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

被引：8

作者：

Dudgeon, Crissy ^{[1
]}

Casabianca, Anthony ^{[2
,3
]}

Harris, Chris ^{[2
,3
]}

Ogier, Charline ^{[4
]}

Bellina, Melanie ^{[5
,6
]}

Fiore, Stephany ^{[5
]}

Bernet, Agnes ^{[5
,6
]}

Ducarouge, Benjamin ^{[6
]}

Goldschneider, David ^{[6
]}

Su, Xiaoyang ^{[1
]}

Pitarresi, Jason ^{[8
]}

Hezel, Aram ^{[7
]}

De, Subhajyoti ^{[1
]}

Narrow, Wade ^{[2
,3
]}

Soliman, Fady ^{[9
]}

Shields, Cory ^{[3
]}

Vendramini-Costa, Debora Barbosa ^{[4
]}

Prela, Orjola ^{[2
]}

Wang, Lan ^{[10
]}

Astsaturov, Igor ^{[4
]}

Mehlen, Patrick ^{[5
,6
]}

Carpizo, Darren R. ^{[2
,3
]}

机构：

[1] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA

[2] Univ Rochester, Sch Med & Dent, Dept Surg, Div Surg Oncol, Rochester, NY 14642 USA

[3] Univ Rochester, Wilmot Canc Ctr, Rochester, NY 14642 USA

[4] Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA USA

[5] Univ Claude Bernard Lyon 1, Univ Lyon, Ctr Leon Berard, Apoptosis Canc & Dev Lab,Equipe Labellisee La Ligu, F-69008 Lyon, France

[6] Netris Pharm, F-69008 Lyon, France

[7] Univ Rochester, Sch Med & Dent, Dept Med, Div Med Oncol, Rochester, NY USA

[8] Univ Massachusetts, Dept Med, Div Hematol Oncol, Worcester, MA USA

[9] Rutgers Robert Wood Johnson Med Sch, New Brunswick, NJ USA

[10] Univ Rochester, Sch Med & Dent, Dept Pathol & Lab Med, Rochester, NY USA

来源：

CELL REPORTS | 2023年 / 42卷 / 11期

关键词：

EXPRESSION; SURVIVAL; CONFERS; GENE; CUES;

D O I：

10.1016/j.celrep.2023.113369

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：23