TY - JOUR
T1 - Longitudinal analysis of human pancreatic adenocarcinoma development reveals transient gene expression signatures
AU - Kim, Jungsun
AU - Ekstrom, Taelor
AU - Yang, Wenli
AU - Donahue, Greg
AU - Grygoryev, Dmytro
AU - Ngo, Thuy T.M.
AU - Muschler, John L.
AU - Morgan, Terry
AU - Zaret, Kenneth S.
N1 - Funding Information:
The work was supported by grants from the Institute for Regenerative Medicine (IRM) at the University of Pennsylvania (UPenn), the Translational Center of Excellence from the Abramson Cancer Center (UPenn), Medical Research Foundation New Investigator Grant (GCNCR1042A, to J. Kim), and CRUK-OHSU Project Award (2018-CRUK-OHSU-001, to J. Kim). We thank the IRM's ES cell core facility, the UPenn Stem Cell & Xenograft Core, the UPenn Small Animal Imaging Facility, and the MPI Core of the Center for Molecular Studies in Digestive and Liver Diseases (NIH/NIDDK P30-DK050306). This article was edited at Life Science Editors.
Funding Information:
The work was supported by grants from the Institute for Regenerative Medicine (IRM) at the University of Pennsylvania (UPenn), the Translational Center of Excellence from the Abramson Cancer Center (UPenn), Medical Research Foundation New Investigator Grant (GCNCR1042A, to J. Kim), and CRUK-OHSU Project Award (2018-CRUK-OHSU-001, to J. Kim). We thank the IRM’s ES cell core facility, the UPenn Stem Cell & Xenograft Core, the UPenn Small Animal Imaging Facility, and the MPI Core of the Center for Molecular Studies in Digestive and Liver Diseases (NIH/NIDDK P30-DK050306). This article was edited at Life Science Editors.
Funding Information:
J. Kim reports grants from Medical Research Foundation New Investigator Grant and CRUK-OHSU Project Award during the conduct of the study. No disclosures were reported by the other authors.
Publisher Copyright:
© 2021 The Authors.
PY - 2021/11
Y1 - 2021/11
N2 - Previous transcriptome studies of human pancreatic ductal adenocarcinoma (PDAC) compare non-cancerous pancreatic intraepithelial neoplasias (PanIN) with late-stage PDAC obtained from different patients, thus have limited ability to discern network dynamics that contribute to the disease progression. We demonstrated previously that the 10-22 cell line, an induced pluripotent stem cell-like line reprogrammed from late-stage human PDAC cells, recapitulated the progression from PanINs to PDAC upon transplantation into NOD/LtSz-scid/IL2R-gammanull mice. Herein, we investigated the transition from precursor to PDAC using the isogenic model. We analyzed transcriptomes of genetically tagged 10-22 cells progressing from PanINs toPDAC in mice and validated the results using The Cancer Genome Atlas PDAC dataset, human clinical PanIN and PDAC tissues, and a well-established murine PDAC model. We functionally studied candidate proteins using human normal (H6C7) and cancerous (Miapaca2, Aspc1) pancreatic ductal epithelial cell lines. 10-22 cell-derived PDAC displayed the molecular signature of clinical human PDAC. Expression changes of many genes were transient during PDAC progression. Pathways for extracellular vesicle transport and neuronal cell differentiation were derepressed in the progression of PanINs to PDAC. HMG-box transcription factor 1 (HBP1) and BTB domain and CNC homolog 1 (BACH1) were implicated in regulating dynamically expressed genes during PDAC progression, and their expressions inversely correlated with PDAC patients' prognosis. Ectopic expression of HBP1 increased proliferation and migration of normal and cancerous pancreatic cells, indicating that HBP1 may confer the cell dissemination capacity in early PDAC progression. This unique longitudinal analysis provides insights into networks underlying human PDAC progression and pathogenesis. Implications: Manipulation of HBP1, BACH1, and RUN3 networks during PDAC progression can be harnessed to develop new targets for treating PDAC.
AB - Previous transcriptome studies of human pancreatic ductal adenocarcinoma (PDAC) compare non-cancerous pancreatic intraepithelial neoplasias (PanIN) with late-stage PDAC obtained from different patients, thus have limited ability to discern network dynamics that contribute to the disease progression. We demonstrated previously that the 10-22 cell line, an induced pluripotent stem cell-like line reprogrammed from late-stage human PDAC cells, recapitulated the progression from PanINs to PDAC upon transplantation into NOD/LtSz-scid/IL2R-gammanull mice. Herein, we investigated the transition from precursor to PDAC using the isogenic model. We analyzed transcriptomes of genetically tagged 10-22 cells progressing from PanINs toPDAC in mice and validated the results using The Cancer Genome Atlas PDAC dataset, human clinical PanIN and PDAC tissues, and a well-established murine PDAC model. We functionally studied candidate proteins using human normal (H6C7) and cancerous (Miapaca2, Aspc1) pancreatic ductal epithelial cell lines. 10-22 cell-derived PDAC displayed the molecular signature of clinical human PDAC. Expression changes of many genes were transient during PDAC progression. Pathways for extracellular vesicle transport and neuronal cell differentiation were derepressed in the progression of PanINs to PDAC. HMG-box transcription factor 1 (HBP1) and BTB domain and CNC homolog 1 (BACH1) were implicated in regulating dynamically expressed genes during PDAC progression, and their expressions inversely correlated with PDAC patients' prognosis. Ectopic expression of HBP1 increased proliferation and migration of normal and cancerous pancreatic cells, indicating that HBP1 may confer the cell dissemination capacity in early PDAC progression. This unique longitudinal analysis provides insights into networks underlying human PDAC progression and pathogenesis. Implications: Manipulation of HBP1, BACH1, and RUN3 networks during PDAC progression can be harnessed to develop new targets for treating PDAC.
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U2 - 10.1158/1541-7786.MCR-21-0483
DO - 10.1158/1541-7786.MCR-21-0483
M3 - Article
C2 - 34330844
AN - SCOPUS:85119123764
SN - 1541-7786
VL - 19
SP - 1854
EP - 1867
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 11
ER -