 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 of KPC cells 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.

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