Single cell profiling of potentiated phospho-protein networks in cancer cells.
Altered growth factor responses in phospho-protein-driven signaling networks are crucial to cancer cell survival and pathology. Profiles of cancer cell signaling networks might therefore identify mechanisms by which such cells interpret environmental cues for continued growth. Using multiparameter flow cytometry, we monitored phospho-protein responses to environmental cues in acute myeloid leukemia at the single cell level. By exposing cancer cell signaling networks to potentiating inputs, rather than relying upon the basal levels of protein phosphorylation alone, we could discern unique cancer network profiles that correlated with genetics and disease outcome. Strikingly, individual cancers manifested multiple cell subsets with unique network profiles, reflecting cancer heterogeneity at the level of signaling response. The results revealed a dramatic remodeling of signaling networks in cancer cells. Thus, single cell measurements of phospho-protein responses reveal shifts in signaling potential of a phospho-protein network, allowing for categorizing of cell network phenotypes by multidimensional molecular profiles of signaling.
Irish
Jonathan M
JM
Department of Microbiology & Immunology, Baxter Laboratory of Genetic Pharmacology, Stanford University, Stanford, CA 94305, USA.
Hovland
Randi
R
Krutzik
Peter O
PO
Perez
Omar D
OD
Bruserud
Øystein
Ø
Gjertsen
Bjørn T
BT
Nolan
Garry P
GP
D000970:Antineoplastic Agents / Q000494:pharmacology; D002274:Carcinogens, Environmental / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D005455:Fluorescent Antibody Technique / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D009154:Mutation / Q000235:genetics; D010750:Phosphoproteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D015534:Trans-Activators / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3; D018631:ras Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D002274:Carcinogens, Environmental; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D018631:ras Proteins