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Soft Three Dimensional Stromal Matrix Confines Pancreatic Cancer Cells Through Induction of Autophagy Lysosome Flux
Author(s) -
Han Yuanping,
Cheng Jingjing,
Wu Pengfei,
Yang Huan,
Zhang Chunyang,
Zeng Yilan,
Liu Yong,
Luo Mei,
Pandol Stephen L
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.lb365
Subject(s) - pancreatic cancer , extracellular matrix , autophagy , cancer research , cancer cell , microbiology and biotechnology , chemistry , stromal cell , cancer , biology , medicine , apoptosis , biochemistry
Pancreas is a soft orang. Malignancy of pancreatic ductal adenocarcinoma (PDAC) is intimately associated with pancreatic fibrogenesis and stiffness, generated by chronic pancreatitis, along with early oncogenetic transformation, indicating that soft stroma may confine tumor growth. Little is understood as to how soft three‐dimensional extracellular matrix (3D ECM) in the stroma can restain tumor progression even the cancer cells having acquired oncogenetic transformation. We noticed that embedded in soft 3D ECM, the pancreatic ductal adenocarcinoma cells (KRas/Trp53R172H) can be arrested at G1 phase, showing up‐regulation of p21 and Pten. In the soft 3D ECM, the cancer cells form tight junctions and epithelial ductal phenotypes. Conversely, on 2D stiff interface, the cancer cells are disseminated and exhibited EMT features. Among the 800 up‐regulated genes by the cancer cells in 3D ECM are the lysosomal genes, including cysteine cathepsins, acidic lipase, and v‐ATPase. Indeed, autophagy is highly active by the cells embedded in 3D ECM, featured by elevation of Atg8/LC3‐II, and turnover of p62, a cargo protein for auto‐lysosomal flux and substrate degradation. Lysosomal stress, induced by drugs of lipophilic amines, can inhibit the acidic proteinases, leading to accumulation of HDAC4 and Yap1, suggesting they are degraded through auto‐lysosome. On stiff interface (2D ECM), turnover of the cellular HDAC4 and is mostly operated by proteosomal pathway, wherein the auto‐lysosomal biogenesis is impaired, leading to HDAC4 and Yap1 accumulation. Animal experiments showed that pre‐programing of PDAC cells (Kras/Trp53) in soft 3D ECM could attenuate tumorigenicity. Conversely, existing liver fibrosis and stiffness can promote the tumorigenicity. Clinical studies showed that high levels of auto‐lysosoamal components such as cathepsins H and cathepsin L are related to better survival rate, indicating auto‐lysosomal flux in tumor suppression. Support or Funding Information National Science Foundation of China, and National Institutes of Health, USA This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .