Enhancing cancer-associated fibroblast fatty acid catabolism within a metabolically challenging tumor microenvironment drives colon cancer peritoneal metastasis

Shaoyong Peng, Daici Chen, Jian Cai, Zixu Yuan, Binjie Huang, Yichen Li, Huaiming Wang, Qianxin Luo, Yingyi Kuang, Wenfeng Liang, Zhihang Liu, Qian Wang, Yanmei Cui, Hui Wang, Xiaoxia Liu, Shaoyong Peng, Daici Chen, Jian Cai, Zixu Yuan, Binjie Huang, Yichen Li, Huaiming Wang, Qianxin Luo, Yingyi Kuang, Wenfeng Liang, Zhihang Liu, Qian Wang, Yanmei Cui, Hui Wang, Xiaoxia Liu

Abstract

Most cancer-related deaths result from the progressive growth of metastases. Patients with peritoneal metastatic (PM) colorectal cancer have reduced overall survival. Currently, it is still unclear why colorectal cancer (CRC) cells home to and proliferate inside the peritoneal cavity, and there is no effective consolidation therapy for improved survival. Using a proteomic approach, we found that key enzymes of fatty acid oxidation (FAO) were decreased in patients with PM colorectal cancer. Furthermore, we confirmed that carnitine palmitoyltransferase IA (CPT1A), a rate-limiting enzyme of FAO, was expressed at significantly low levels in patients with PM colorectal cancer, as determined by RT-qPCR, IHC, and GEO dataset analysis. However, lipidomics revealed no difference in FFA levels between PM and non-PM primary tumors. Here, we showed that cancer-associated fibroblasts (CAFs) promote the proliferation, migration, and invasion of colon cancer cells via upregulating CPT1A to actively oxidize FAs and conduct minimal glycolysis. In addition, coculture-induced glycolysis increased in cancer cells while fatty acid catabolism decreased with lower adiponectin levels. Importantly, inhibition of glycolysis significantly reduced the survival of CRC cells after incubation with conditioned medium from CAFsCPT1A-OE in vitro and impaired the survival and growth of organoids derived from CRC-PM. Finally, we found that directly blocking FAO in CAFsCPT1A-OE with etomoxir inhibits migration and invasion in vitro and decreases tumor growth and intraperitoneal dissemination in vivo, revealing a role for CAF CPT1A in promoting tumor growth and invasion. In conclusion, our results suggest the possibility of testing FAO inhibition as a novel approach and clinical strategy against CAF-induced colorectal cancer with peritoneal dissemination/metastases.

Trial registration: ClinicalTrials.gov NCT02758951.

Keywords: CAF; CPT1A; FAO; colorectal cancer; glycolysis; peritoneal metastases.

Conflict of interest statement

The authors declare no conflict of interest.

© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Figures

Fig. 1
Fig. 1
CPT1A is expressed at low levels in colon cancer patients with peritoneal metastasis and is associated with poor prognosis. (A) Schematic of label‐free, quantitative proteomics strategy in primary tumors from patients with nonperitoneal metastatic colorectal cancer (non‐PM) or patients with peritoneal metastatic colorectal cancer (PM). (B) Expression heatmap of 16 enzymes selected for FAO (fatty acid oxidation) and FAS (fatty acid synthase) pathways. Scales in log2‐normalized gene counts. (C) CPT1A expression in non‐PM (n = 15) and PM (n = 16) primary tumors derived from label‐free, quantitative proteomics (Student’s t‐test). (D) Scatter plots show the relative transcript abundance of CPT1A within patient samples from gene expression omnibus (GEO) PM and non‐PM colon cancer cohorts (Student’s t‐test). (E) qRT‐PCR for CPT1A in primary tumors from patients with non‐PM or PM (Student’s t‐test). (F) Immunohistochemical staining to detect CPT1A expression in primary tumors from patients with non‐PM or PM. (G) Kaplan–Meier curves showing survival for patients from TCGA cohorts partitioned by the relative abundance of CPT1A (high risk/low expression and low risk/high expression)(Student’s t‐test and Kaplan–Meier). (H) Kaplan–Meier curves showing survival for patients from the GEO (GSE12945) cohort partitioned by the relative abundance of CPT1A (high risk/low expression and low risk/high expression) (Student’s t‐test and Kaplan–Meier). Bars, mean ± SD. *P < 0.05, **P < 0.01.
Fig. 2
Fig. 2
Low expression of CPT1A induces metabolic shift toward glycolysis in CRC cells. (A) Western blot analysis of CPT1A expression in CPT1AKD DLD1 cells. (B) The number of colonies in CPT1AKD DLD1 cells (one‐way ANOVA). (C) The proliferation rate of CPT1AKD DLD1 cells evaluated by phase object confluence (%) with the IncuCyte ZOOM (one‐way ANOVA). Image data for phase object confluence processed by IncuCyte ZOOM software (Right). (D) Quantitative analysis of total ATP generation in CPT1AKD DLD1 cells (one‐way ANOVA). (E) Heatmap of metabolites in the energy pathway detected by Metabolomics in CPT1AKD DLD1 cells. The main discriminant metabolites are shown in Table S3. (F) Pharmacological profile of ECAR monitored with a Seahorse XF24 analyzer for 100 min in CPT1AKD DLD1 cells. The metabolic inhibitors glucose, oligomycin A, and 2‐DG were injected sequentially at different time points as indicated. (G) qRT‐PCR for GLUT1 in primary tumors from patients with non‐PM or PM (Student’s t‐test). (H and I) Correlation analysis of the mRNA levels of GLUT1 and CPT1A in CRC patients from the GSE12945 (H) and TCGA (I) datasets (Pearson's correlation analysis). Bars, mean ± SD. *P < 0.05, **P < 0.01.
Fig. 3
Fig. 3
Cell metabolism switches to FAO by upregulating CPT1A in CAFs from patients with peritoneal metastasis. (A) Score plots are shown for PM (red) versus non‐PM (blue) from the orthogonal partial least squares discriminant analysis (OPLS‐DA) model. (B) Permutation is shown for PM versus non‐PM from the OPLS‐DA model. (C) A total of 1678 lipid species involved in cell metabolism are depicted in a volcano plot. The main discriminant metabolites are shown as pink cycles. (D) Measurements of FFA in primary tumors from patients with non‐PM or PM (Student’s t‐test). (E) The serial sections and immunohistochemical for CPT1A and α‐SMA in tumor tissues. 'T' (blue areas) indicates the tumor cells, and CAFs (red areas) were identified by α‐SMA. (F) The expression of CPT1A in CAFs from patients by immunofluorescence. Tumors of frozen colorectum sections were costained with CPT1A (red) and α‐SMA (green) antibodies and DAPI (blue), scale bar is 50 µm. Representative images of immunofluorescence staining in tumors from each group. (G) Expression of CPT1A (qRT‐PCR) in CAFs isolated from colon cancer samples with PM or non‐PM (Student’s t‐test). (H) Expression of CPT1A (western blot) in CAFs isolated from colon cancer samples with PM or non‐PM (Student’s t‐test). (I) Relative levels (% of control) of glucose uptake and lactate production in CAFPM cells compared with CAFnPM cells (Student’s t‐test). (J) The extracellular acidification rate (ECAR) was monitored with a Seahorse XF24 analyzer for 100 min. The metabolic inhibitors glucose, oligomycin A, and 2‐DG were injected sequentially at different time points as indicated. (K) The oxygen consumption rate (OCR) was monitored with a Seahorse XF24 analyzer for 100 min. The metabolic inhibitors oligomycin, FCCP, rotenone, and antimycin were injected sequentially at different time points as indicated. (L) OCR/ECAR ratios (Student’s t‐test). ECAR measurement equation used for glycolysis; OCR measurement equation used for basal respiration. Bars, mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, n = 3. ns, not significant.
Fig. 4
Fig. 4
Upregulation of CPT1A in CAFs promotes CRC cell migration, invasion, and growth. (A) The cell number of crystal violet staining to quantify DLD1 cell Transwell invasion after 24 h of exposure to CAFsPM or CAFsnPM and ETO treatment (one‐way ANOVA), n = 3. (B) The wound healing ability of DLD1 incubated with CM from CAFsPM or CAFsnPM and ETO treatment detected by IncuCyte ZOOM (one‐way ANOVA), n = 3. (C) Schematic of CRC cells cocultured with CAFs under high/low‐glucose conditions (left panel). The cell number of crystal violet staining to quantify DLD1 cell Transwell invasion after 24 h of exposure to CAFsPM or CAFsnPM under high/low‐glucose conditions (right panel) (one‐way ANOVA), n = 3. (D) CAFs stably expressing high levels of CPT1A (western blot) established by lentivirus transfection. (E) The cell number of crystal violet staining to quantify DLD1 cell Transwell invasion after 24 h of exposure to CAFsCPT1A‐VC or CAFsCPT1A‐OE. # means compared with the corresponding control groups (one‐way ANOVA), n = 3. (F) The wound healing ability of DLD1 cells incubated with CM from CAFsCPT1A‐VC or CAFsCPT1A‐OE detected by IncuCyte ZOOM(one‐way ANOVA), n = 3. (G) Injection sites in the xenograft mouse model. (H) Representative tumors from the indicated groups, n = 4 mice per group. (I) Tumor growth of DLD1 cells coinjected with CAFsCPT1A‐VC or CAFsCPT1A‐OE(two‐way ANOVA), n = 4 mice per group. (J) Tumor weight of DLD1 cells coinjected with CAFsCPT1A‐VC or CAFsCPT1A‐OE(Student’s t‐test), n = 4 mice per group. (K) Representative tumors from the indicated groups, n = 4 mice per group. (L) Tumor growth of DLD1 cells coinjected with CAFsCPT1A‐OE after treatment with OA or ETO, n = 4 mice per group (one‐way ANOVA). (M) Tumor weight from mice coinjected with DLD1 cells and CAFsCPT1A‐OE after treatment with OA or ETO, n = 4 mice per group (one‐way ANOVA). (N) Body weight of mice coinjected with DLD1 cells and CAFsCPT1A‐OE after treatment with OA or ETO (one‐way ANOVA), n = 4 mice per group. Bars, mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001.
Fig. 5
Fig. 5
Glycolysis compensates for FAO loss in CRC cells and were sensitive to glycolysis inhibitor 2‐DG. (A) Western blot showing CPT1A expression in DLD1/HCT116 cells cocultured with CAFsCPT1A‐VC or CAFsCPT1A‐OE separated by a Transwell cell culture insert or in the CM under high‐glucose conditions. (B) The Human Adipokine Array detects multiple adipokines in primary tumor tissue lysates from patients with PM or non‐PM. (C and D) Luminex magnetic bead‐based suspension array was used for adiponectin/Acrp30 quantification in primary tumor tissue lysates from patients with PM or non‐PM (C) (Student’s t‐test) and in supernatant medium from CRC cells cocultured with CAFs (D) (one‐way ANOVA). (E) ECAR and (F) OCR were measured under basal conditions and after the addition of the indicated drugs to DLD1 cells by a Seahorse XF24 analyzer, n = 3. (G) ECAR/OCR ratios (one‐way ANOVA). ECAR measurement equation used for glycolysis; OCR measurement equation used for basal respiration. (H) Tumor images of DLD1CPT1A‐VC or DLD1CPT1A‐KD cells coinjected with CAFsCPT1A‐OE, n = 4 mice per group. (I) Tumor growth of DLD1CPT1A‐VC or DLD1CPT1A‐KD cells coinjected with CAFsCPT1A‐OE(two‐way ANOVA), n = 4 mice per group. (J) Tumor weight of DLD1CPT1A‐VC or DLD1CPT1A‐KD cells coinjected with CAFsCPT1A‐OE(Student’s t‐test), n = 4 mice per group. (K) The wound healing ability of DLD1 (left panel) and HCT116 (right panel) cells incubated with CM (conditioned medium) from CAFsCPT1A‐VC or CAFsCPT1A‐OE and then treated with 2‐DG by IncuCyte ZOOM (one‐way ANOVA), n = 3. (L) The survival rate of DLD1/HCT116 cells evaluated by CCK‐8 after incubation with CM (conditioned medium) from CAFsCPT1A‐VC or CAFsCPT1A‐OE and treatment with 2‐DG (5 mm) for 72 h (Student’s t‐test), n = 3. (M) Cell viability of DLD1 cells was assessed by annexin V/PI assay after 48‐h treatment with 3‐BrPA. The value in each panel indicates the % of survival cells. (N) Morphological comparison of the therapeutic activity of the glycolysis inhibitor 2‐DG combined with mitomycin C in organoids derived from CRC‐PM (bright field, scale bar 100 μm), Bars, mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, n = 3.
Fig. 6
Fig. 6
Cytokines derived from CAFs that enhance FA metabolism and may contribute to the proliferation, invasion, and metastasis of CRC. (A) The Luminex magnetic bead‐based suspension array was used for CCL2 (left panel), VEGF‐A (middle panel) and MMP2 (right panel) quantification in supernatant medium from CRC cells cocultured with CAFs (one‐way ANOVA). (B) The Luminex magnetic bead‐based suspension array was used for CCL2 (left panel), VEGF‐A (middle panel) and MMP2 (right panel) quantification in primary tumor tissue lysates from patients with PM or non‐PM (Student’s t‐test). (C) The Luminex magnetic bead‐based suspension array was used for CCL2 (left panel), VEGF‐A (middle panel), and MMP2 (right panel) quantification in supernatant medium from HCT116 cells cocultured with CAFs after the indicated drug treatment (one‐way ANOVA). (D) The Luminex magnetic bead‐based suspension array was used for CCL2 (left panel), VEGF‐A (middle panel), and MMP2 (right panel) quantification in supernatant medium from DLD1 cells cocultured with CAFs after the indicated drug treatment (one‐way ANOVA). Bars, mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, n = 3.
Fig. 7
Fig. 7
Upregulation of CPT1A in CAFs is responsible for intraperitoneal tumor dissemination and growth. (A) Experimental schema used to treat HCT116‐luc + cells before i.p. injection into BALB/C nude mice. (B) Animals from each test group were bioimaged (Xenogen IVIS system) by detecting the luciferase emission spectrum at 1 week post i.p. injection to visualize the progression of tumor growth in the peritoneum. (C) Animals from each test group were bioimaged (Xenogen IVIS system) by detecting the luciferase emission spectrum at 2 weeks post i.p. injection to visualize the progression of tumor growth in the peritoneum. (D) Summary of metabolic changes that occur in interacting colon cancer cells and CAFs as described in the text.

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