TY - JOUR
T1 - Collagen production and niche engineering
T2 - A novel strategy for cancer cells to survive acidosis in DCIS and evolve
AU - Damaghi, Mehdi
AU - Mori, Hidetoshi
AU - Byrne, Samantha
AU - Xu, Liping
AU - Chen, Tingan
AU - Johnson, Joseph
AU - Gallant, Nathan D.
AU - Marusyk, Andriy
AU - Borowsky, Alexander D.
AU - Gillies, Robert J.
N1 - Funding Information:
We thank the staff of the Molecular Genomics Core, Proteomics and Metabolomics Core, and Analytical Microscopy Core of the Moffitt Cancer Center for their assistance with these studies. The Cores are partially funded by the National Cancer Institute through P30CA076292 as a Cancer Center Support Grant. A.D.B and H.M were supported by a grant from NIH/NCI (U01CA196406). M.D. and R.J.G. were supported by grants from NCI (R01CA077571) and NIH/NCI PSOC(1U54CA193489).
PY - 2020/12
Y1 - 2020/12
N2 - Growing tumors are dynamic and nonlinear ecosystems, wherein cancer cells adapt to their local microenvironment, and these adaptations further modify the environment, inducing more changes. From nascent intraductal neoplasms to disseminated metastatic disease, several levels of evolutionary adaptations and selections occur. Here, we focus on one example of such an adaptation mechanism, namely, “niche construction” promoted by adaptation to acidosis, which is a metabolic adaptation to the early harsh environment in intraductal neoplasms. The avascular characteristics of ductal carcinoma in situ (DCIS) make the periluminal volume profoundly acidic, and cancer cells must adapt to this to survive. Based on discovery proteomics, we hypothesized that a component of acid adaptation involves production of collagen by pre-cancer cells that remodels the extracellular matrix (ECM) and stabilizes cells under acid stress. The proteomic data were surprising as collagen production and deposition are commonly believed to be the responsibility of mesenchymally derived fibroblasts, and not cells of epithelial origin. Subsequent experiments in 3D culture, spinning disk and second harmonic generation microscopy of DCIS lesions in patients’ samples are concordant. Collagen production assay by acid-adapted cells in vitro demonstrated that the mechanism of induction involves the RAS and SMAD pathways. Secretome analyses show upregulation of ECM remodeling enzymes such as TGM2 and LOXL2 that are collagen crosslinkers. These data strongly indicate that acidosis in incipient cancers induces collagen production by cancer cells and support the hypothesis that this adaptation initiates a tumor-permissive microenvironment promoting survival and growth of nascent cancers.
AB - Growing tumors are dynamic and nonlinear ecosystems, wherein cancer cells adapt to their local microenvironment, and these adaptations further modify the environment, inducing more changes. From nascent intraductal neoplasms to disseminated metastatic disease, several levels of evolutionary adaptations and selections occur. Here, we focus on one example of such an adaptation mechanism, namely, “niche construction” promoted by adaptation to acidosis, which is a metabolic adaptation to the early harsh environment in intraductal neoplasms. The avascular characteristics of ductal carcinoma in situ (DCIS) make the periluminal volume profoundly acidic, and cancer cells must adapt to this to survive. Based on discovery proteomics, we hypothesized that a component of acid adaptation involves production of collagen by pre-cancer cells that remodels the extracellular matrix (ECM) and stabilizes cells under acid stress. The proteomic data were surprising as collagen production and deposition are commonly believed to be the responsibility of mesenchymally derived fibroblasts, and not cells of epithelial origin. Subsequent experiments in 3D culture, spinning disk and second harmonic generation microscopy of DCIS lesions in patients’ samples are concordant. Collagen production assay by acid-adapted cells in vitro demonstrated that the mechanism of induction involves the RAS and SMAD pathways. Secretome analyses show upregulation of ECM remodeling enzymes such as TGM2 and LOXL2 that are collagen crosslinkers. These data strongly indicate that acidosis in incipient cancers induces collagen production by cancer cells and support the hypothesis that this adaptation initiates a tumor-permissive microenvironment promoting survival and growth of nascent cancers.
KW - anoikis
KW - cancer evolution
KW - collagen production
KW - extracellular matrix remodeling enzymes
KW - K-RAS
KW - Niche construction and engineering
KW - SMAD
KW - tumor microenvironment
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U2 - 10.1111/eva.13075
DO - 10.1111/eva.13075
M3 - Article
AN - SCOPUS:85096575253
VL - 13
SP - 2689
EP - 2703
JO - Evolutionary Applications
JF - Evolutionary Applications
SN - 1752-4571
IS - 10
ER -