A stromal lysolipid–autotaxin signaling axis promotes pancreatic tumor progression

Francesca R. Auciello, Vinay Bulusu, Chet Oon, Jacqueline Tait-Mulder, Mark Berry, Sohinee Bhattacharyya, Sergey Tumanov, Brittany L. Allen-Petersen, Jason Link, Nicholas D. Kendsersky, Esmee Vringer, Michelle Schug, David Novo, Rosa Frances Hwang, Ronald M. Evans, Colin Nixon, Craig Dorrell, Jennifer P. Morton, Jim C. Norman, Rosalie C. SearsJurre J. Kamphorst, Mara H. Sherman

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) develops a pronounced stromal response reflecting an aberrant wound-healing process. This stromal reaction features trans-differentiation of tissue-resident pancreatic stellate cells (PSC) into activated cancer-associated fibroblasts, a process induced by PDAC cells but of unclear significance for PDAC progression. Here, we show that PSCs undergo a dramatic lipid metabolic shift during differentiation in the context of pancreatic tumorigenesis, including remodeling of the intracellular lipidome and secretion of abundant lipids in the activated, fibroblastic state. Specifically, stroma-derived lysophosphatidylcholines support PDAC cell synthesis of phosphatidylcholines, key components of cell membranes, and also facilitate production of the potent wound-healing mediator lysophosphatidic acid (LPA) by the extracellular enzyme autotaxin, which is overexpressed in PDAC. The autotaxin–LPA axis promotes PDAC cell proliferation, migration, and AKT activation, and genetic or pharmacologic autotaxin inhibition suppresses PDAC growth in vivo. Our work demonstrates how PDAC cells exploit the local production of wound-healing mediators to stimulate their own growth and migration. Significance: Our work highlights an unanticipated role for PSCs in producing the oncogenic LPA signaling lipid and demonstrates how PDAC tumor cells co-opt the release of wound-healing mediators by neighboring PSCs to promote their own proliferation and migration.

Original languageEnglish (US)
Pages (from-to)617-627
Number of pages11
JournalCancer discovery
Volume9
Issue number5
DOIs
StatePublished - May 1 2019

Fingerprint

Adenocarcinoma
Neoplasms
Wound Healing
Lipids
Pancreatic Stellate Cells
Lysophosphatidylcholines
Growth
Phosphatidylcholines
Cell Movement
Carcinogenesis
Cell Proliferation
Cell Membrane
Enzymes

ASJC Scopus subject areas

  • Oncology

Cite this

Auciello, F. R., Bulusu, V., Oon, C., Tait-Mulder, J., Berry, M., Bhattacharyya, S., ... Sherman, M. H. (2019). A stromal lysolipid–autotaxin signaling axis promotes pancreatic tumor progression. Cancer discovery, 9(5), 617-627. https://doi.org/10.1158/2159-8290.CD-18-1212

A stromal lysolipid–autotaxin signaling axis promotes pancreatic tumor progression. / Auciello, Francesca R.; Bulusu, Vinay; Oon, Chet; Tait-Mulder, Jacqueline; Berry, Mark; Bhattacharyya, Sohinee; Tumanov, Sergey; Allen-Petersen, Brittany L.; Link, Jason; Kendsersky, Nicholas D.; Vringer, Esmee; Schug, Michelle; Novo, David; Hwang, Rosa Frances; Evans, Ronald M.; Nixon, Colin; Dorrell, Craig; Morton, Jennifer P.; Norman, Jim C.; Sears, Rosalie C.; Kamphorst, Jurre J.; Sherman, Mara H.

In: Cancer discovery, Vol. 9, No. 5, 01.05.2019, p. 617-627.

Research output: Contribution to journalArticle

Auciello, FR, Bulusu, V, Oon, C, Tait-Mulder, J, Berry, M, Bhattacharyya, S, Tumanov, S, Allen-Petersen, BL, Link, J, Kendsersky, ND, Vringer, E, Schug, M, Novo, D, Hwang, RF, Evans, RM, Nixon, C, Dorrell, C, Morton, JP, Norman, JC, Sears, RC, Kamphorst, JJ & Sherman, MH 2019, 'A stromal lysolipid–autotaxin signaling axis promotes pancreatic tumor progression', Cancer discovery, vol. 9, no. 5, pp. 617-627. https://doi.org/10.1158/2159-8290.CD-18-1212
Auciello FR, Bulusu V, Oon C, Tait-Mulder J, Berry M, Bhattacharyya S et al. A stromal lysolipid–autotaxin signaling axis promotes pancreatic tumor progression. Cancer discovery. 2019 May 1;9(5):617-627. https://doi.org/10.1158/2159-8290.CD-18-1212
Auciello, Francesca R. ; Bulusu, Vinay ; Oon, Chet ; Tait-Mulder, Jacqueline ; Berry, Mark ; Bhattacharyya, Sohinee ; Tumanov, Sergey ; Allen-Petersen, Brittany L. ; Link, Jason ; Kendsersky, Nicholas D. ; Vringer, Esmee ; Schug, Michelle ; Novo, David ; Hwang, Rosa Frances ; Evans, Ronald M. ; Nixon, Colin ; Dorrell, Craig ; Morton, Jennifer P. ; Norman, Jim C. ; Sears, Rosalie C. ; Kamphorst, Jurre J. ; Sherman, Mara H. / A stromal lysolipid–autotaxin signaling axis promotes pancreatic tumor progression. In: Cancer discovery. 2019 ; Vol. 9, No. 5. pp. 617-627.
@article{b30010633eaf408c8a04d17c8f797690,
title = "A stromal lysolipid–autotaxin signaling axis promotes pancreatic tumor progression",
abstract = "Pancreatic ductal adenocarcinoma (PDAC) develops a pronounced stromal response reflecting an aberrant wound-healing process. This stromal reaction features trans-differentiation of tissue-resident pancreatic stellate cells (PSC) into activated cancer-associated fibroblasts, a process induced by PDAC cells but of unclear significance for PDAC progression. Here, we show that PSCs undergo a dramatic lipid metabolic shift during differentiation in the context of pancreatic tumorigenesis, including remodeling of the intracellular lipidome and secretion of abundant lipids in the activated, fibroblastic state. Specifically, stroma-derived lysophosphatidylcholines support PDAC cell synthesis of phosphatidylcholines, key components of cell membranes, and also facilitate production of the potent wound-healing mediator lysophosphatidic acid (LPA) by the extracellular enzyme autotaxin, which is overexpressed in PDAC. The autotaxin–LPA axis promotes PDAC cell proliferation, migration, and AKT activation, and genetic or pharmacologic autotaxin inhibition suppresses PDAC growth in vivo. Our work demonstrates how PDAC cells exploit the local production of wound-healing mediators to stimulate their own growth and migration. Significance: Our work highlights an unanticipated role for PSCs in producing the oncogenic LPA signaling lipid and demonstrates how PDAC tumor cells co-opt the release of wound-healing mediators by neighboring PSCs to promote their own proliferation and migration.",
author = "Auciello, {Francesca R.} and Vinay Bulusu and Chet Oon and Jacqueline Tait-Mulder and Mark Berry and Sohinee Bhattacharyya and Sergey Tumanov and Allen-Petersen, {Brittany L.} and Jason Link and Kendsersky, {Nicholas D.} and Esmee Vringer and Michelle Schug and David Novo and Hwang, {Rosa Frances} and Evans, {Ronald M.} and Colin Nixon and Craig Dorrell and Morton, {Jennifer P.} and Norman, {Jim C.} and Sears, {Rosalie C.} and Kamphorst, {Jurre J.} and Sherman, {Mara H.}",
year = "2019",
month = "5",
day = "1",
doi = "10.1158/2159-8290.CD-18-1212",
language = "English (US)",
volume = "9",
pages = "617--627",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "5",

}

TY - JOUR

T1 - A stromal lysolipid–autotaxin signaling axis promotes pancreatic tumor progression

AU - Auciello, Francesca R.

AU - Bulusu, Vinay

AU - Oon, Chet

AU - Tait-Mulder, Jacqueline

AU - Berry, Mark

AU - Bhattacharyya, Sohinee

AU - Tumanov, Sergey

AU - Allen-Petersen, Brittany L.

AU - Link, Jason

AU - Kendsersky, Nicholas D.

AU - Vringer, Esmee

AU - Schug, Michelle

AU - Novo, David

AU - Hwang, Rosa Frances

AU - Evans, Ronald M.

AU - Nixon, Colin

AU - Dorrell, Craig

AU - Morton, Jennifer P.

AU - Norman, Jim C.

AU - Sears, Rosalie C.

AU - Kamphorst, Jurre J.

AU - Sherman, Mara H.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Pancreatic ductal adenocarcinoma (PDAC) develops a pronounced stromal response reflecting an aberrant wound-healing process. This stromal reaction features trans-differentiation of tissue-resident pancreatic stellate cells (PSC) into activated cancer-associated fibroblasts, a process induced by PDAC cells but of unclear significance for PDAC progression. Here, we show that PSCs undergo a dramatic lipid metabolic shift during differentiation in the context of pancreatic tumorigenesis, including remodeling of the intracellular lipidome and secretion of abundant lipids in the activated, fibroblastic state. Specifically, stroma-derived lysophosphatidylcholines support PDAC cell synthesis of phosphatidylcholines, key components of cell membranes, and also facilitate production of the potent wound-healing mediator lysophosphatidic acid (LPA) by the extracellular enzyme autotaxin, which is overexpressed in PDAC. The autotaxin–LPA axis promotes PDAC cell proliferation, migration, and AKT activation, and genetic or pharmacologic autotaxin inhibition suppresses PDAC growth in vivo. Our work demonstrates how PDAC cells exploit the local production of wound-healing mediators to stimulate their own growth and migration. Significance: Our work highlights an unanticipated role for PSCs in producing the oncogenic LPA signaling lipid and demonstrates how PDAC tumor cells co-opt the release of wound-healing mediators by neighboring PSCs to promote their own proliferation and migration.

AB - Pancreatic ductal adenocarcinoma (PDAC) develops a pronounced stromal response reflecting an aberrant wound-healing process. This stromal reaction features trans-differentiation of tissue-resident pancreatic stellate cells (PSC) into activated cancer-associated fibroblasts, a process induced by PDAC cells but of unclear significance for PDAC progression. Here, we show that PSCs undergo a dramatic lipid metabolic shift during differentiation in the context of pancreatic tumorigenesis, including remodeling of the intracellular lipidome and secretion of abundant lipids in the activated, fibroblastic state. Specifically, stroma-derived lysophosphatidylcholines support PDAC cell synthesis of phosphatidylcholines, key components of cell membranes, and also facilitate production of the potent wound-healing mediator lysophosphatidic acid (LPA) by the extracellular enzyme autotaxin, which is overexpressed in PDAC. The autotaxin–LPA axis promotes PDAC cell proliferation, migration, and AKT activation, and genetic or pharmacologic autotaxin inhibition suppresses PDAC growth in vivo. Our work demonstrates how PDAC cells exploit the local production of wound-healing mediators to stimulate their own growth and migration. Significance: Our work highlights an unanticipated role for PSCs in producing the oncogenic LPA signaling lipid and demonstrates how PDAC tumor cells co-opt the release of wound-healing mediators by neighboring PSCs to promote their own proliferation and migration.

UR - http://www.scopus.com/inward/record.url?scp=85065509059&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065509059&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-18-1212

DO - 10.1158/2159-8290.CD-18-1212

M3 - Article

C2 - 30837243

AN - SCOPUS:85065509059

VL - 9

SP - 617

EP - 627

JO - Cancer Discovery

JF - Cancer Discovery

SN - 2159-8274

IS - 5

ER -