TY - JOUR
T1 - Surveillance of Cancer Stem Cell Plasticity Using an Isoform-Selective Fluorescent Probe for Aldehyde Dehydrogenase 1A1
AU - Anorma, Chelsea
AU - Hedhli, Jamila
AU - Bearrood, Thomas E.
AU - Pino, Nicholas W.
AU - Gardner, Sarah H.
AU - Inaba, Hiroshi
AU - Zhang, Pamela
AU - Li, Yanfen
AU - Feng, Daven
AU - Dibrell, Sara E.
AU - Kilian, Kristopher A.
AU - Dobrucki, Lawrence W.
AU - Fan, Timothy M.
AU - Chan, Jefferson
N1 - Funding Information:
This work was supported by the Chemistry-Biology Interface Training Grant (T32 GM070421 to C.A. and N.W.P.), the National Science Foundation Graduate Research Fellowship Program (DGE 1144245 to C.A.), the Robert C. and Carolyn J. Springborn Graduate Fellowship (to C.A. and N.W.P.), the National Institute of Biomedical Imaging and Bioengineering Training Grant (T32EB019944 to J.H.), the Beckman Postdoctoral Fellowship (to J.H.), the Alfred P. Sloan Foundation MPHD Fellowship (to N.W.P.), and the Alfred P. Sloan fellowship (FG-2017-8964 to J.C.). Major funding for the 500 MHz Bruker CryoProbeTM was provided by the Roy J. Carver Charitable Trust (Muscatine, Iowa; Grant No. 15-4521) to the School of Chemical Sciences NMR Lab. The Q-T of Ultima mass spectrometer was purchased in part with a grant from the National Science Foundation, Division of Biological Infrastructure (DBI-0100085).
Funding Information:
This work was supported by the Chemistry-Biology Interface Training Grant (T32 GM070421 to C.A. and N.W.P.), the National Science Foundation Graduate Research Fellowship Program (DGE − 1144245 to C.A.), the Robert C. and Carolyn J. Springborn Graduate Fellowship (to C.A. and N.W.P.), the National Institute of Biomedical Imaging and Bioengineering Training Grant (T32EB019944 to J.H.), the Beckman Postdoctoral Fellowship (to J.H.), the Alfred P. Sloan Foundation MPHD Fellowship (to N.W.P.), and the Alfred P. Sloan fellowship (FG-2017-8964 to J.C.). Major funding for the 500 MHz Bruker CryoProbeTM was provided by the Roy J. Carver Charitable Trust (Muscatine, Iowa; Grant No. 15-4521) to the School of Chemical Sciences NMR Lab. The Q-T of Ultima mass spectrometer was purchased in part with a grant from the National Science Foundation, Division of Biological Infrastructure (DBI-0100085). We thank the Core Facilities at the Carl R. Woese Institute for Genomic Biology for access to the Zeiss LSM 700 Confocal Microscope and corresponding software. We acknowledge Dr. Iwona Dobrucka and the Molecular Imaging Laboratory at the Beckman Institute for use of the IVIS imaging system. We thank Dr. Barbara Pilas and the Flow Cytometry Facility for help with data analysis. We thank Dr. Sandra McMasters and the Cell Media Facility for assistance preparing cell culture media and advising on growth conditions. We thank Professor Daria Mochly-Rosen and Dr. Che-Hong Chen for ALDH plasmids. We thank Professor Tom Hurley for consultation on the crystal structure.
Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/8/22
Y1 - 2018/8/22
N2 - Cancer stem cells (CSCs) are progenitor cells that contribute to treatment-resistant phenotypes during relapse. CSCs exist in specific tissue microenvironments that cell cultures and more complex models cannot mimic. Therefore, the development of new approaches that can detect CSCs and report on specific properties (e.g., stem cell plasticity) in their native environment have profound implications for studying CSC biology. Herein, we present AlDeSense, a turn-on fluorescent probe for aldehyde dehydrogenase 1A1 (ALDH1A1) and Ctrl-AlDeSense, a matching nonresponsive reagent. Although ALDH1A1 contributes to the detoxification of reactive aldehydes, it is also associated with stemness and is highly elevated in CSCs. AlDeSense exhibits a 20-fold fluorescent enhancement when treated with ALDH1A1. Moreover, we established that AlDeSense is selective against a panel of common ALDH isoforms and exhibits exquisite chemostability against a collection of biologically relevant species. Through the application of surface marker antibody staining, tumorsphere assays, and assessment of tumorigenicity, we demonstrate that cells exhibiting high AlDeSense signal intensity have properties of CSCs. Using these probes in tandem, we have identified CSCs at the cellular level via flow cytometry and confocal imaging, as well as monitored their states in animal models.
AB - Cancer stem cells (CSCs) are progenitor cells that contribute to treatment-resistant phenotypes during relapse. CSCs exist in specific tissue microenvironments that cell cultures and more complex models cannot mimic. Therefore, the development of new approaches that can detect CSCs and report on specific properties (e.g., stem cell plasticity) in their native environment have profound implications for studying CSC biology. Herein, we present AlDeSense, a turn-on fluorescent probe for aldehyde dehydrogenase 1A1 (ALDH1A1) and Ctrl-AlDeSense, a matching nonresponsive reagent. Although ALDH1A1 contributes to the detoxification of reactive aldehydes, it is also associated with stemness and is highly elevated in CSCs. AlDeSense exhibits a 20-fold fluorescent enhancement when treated with ALDH1A1. Moreover, we established that AlDeSense is selective against a panel of common ALDH isoforms and exhibits exquisite chemostability against a collection of biologically relevant species. Through the application of surface marker antibody staining, tumorsphere assays, and assessment of tumorigenicity, we demonstrate that cells exhibiting high AlDeSense signal intensity have properties of CSCs. Using these probes in tandem, we have identified CSCs at the cellular level via flow cytometry and confocal imaging, as well as monitored their states in animal models.
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U2 - 10.1021/acscentsci.8b00313
DO - 10.1021/acscentsci.8b00313
M3 - Article
C2 - 30159402
AN - SCOPUS:85051986855
SN - 2374-7943
VL - 4
SP - 1045
EP - 1055
JO - ACS Central Science
JF - ACS Central Science
IS - 8
ER -