Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring

Yu Shi, Weina Gao, Nikki K. Lytle, Peiwu Huang, Xiao Yuan, Amanda M. Dann, Maya Ridinger-Saison, Kathleen E. DelGiorno, Corina E. Antal, Gaoyang Liang, Annette R. Atkins, Galina Erikson, Huaiyu Sun, Jill Meisenhelder, Elena Terenziani, Gyunghwi Woo, Linjing Fang, Thom P. Santisakultarm, Uri Manor, Ruilian Xu & 18 others Carlos R. Becerra, Erkut Borazanci, Daniel D. Von Hoff, Paul M. Grandgenett, Michael A Hollingsworth, Mathias Leblanc, Sarah E. Umetsu, Eric A. Collisson, Miriam Scadeng, Andrew M. Lowy, Timothy R. Donahue, Tannishtha Reya, Michael Downes, Ronald M. Evans, Geoffrey M. Wahl, Tony Pawson, Ruijun Tian, Tony Hunter

Research output: Contribution to journalLetter

6 Citations (Scopus)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology 1,2 . The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance 3–7 . Furthermore, PSC activation occurs very early during PDAC tumorigenesis 8–10 , and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial–mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell–cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy.

Original languageEnglish (US)
Pages (from-to)131-135
Number of pages5
JournalNature
Volume569
Issue number7754
DOIs
StatePublished - May 2 2019

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Pancreatic Stellate Cells
Leukemia Inhibitory Factor
Pancreatic Neoplasms
Adenocarcinoma
Neoplasms
Carcinogenesis
Drug Resistance
Therapeutics
Communication
Tumor Microenvironment
Proteomics
Cell Differentiation
Pancreas
Neoplasm Metastasis
Drug Therapy
Survival

ASJC Scopus subject areas

  • General

Cite this

Shi, Y., Gao, W., Lytle, N. K., Huang, P., Yuan, X., Dann, A. M., ... Hunter, T. (2019). Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring. Nature, 569(7754), 131-135. https://doi.org/10.1038/s41586-019-1130-6

Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring. / Shi, Yu; Gao, Weina; Lytle, Nikki K.; Huang, Peiwu; Yuan, Xiao; Dann, Amanda M.; Ridinger-Saison, Maya; DelGiorno, Kathleen E.; Antal, Corina E.; Liang, Gaoyang; Atkins, Annette R.; Erikson, Galina; Sun, Huaiyu; Meisenhelder, Jill; Terenziani, Elena; Woo, Gyunghwi; Fang, Linjing; Santisakultarm, Thom P.; Manor, Uri; Xu, Ruilian; Becerra, Carlos R.; Borazanci, Erkut; Von Hoff, Daniel D.; Grandgenett, Paul M.; Hollingsworth, Michael A; Leblanc, Mathias; Umetsu, Sarah E.; Collisson, Eric A.; Scadeng, Miriam; Lowy, Andrew M.; Donahue, Timothy R.; Reya, Tannishtha; Downes, Michael; Evans, Ronald M.; Wahl, Geoffrey M.; Pawson, Tony; Tian, Ruijun; Hunter, Tony.

In: Nature, Vol. 569, No. 7754, 02.05.2019, p. 131-135.

Research output: Contribution to journalLetter

Shi, Y, Gao, W, Lytle, NK, Huang, P, Yuan, X, Dann, AM, Ridinger-Saison, M, DelGiorno, KE, Antal, CE, Liang, G, Atkins, AR, Erikson, G, Sun, H, Meisenhelder, J, Terenziani, E, Woo, G, Fang, L, Santisakultarm, TP, Manor, U, Xu, R, Becerra, CR, Borazanci, E, Von Hoff, DD, Grandgenett, PM, Hollingsworth, MA, Leblanc, M, Umetsu, SE, Collisson, EA, Scadeng, M, Lowy, AM, Donahue, TR, Reya, T, Downes, M, Evans, RM, Wahl, GM, Pawson, T, Tian, R & Hunter, T 2019, 'Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring', Nature, vol. 569, no. 7754, pp. 131-135. https://doi.org/10.1038/s41586-019-1130-6
Shi, Yu ; Gao, Weina ; Lytle, Nikki K. ; Huang, Peiwu ; Yuan, Xiao ; Dann, Amanda M. ; Ridinger-Saison, Maya ; DelGiorno, Kathleen E. ; Antal, Corina E. ; Liang, Gaoyang ; Atkins, Annette R. ; Erikson, Galina ; Sun, Huaiyu ; Meisenhelder, Jill ; Terenziani, Elena ; Woo, Gyunghwi ; Fang, Linjing ; Santisakultarm, Thom P. ; Manor, Uri ; Xu, Ruilian ; Becerra, Carlos R. ; Borazanci, Erkut ; Von Hoff, Daniel D. ; Grandgenett, Paul M. ; Hollingsworth, Michael A ; Leblanc, Mathias ; Umetsu, Sarah E. ; Collisson, Eric A. ; Scadeng, Miriam ; Lowy, Andrew M. ; Donahue, Timothy R. ; Reya, Tannishtha ; Downes, Michael ; Evans, Ronald M. ; Wahl, Geoffrey M. ; Pawson, Tony ; Tian, Ruijun ; Hunter, Tony. / Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring. In: Nature. 2019 ; Vol. 569, No. 7754. pp. 131-135.
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title = "Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring",
abstract = "Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology 1,2 . The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance 3–7 . Furthermore, PSC activation occurs very early during PDAC tumorigenesis 8–10 , and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial–mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell–cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy.",
author = "Yu Shi and Weina Gao and Lytle, {Nikki K.} and Peiwu Huang and Xiao Yuan and Dann, {Amanda M.} and Maya Ridinger-Saison and DelGiorno, {Kathleen E.} and Antal, {Corina E.} and Gaoyang Liang and Atkins, {Annette R.} and Galina Erikson and Huaiyu Sun and Jill Meisenhelder and Elena Terenziani and Gyunghwi Woo and Linjing Fang and Santisakultarm, {Thom P.} and Uri Manor and Ruilian Xu and Becerra, {Carlos R.} and Erkut Borazanci and {Von Hoff}, {Daniel D.} and Grandgenett, {Paul M.} and Hollingsworth, {Michael A} and Mathias Leblanc and Umetsu, {Sarah E.} and Collisson, {Eric A.} and Miriam Scadeng and Lowy, {Andrew M.} and Donahue, {Timothy R.} and Tannishtha Reya and Michael Downes and Evans, {Ronald M.} and Wahl, {Geoffrey M.} and Tony Pawson and Ruijun Tian and Tony Hunter",
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T1 - Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring

AU - Shi, Yu

AU - Gao, Weina

AU - Lytle, Nikki K.

AU - Huang, Peiwu

AU - Yuan, Xiao

AU - Dann, Amanda M.

AU - Ridinger-Saison, Maya

AU - DelGiorno, Kathleen E.

AU - Antal, Corina E.

AU - Liang, Gaoyang

AU - Atkins, Annette R.

AU - Erikson, Galina

AU - Sun, Huaiyu

AU - Meisenhelder, Jill

AU - Terenziani, Elena

AU - Woo, Gyunghwi

AU - Fang, Linjing

AU - Santisakultarm, Thom P.

AU - Manor, Uri

AU - Xu, Ruilian

AU - Becerra, Carlos R.

AU - Borazanci, Erkut

AU - Von Hoff, Daniel D.

AU - Grandgenett, Paul M.

AU - Hollingsworth, Michael A

AU - Leblanc, Mathias

AU - Umetsu, Sarah E.

AU - Collisson, Eric A.

AU - Scadeng, Miriam

AU - Lowy, Andrew M.

AU - Donahue, Timothy R.

AU - Reya, Tannishtha

AU - Downes, Michael

AU - Evans, Ronald M.

AU - Wahl, Geoffrey M.

AU - Pawson, Tony

AU - Tian, Ruijun

AU - Hunter, Tony

PY - 2019/5/2

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N2 - Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology 1,2 . The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance 3–7 . Furthermore, PSC activation occurs very early during PDAC tumorigenesis 8–10 , and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial–mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell–cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy.

AB - Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology 1,2 . The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance 3–7 . Furthermore, PSC activation occurs very early during PDAC tumorigenesis 8–10 , and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial–mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell–cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy.

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