Netrin-1 feedforward mechanism promotes pancreatic cancer liver metastasis via hepatic stellate cell activation, retinoid, and ELF3 signaling

Crissy Dudgeon; Anthony Casabianca; Chris Harris; Charline Ogier; Mélanie Bellina; Stephany Fiore; Agnes Bernet; Benjamin Ducarouge; David Goldschneider; Xiaoyang Su; Jason Pitarresi; Aram Hezel; Subhajyoti De; Wade Narrow; Fady Soliman; Cory Shields; Debora Barbosa Vendramini-Costa; Orjola Prela; Lan Wang; Igor Astsaturov; Patrick Mehlen; Darren R Carpizo

doi:10.1016/j.celrep.2023.113369

Netrin-1 feedforward mechanism promotes pancreatic cancer liver metastasis via hepatic stellate cell activation, retinoid, and ELF3 signaling

Crissy Dudgeon, Anthony Casabianca, Chris Harris, Charline Ogier, Mélanie Bellina, Stephany Fiore, Agnes Bernet, Benjamin Ducarouge, David Goldschneider, Xiaoyang Su, Jason Pitarresi, Aram Hezel, Subhajyoti De, Wade Narrow, Fady Soliman, Cory Shields, Debora Barbosa Vendramini-Costa, Orjola Prela, Lan Wang, Igor AstsaturovPatrick Mehlen, Darren R Carpizo

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

The biology of metastatic pancreatic ductal adenocarcinoma (PDAC) is distinct from that of the primary tumor due to changes in cell plasticity governed by a distinct transcriptome. Therapeutic strategies that target this distinct biology are needed. We detect an upregulation of the neuronal axon guidance molecule Netrin-1 in PDAC liver metastases that signals through its dependence receptor (DR), uncoordinated-5b (Unc5b), to facilitate metastasis in vitro and in vivo. The mechanism of Netrin-1 induction involves a feedforward loop whereby Netrin-1 on the surface of PDAC-secreted extracellular vesicles prepares the metastatic niche by inducing hepatic stellate cell activation and retinoic acid secretion that in turn upregulates Netrin-1 in disseminated tumor cells via RAR/RXR and Elf3 signaling. While this mechanism promotes PDAC liver metastasis, it also identifies a therapeutic vulnerability, as it can be targeted using anti-Netrin-1 therapy to inhibit metastasis using the Unc5b DR cell death mechanism.

Original language	English
Article number	113369
Pages (from-to)	113369
Journal	Cell Reports
Volume	42
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2023.113369
State	Published - Nov 28 2023

Keywords

Humans
Netrin-1
Retinoids
Hepatic Stellate Cells/metabolism
Cell Line, Tumor
Pancreatic Neoplasms/pathology
Carcinoma, Pancreatic Ductal/pathology
Liver Neoplasms/metabolism
Netrin Receptors
DNA-Binding Proteins
Transcription Factors
Proto-Oncogene Proteins c-ets
hepatic stellate cells
extracellular vesicles
metastatic niche
pancreatic cancer
retinoic acid
Elf3
metastasis
CP: Cancer
Unc5b
axon guidance

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2023.113369

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Dudgeon, C., Casabianca, A., Harris, C., Ogier, C., Bellina, M., Fiore, S., Bernet, A., Ducarouge, B., Goldschneider, D., Su, X., Pitarresi, J., Hezel, A., De, S., Narrow, W., Soliman, F., Shields, C., Vendramini-Costa, D. B., Prela, O., Wang, L., ... Carpizo, D. R. (2023). Netrin-1 feedforward mechanism promotes pancreatic cancer liver metastasis via hepatic stellate cell activation, retinoid, and ELF3 signaling. Cell Reports, 42(11), 113369. Article 113369. https://doi.org/10.1016/j.celrep.2023.113369

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title = "Netrin-1 feedforward mechanism promotes pancreatic cancer liver metastasis via hepatic stellate cell activation, retinoid, and ELF3 signaling",

abstract = "The biology of metastatic pancreatic ductal adenocarcinoma (PDAC) is distinct from that of the primary tumor due to changes in cell plasticity governed by a distinct transcriptome. Therapeutic strategies that target this distinct biology are needed. We detect an upregulation of the neuronal axon guidance molecule Netrin-1 in PDAC liver metastases that signals through its dependence receptor (DR), uncoordinated-5b (Unc5b), to facilitate metastasis in vitro and in vivo. The mechanism of Netrin-1 induction involves a feedforward loop whereby Netrin-1 on the surface of PDAC-secreted extracellular vesicles prepares the metastatic niche by inducing hepatic stellate cell activation and retinoic acid secretion that in turn upregulates Netrin-1 in disseminated tumor cells via RAR/RXR and Elf3 signaling. While this mechanism promotes PDAC liver metastasis, it also identifies a therapeutic vulnerability, as it can be targeted using anti-Netrin-1 therapy to inhibit metastasis using the Unc5b DR cell death mechanism.",

keywords = "Humans, Netrin-1, Retinoids, Hepatic Stellate Cells/metabolism, Cell Line, Tumor, Pancreatic Neoplasms/pathology, Carcinoma, Pancreatic Ductal/pathology, Liver Neoplasms/metabolism, Netrin Receptors, DNA-Binding Proteins, Transcription Factors, Proto-Oncogene Proteins c-ets, hepatic stellate cells, extracellular vesicles, metastatic niche, pancreatic cancer, retinoic acid, Elf3, metastasis, CP: Cancer, Unc5b, axon guidance",

author = "Crissy Dudgeon and Anthony Casabianca and Chris Harris and Charline Ogier and M{\'e}lanie Bellina and Stephany Fiore and Agnes Bernet and Benjamin Ducarouge and David Goldschneider and Xiaoyang Su and Jason Pitarresi and Aram Hezel and Subhajyoti De and Wade Narrow and Fady Soliman and Cory Shields and Vendramini-Costa, {Debora Barbosa} and Orjola Prela and Lan Wang and Igor Astsaturov and Patrick Mehlen and Carpizo, {Darren R}",

year = "2023",

month = nov,

day = "28",

doi = "10.1016/j.celrep.2023.113369",

language = "English",

volume = "42",

pages = "113369",

journal = "Cell Reports",

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Dudgeon, C, Casabianca, A, Harris, C, Ogier, C, Bellina, M, Fiore, S, Bernet, A, Ducarouge, B, Goldschneider, D, Su, X, Pitarresi, J, Hezel, A, De, S, Narrow, W, Soliman, F, Shields, C, Vendramini-Costa, DB, Prela, O, Wang, L, Astsaturov, I, Mehlen, P & Carpizo, DR 2023, 'Netrin-1 feedforward mechanism promotes pancreatic cancer liver metastasis via hepatic stellate cell activation, retinoid, and ELF3 signaling', Cell Reports, vol. 42, no. 11, 113369, pp. 113369. https://doi.org/10.1016/j.celrep.2023.113369

TY - JOUR

T1 - Netrin-1 feedforward mechanism promotes pancreatic cancer liver metastasis via hepatic stellate cell activation, retinoid, and ELF3 signaling

AU - Dudgeon, Crissy

AU - Casabianca, Anthony

AU - Harris, Chris

AU - Ogier, Charline

AU - Bellina, Mélanie

AU - Fiore, Stephany

AU - Bernet, Agnes

AU - Ducarouge, Benjamin

AU - Goldschneider, David

AU - Su, Xiaoyang

AU - Pitarresi, Jason

AU - Hezel, Aram

AU - De, Subhajyoti

AU - Narrow, Wade

AU - Soliman, Fady

AU - Shields, Cory

AU - Vendramini-Costa, Debora Barbosa

AU - Prela, Orjola

AU - Wang, Lan

AU - Astsaturov, Igor

AU - Mehlen, Patrick

AU - Carpizo, Darren R

PY - 2023/11/28

Y1 - 2023/11/28

N2 - The biology of metastatic pancreatic ductal adenocarcinoma (PDAC) is distinct from that of the primary tumor due to changes in cell plasticity governed by a distinct transcriptome. Therapeutic strategies that target this distinct biology are needed. We detect an upregulation of the neuronal axon guidance molecule Netrin-1 in PDAC liver metastases that signals through its dependence receptor (DR), uncoordinated-5b (Unc5b), to facilitate metastasis in vitro and in vivo. The mechanism of Netrin-1 induction involves a feedforward loop whereby Netrin-1 on the surface of PDAC-secreted extracellular vesicles prepares the metastatic niche by inducing hepatic stellate cell activation and retinoic acid secretion that in turn upregulates Netrin-1 in disseminated tumor cells via RAR/RXR and Elf3 signaling. While this mechanism promotes PDAC liver metastasis, it also identifies a therapeutic vulnerability, as it can be targeted using anti-Netrin-1 therapy to inhibit metastasis using the Unc5b DR cell death mechanism.

AB - The biology of metastatic pancreatic ductal adenocarcinoma (PDAC) is distinct from that of the primary tumor due to changes in cell plasticity governed by a distinct transcriptome. Therapeutic strategies that target this distinct biology are needed. We detect an upregulation of the neuronal axon guidance molecule Netrin-1 in PDAC liver metastases that signals through its dependence receptor (DR), uncoordinated-5b (Unc5b), to facilitate metastasis in vitro and in vivo. The mechanism of Netrin-1 induction involves a feedforward loop whereby Netrin-1 on the surface of PDAC-secreted extracellular vesicles prepares the metastatic niche by inducing hepatic stellate cell activation and retinoic acid secretion that in turn upregulates Netrin-1 in disseminated tumor cells via RAR/RXR and Elf3 signaling. While this mechanism promotes PDAC liver metastasis, it also identifies a therapeutic vulnerability, as it can be targeted using anti-Netrin-1 therapy to inhibit metastasis using the Unc5b DR cell death mechanism.

KW - Humans

KW - Netrin-1

KW - Retinoids

KW - Hepatic Stellate Cells/metabolism

KW - Cell Line, Tumor

KW - Pancreatic Neoplasms/pathology

KW - Carcinoma, Pancreatic Ductal/pathology

KW - Liver Neoplasms/metabolism

KW - Netrin Receptors

KW - DNA-Binding Proteins

KW - Transcription Factors

KW - Proto-Oncogene Proteins c-ets

KW - hepatic stellate cells

KW - extracellular vesicles

KW - metastatic niche

KW - pancreatic cancer

KW - retinoic acid

KW - Elf3

KW - metastasis

KW - CP: Cancer

KW - Unc5b

KW - axon guidance

UR - http://www.scopus.com/inward/record.url?scp=85175445845&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2023.113369

DO - 10.1016/j.celrep.2023.113369

M3 - Article

C2 - 37922311

SN - 2211-1247

VL - 42

SP - 113369

JO - Cell Reports

JF - Cell Reports

IS - 11

M1 - 113369

ER -

Netrin-1 feedforward mechanism promotes pancreatic cancer liver metastasis via hepatic stellate cell activation, retinoid, and ELF3 signaling

Abstract

Keywords

UN SDGs

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