TGFB1-induced autophagy affects the pattern of pancreatic cancer progression in distinct ways depending on SMAD4 status

Autophagy. 2020 Mar;16(3):486-500. doi: 10.1080/15548627.2019.1628540. Epub 2019 Jun 17.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies. Given that macroautophagy/autophagy activation is prevalent in PDAC, the dual roles of autophagy could be involved in PDAC heterogeneity. In this work, we demonstrated that TGFB1 induced autophagic flux through SMAD4-dependent or SMAD4-independent pathways based on a distinct genetic context. In SMAD4-positive PDAC cells, TGFB1-induced autophagy promoted proliferation and inhibited migration by decreasing the nuclear translocation of SMAD4. Conversely, TGFB1-induced autophagy inhibited proliferation and promoted migration in SMAD4-negative cells through the regulation of MAPK/ERK activation. TGFB1 expression also positively correlated with LC3B expression in PDAC specimens. A high level of LC3B was associated with unfavorable overall survival (OS) and disease-free survival (DFS) in SMAD4-negative PDAC patients, although LC3B could not predict OS and DFS for the 110 PDAC patients. Thus, TGFB1-induced autophagy contributed to the different patterns of PDAC progression. This knowledge can aid in improving our understanding of the molecular classification of PDAC and might guide the development of therapeutic strategies for PDAC, especially for SMAD4-negative PDAC.Abbreviations: CDH1: cadherin 1; CDH2: cadherin 2; CI: combination index; CQ: chloroquine; DFS: disease-free survival; EMT: epithelial-to-mesenchymal transition; ERK: extracellular signal-regulated protein kinase; GFP: green fluorescent protein; IHC: immunohistochemistry; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPK: mitogen-activated protein kinase; OS: overall survival; PBS: phosphate-buffered saline; PDAC: pancreatic ductal adenocarcinoma; RAP: rapamycin; RFP: red fluorescent protein; RT: room temperature; shRNA: short-hairpin RNA; SQSTM1: sequestosome 1; TCGA: The Cancer Genome Atlas; TEM: transmission electron microscopy; TGFB1: transforming growth factor beta 1; TMA: tissue microarray.

Keywords: Autophagic flux; LC3B; metastasis; pancreatic ductal adenocarcinoma; proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Adenocarcinoma / ultrastructure
  • Autophagy*
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Carcinoma, Pancreatic Ductal / ultrastructure
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Disease Progression*
  • Female
  • Humans
  • MAP Kinase Signaling System
  • Male
  • Microtubule-Associated Proteins / metabolism
  • Middle Aged
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Pancreatic Neoplasms / ultrastructure
  • Prognosis
  • Sequestosome-1 Protein / metabolism
  • Smad4 Protein / metabolism*
  • Transforming Growth Factor beta1 / metabolism*

Substances

  • MAP1LC3B protein, human
  • Microtubule-Associated Proteins
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Smad4 Protein
  • TGFB1 protein, human
  • Transforming Growth Factor beta1

Grants and funding

This study was jointly funded by the National Science Foundation for Distinguished Young Scholars of China [No. 81625016]; the National Natural Science Foundation of China [No. 81502031] and the Shanghai Sailing Program [NO.17YF1402500].