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. 2022 Mar 21;41(9):e110466. doi: 10.15252/embj.2021110466

Figure 1. βOHB promotes PDA aggressiveness.

Figure 1

  • A
    Tumor weight in KIC mice treated with βOHB (100 mg/kg/day, i.p.) or 0.9% NaCl (i.p.) (n = 13 mice for NaCl and n = 15 mice for βOHB). Data are expressed as mean ± SEM. Significance was defined by Mann‐Whitney test. *P < 0.05.
  • B
    Kinetic of spheroid area from PK4a cells cultured during 12 days in medium alone (untreated) or with βOHB 1 or 10 mM (n = 4, and 5 respectively). Data are expressed as mean ± SEM. Significance compared to untreated cells was defined by two‐way ANOVA followed by a Dunnett’s multiple comparisons test. **P < 0.01, ****P < 0.0001.
  • C
    Representative images of mouse PDA and human PDA primary cells‐derived organoids after 7 days of culture in medium alone (untreated) or supplemented with 1 or 10 mM of βOHB. Scale bar: 1000 µm.
  • D, E
    Immunostaining of MCT2 and SMCT1 in tumors of KIC mice treated with βOHB (100 mg/kg/day, i.p.) or 0.9% NaCl (i.p.) (n = 5 mice/group). Areas of MCT2 (upper panel) and SMCT1 (lower panel) stainings (D) are expressed as mean of percentage of total tissue area ± SEM. Significance was defined by Mann–Whitney test. *P < 0.05, **P < 0.01. Representative images of MCT2 and SMCT1 stainings (E) in tumors from KIC mice treated with βOHB or NaCl. Scale bar: 100 µm.
  • F
    Histological characterization of liver and spleen of KIC mice treated with βOHB (100 mg/kg/day, i.p.) or 0.9% NaCl (i.p.) (n = 14 mice/group). Number of mice displaying metastatic liver or spleen in each experimental group is reported.
  • G
    Schematic showing isotopomer transition from [U‐13C]βOHB to label TCA‐cycle intermediates, glutamate, and proline. Gray filled circles indicate 13C carbon derived from labeled βOHB. Empty circles illustrate unlabeled 12C‐species.
  • H
    [U‐13C]βOHB tracing into the TCA intermediate: citrate in poorly differentiated PDA explants from KIC mice (n = 5). Data are expressed as mean ± SEM.
  • I
    Schematic showing ketone metabolism pathway (left panel). Reversible enzymes involved in the production of acetyl‐CoA, acetoacetyl‐CoA, acetoacetate, βOHB, mT, SCOT1/2, and BDH1/2 are indicated in bold case. Immunoblots of ketone metabolic enzymes (BDH1/2, SCOT1/2, mT) (right panel) in pancreatic tissues from 7‐week‐old KI (n = 3 for BDH1/2, SCOT1/2, and n = 4 for mT) and KIC mice (n = 4).

Source data are available online for this figure.