TY - JOUR
T1 - PGC1a-mediated metabolic reprogramming drives the stemness of pancreatic precursor lesions
AU - Nimmakayala, Rama Krishna
AU - Rauth, Sanchita
AU - Venkata, Ramakanth Chirravuri
AU - Marimuthu, Saravanakumar
AU - Nallasamy, Palanisamy
AU - Vengoji, Raghupathy
AU - Lele, Subodh M.
AU - Rachagani, Satyanarayana
AU - Mallya, Kavita
AU - Malafa, Mokenge P.
AU - Ponnusamy, Moorthy P.
AU - Batra, Surinder K.
N1 - Funding Information:
We thank Corinn E. Grabow for all the technical support. We thank Craig Semerad, Victoria B. Smith, and Samantha Wall of the Flow Cytometry Research Facility, University of Nebraska Medical Center, for assisting with flow cytometry. We thank Anirban Maitra, MD Anderson Cancer Center, for providing the LGKC1 cell line. This work was supported, in part, by the NIH (P01 CA217798, R01 CA183459, R01 CA195586, R01 CA210637, U01 CA200466, and U01 CA210240). We thank Dr. Jessica Mercer for the editorial contribution to the article.
Publisher Copyright:
© 2021 American Association for Cancer Research
PY - 2021/10/1
Y1 - 2021/10/1
N2 - 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 PGC1a, and short hairpin RNA was used to knockdown (KD) PGC1a. 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 PGC1a and oxidative phosphorylation (OXPhos) but reduced CPT1A. IPMN showed elevated PGC1a, fatty acid b-oxidation (FAO) gene expression, and FAO-OXPhos. PGC1a was co-overexpressed with its coactivator NRF1 in ADM/PanINs and with PPARg in IPMN. PGC1a 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 PGC1a using SR18292 diminishes the specific stemness by targeting FAO-independent and FAO-dependent OXPhos of ADM/PanINs and IPMNs, respectively.
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 PGC1a, and short hairpin RNA was used to knockdown (KD) PGC1a. 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 PGC1a and oxidative phosphorylation (OXPhos) but reduced CPT1A. IPMN showed elevated PGC1a, fatty acid b-oxidation (FAO) gene expression, and FAO-OXPhos. PGC1a was co-overexpressed with its coactivator NRF1 in ADM/PanINs and with PPARg in IPMN. PGC1a 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 PGC1a using SR18292 diminishes the specific stemness by targeting FAO-independent and FAO-dependent OXPhos of ADM/PanINs and IPMNs, respectively.
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U2 - 10.1158/1078-0432.CCR-20-5020
DO - 10.1158/1078-0432.CCR-20-5020
M3 - Article
C2 - 34172498
AN - SCOPUS:85115155636
SN - 1078-0432
VL - 27
SP - 5415
EP - 5429
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19
ER -