PMID- 34172498
OWN - NLM
STAT- MEDLINE
DCOM- 20220407
LR  - 20220615
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 27
IP  - 19
DP  - 2021 Oct 1
TI  - PGC1alpha-Mediated Metabolic Reprogramming Drives the Stemness of Pancreatic 
      Precursor Lesions.
PG  - 5415-5429
LID - 10.1158/1078-0432.CCR-20-5020 [doi]
AB  - PURPOSE: Metabolic reprogramming and cancer stem cells drive the aggressiveness 
      of pancreatic ductal adenocarcinoma (PDAC). However, the metabolic and stemness 
      programs of pancreatic precursor lesions (PPL), considered early PDAC development 
      events, have not been thoroughly explored. EXPERIMENTAL DESIGN: Meta-analyses 
      using gene expression profile data from NCBI Gene Expression Omnibus and IHC on 
      tissue microarrays (TMA) were performed. The following animal and cellular models 
      were used: cerulean-induced KrasG12D; Pdx1 Cre (KC) acinar-to-ductal metaplasia 
      (ADM) mice, KrasG12D; Smad4Loss; Pdx-1 Cre (KCSmad4-) intraductal papillary 
      mucinous neoplasm (IPMN) mice, LGKC1 cell line derived from the 
      doxycycline-inducible Gnas IPMN model, and human IPMN organoids. Flow cytometry, 
      Seahorse extracellular flux analyzer, qRT-PCR, and sphere assay were used to 
      analyze metabolic and stemness features. SR18292 was used to inhibit PGC1alpha, and 
      short hairpin RNA was used to knockdown (KD) PGC1alpha. RESULTS: The meta-analysis 
      revealed a significant upregulation of specific stemness genes in ADM-mediated 
      pancreatic intraepithelial neoplasms (PanIN) and IPMN. Meta- and TMA analyses 
      followed by in vitro and in vivo validation revealed that ADM/PanIN exhibit 
      increased PGC1alpha and oxidative phosphorylation (OXPhos) but reduced CPT1A. IPMN 
      showed elevated PGC1alpha, fatty acid beta-oxidation (FAO) gene expression, and 
      FAO-OXPhos. PGC1alpha was co-overexpressed with its coactivator NRF1 in ADM/PanINs 
      and with PPARgamma in IPMN. PGC1alpha KD or SR18292 inhibited the specific metabolic and 
      stemness features of PPLs and repressed IPMN organoid growth. CONCLUSIONS: 
      ADM/PanINs and IPMNs show specific stemness signatures with unique metabolisms. 
      Inhibition of PGC1alpha using SR18292 diminishes the specific stemness by targeting 
      FAO-independent and FAO-dependent OXPhos of ADM/PanINs and IPMNs, respectively.
CI  - (c)2021 American Association for Cancer Research.
FAU - Nimmakayala, Rama Krishna
AU  - Nimmakayala RK
AUID- ORCID: 0000-0003-4637-4828
AD  - Department of Biochemistry and Molecular Biology, College of Medicine, University 
      of Nebraska Medical Center, Omaha, Nebraska.
FAU - Rauth, Sanchita
AU  - Rauth S
AUID- ORCID: 0000-0002-2441-8546
AD  - Department of Biochemistry and Molecular Biology, College of Medicine, University 
      of Nebraska Medical Center, Omaha, Nebraska.
FAU - Chirravuri Venkata, Ramakanth
AU  - Chirravuri Venkata R
AD  - Department of Biochemistry and Molecular Biology, College of Medicine, University 
      of Nebraska Medical Center, Omaha, Nebraska.
FAU - Marimuthu, Saravanakumar
AU  - Marimuthu S
AD  - Department of Biochemistry and Molecular Biology, College of Medicine, University 
      of Nebraska Medical Center, Omaha, Nebraska.
FAU - Nallasamy, Palanisamy
AU  - Nallasamy P
AD  - Department of Biochemistry and Molecular Biology, College of Medicine, University 
      of Nebraska Medical Center, Omaha, Nebraska.
FAU - Vengoji, Raghupathy
AU  - Vengoji R
AD  - Department of Biochemistry and Molecular Biology, College of Medicine, University 
      of Nebraska Medical Center, Omaha, Nebraska.
FAU - Lele, Subodh M
AU  - Lele SM
AD  - Department of Pathology and Microbiology, College of Medicine, University of 
      Nebraska Medical Center, Omaha, Nebraska.
FAU - Rachagani, Satyanarayana
AU  - Rachagani S
AD  - Department of Biochemistry and Molecular Biology, College of Medicine, University 
      of Nebraska Medical Center, Omaha, Nebraska.
FAU - Mallya, Kavita
AU  - Mallya K
AD  - Department of Biochemistry and Molecular Biology, College of Medicine, University 
      of Nebraska Medical Center, Omaha, Nebraska.
FAU - Malafa, Mokenge P
AU  - Malafa MP
AUID- ORCID: 0000-0003-2716-4315
AD  - Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and 
      Research Institute, Tampa, Florida.
FAU - Ponnusamy, Moorthy P
AU  - Ponnusamy MP
AD  - Department of Biochemistry and Molecular Biology, College of Medicine, University 
      of Nebraska Medical Center, Omaha, Nebraska.
AD  - Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela 
      Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska.
FAU - Batra, Surinder K
AU  - Batra SK
AD  - Department of Biochemistry and Molecular Biology, College of Medicine, University 
      of Nebraska Medical Center, Omaha, Nebraska.
AD  - Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela 
      Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska.
LA  - eng
GR  - U01 CA200466/CA/NCI NIH HHS/United States
GR  - R01 CA195586/CA/NCI NIH HHS/United States
GR  - U01 CA210240/CA/NCI NIH HHS/United States
GR  - R01 CA183459/CA/NCI NIH HHS/United States
GR  - R01 CA210637/CA/NCI NIH HHS/United States
GR  - P01 CA217798/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Meta-Analysis
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (PPARGC1A protein, human)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
SB  - IM
MH  - Animals
MH  - *Carcinoma, Pancreatic Ductal/pathology
MH  - Humans
MH  - Mice
MH  - Pancreas/pathology
MH  - Pancreatic Ducts/pathology
MH  - *Pancreatic Neoplasms/pathology
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 
      1-alpha/genetics/metabolism
PMC - PMC8709878
MID - NIHMS1720154
COIS- Conflicts of interest SKB is one of the co-founders of Sanguine Diagnostics and 
      Therapeutics, Inc. The other authors disclosed no potential conflicts of 
      interest.
EDAT- 2021/06/27 06:00
MHDA- 2022/04/08 06:00
PMCR- 2022/04/01
CRDT- 2021/06/26 05:41
PHST- 2020/12/30 00:00 [received]
PHST- 2021/04/06 00:00 [revised]
PHST- 2021/06/21 00:00 [accepted]
PHST- 2021/06/27 06:00 [pubmed]
PHST- 2022/04/08 06:00 [medline]
PHST- 2021/06/26 05:41 [entrez]
PHST- 2022/04/01 00:00 [pmc-release]
AID - 1078-0432.CCR-20-5020 [pii]
AID - 10.1158/1078-0432.CCR-20-5020 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2021 Oct 1;27(19):5415-5429. doi: 10.1158/1078-0432.CCR-20-5020.