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 F. 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

16 Scopus citations

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 2019

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'A stromal lysolipid–autotaxin signaling axis promotes pancreatic tumor progression'. Together they form a unique fingerprint.

  • Cite this

    Auciello, F. R., Bulusu, V., Oon, C., Tait-Mulder, J., Berry, M., Bhattacharyya, S., Tumanov, S., Allen-Petersen, B. L., Link, J., Kendsersky, N. D., Vringer, E., Schug, M., Novo, D., Hwang, R. F., Evans, R. M., Nixon, C., Dorrell, C., Morton, J. P., Norman, J. C., ... 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