PGC1a-mediated metabolic reprogramming drives the stemness of pancreatic precursor lesions

Rama Krishna Nimmakayala, Sanchita Rauth, Ramakanth Chirravuri Venkata, Saravanakumar Marimuthu, Palanisamy Nallasamy, Raghupathy Vengoji, Subodh M. Lele, Satyanarayana Rachagani, Kavita Mallya, Mokenge P. Malafa, Moorthy P. Ponnusamy, Surinder K. Batra

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5415-5429
Number of pages15
JournalClinical Cancer Research
Volume27
Issue number19
DOIs
StatePublished - Oct 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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