TGF-β1 secreted by pancreatic stellate cells promotes stemness and tumourigenicity in pancreatic cancer cells through L1CAM downregulation

被引：64

作者：

Dellle Cave, Donatella ^{[1
]}

Di Guida, Martina ^{[1
]}

Costa, Valerio ^{[1
]}

Sevillano, Marta ^{[2
]}

Ferrante, Luigi ^{[1
]}

Heeschen, Christopher ^{[3
]}

Corona, Marco ^{[1
]}

Cucciardi, Antonio ^{[1
]}

Lonardo, Enza ^{[1
,3
]}

机构：

[1] CNR, Inst Genet & Biophys Adriano Buzzati Traverso IGB, Via Pietro Castellino 111, I-80131 Naples, Italy

[2] Barcelona Inst Sci & Technol, IRB, Barcelona, Spain

[3] CNIO, Spanish Natl Canc Res Ctr, Madrid, Spain

来源：

ONCOGENE | 2020年 / 39卷 / 21期

基金：

欧盟地平线“2020”;

关键词：

DUCTAL ADENOCARCINOMA; ADHESION MOLECULE; PROGNOSTIC VALUE; UP-REGULATION; SELF-RENEWAL; EXPRESSION; L1; PROTEIN; PROVIDES; BINDING;

D O I：

10.1038/s41388-020-1289-1

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Pancreatic stellate cells (PSCs) secrete high levels of transforming growth factor-beta 1 (TGF-beta 1) that contributes to the development of pancreatic ductal adenocarcinoma (PDAC). TGF-beta 1 modulates the expression of L1 cell adhesion molecule (L1CAM), but its role in tumour progression still remains controversial. To clarify L1 function in PDAC and cellular phenotypes, we performed L1CAM cell sorting, silencing and overexpression in several primary pancreatic cancer cells. PSCs silenced for TGF-beta 1 were used for crosstalk experiments. We found that TGF-beta 1 secreted by PSCs negatively regulates L1CAM expression, through canonical TGF-beta-Smad2/3 signalling, leading to a more aggressive PDAC phenotype. Cells with reduced expression of L1CAM harboured enhanced stemness potential and tumourigenicity. Inactivation of TGF-beta 1 signalling in PSCs strongly reduced the aggressiveness of PDAC cells. Our data provide functional proof and mechanistic insights for the tumour-suppressive function of L1CAM via reducing stemness. Rescuing L1CAM expression in cancer cells through targeting of TGF-beta 1 reverses stemness and bears the potential to improve the still miserable prognosis of PDAC patients.

引用

页码：4271 / 4285

页数：15

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