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

Figure 4. HMGCL and βOHB promote pancreatic tumor aggressiveness.

Figure 4

  • A, B
    Quantification of volume with representative images (A) and weight (B) of sg‐CTRL (n = 15 for A and n = 9 for B), sg HMGCL #2 (n = 19 for A and n = 8 for B), #3 (n = 7 for A and B) pancreatic tumors. Data are expressed as mean of tumor volume or weight ± SEM. Significance was defined by Mann–Whitney test. *P < 0.05, **P < 0.01, ***P < 0.001.
  • C
    Extracellular matrix quantification following trichrome staining in sg‐CTRL and sg‐HMGCL #2 pancreatic tumors sections (n = 8 and 9 mice/group respectively, left panel). Data are expressed as mean of percentage of total tissue area ± SEM. Significance was defined by Mann–Whitney test. **P < 0.01. Representative images of trichrome staining in sg‐CTRL and sg‐HMGCL pancreatic tumors. Scale bar: 100 µm (right panel).
  • D, E
    Quantification of volume (D) and weight (E) of sg‐CTRL pancreatic tumors treated with 0.9% NaCl (i.p.) (n = 4), and pancreatic tumors from two different clones of sg‐HMGCL treated with 0.9% NaCl (i.p.) or βOHB (100 mg/kg/bi‐weekly, i.p.) (n = 10/group). Data are expressed as mean of tumor volume or weight ± SEM. Significance was defined by Mann–Whitney test. ns: not significant, **P < 0.01.
  • F
    Histological characterization and representative picture of liver from mice orthotopically xenografted with sg‐CTRL or sg‐HMGCL PANC‐1 cells and treated with 0.9% NaCl (i.p.) or βOHB (100 mg/kg/bi‐weekly, i.p.). Number of mice displaying healthy or metastatic liver in each experimental group is reported. Metastatic area (orange star) is separated from liver (green circle) by dotted lines. Scale bar: 100 µm (inset images scale bar: 20 µm).
  • 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 TCA intermediate: citrate in sg‐CTRL and sg‐HMGCL #2 and #3 PANC‐1 cells cultured in indicated glucose concentrations. Data are expressed as mean ± SEM (n = 2 independent experiments). Significance was defined by one‐way ANOVA followed by a Bonferroni’s multiple comparisons test, only significances between sg‐HMGCL #2, #3 PANC‐1 cells and sg‐CTRL PANC‐1 cells under the same culture condition are mentioned. ***P < 0.001.

Source data are available online for this figure.