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Abstract
Background Colorectal cancer (CRC) has been a leading cause of cancer-associated death worldwide. Several promising targeted therapies for CRC treatment, like anti-EGFR antibody, while the unforeseen non-responders limit its clinical application. An imbalance of ceramides, the core metabolites involved in the sphingolipid metabolism, is found in CRC patients, while its role and underlying mechanism in CRC progression and treatment remains unclear.
Methods A clinical cohort of 41 CRC patients was established for the identification of CRC-related lipid biomarkers. MC38 cell line, xenograft and AOM/DSS mouse models, and patient-derived CRC organoids were applied to explore the underlying mechanism. Another cohort of 32 CRC patients was established for patient-derived organoid culturing and screening for anti-EGFR therapy response.
Results Based on lipidomic, VIP score analysis showed that several ceramide metabolites were the primary ones leading to clustering in non-tumor and tumor tissues of CRC patients (IDDF2024-ABS-0220-Figure 1 (A)). Of note, ceramide (d18:1/C26:0) (C26) was most significantly elevated in patients with advanced stages (IDDF2024-ABS-0220-Figure 1 (B,C)). Administration of C26 obviously enhanced the proliferation of human CRC organoids both in morphology and as shown in EdU staining (IDDF2024-ABS-0220-Figure 1 (D)). To figure out the key ceramide-related enzyme involved in CRC progression, we set up the LC-MS-based enzyme screening method. Based on that, we found that CERS3 activity was significantly activated in CRC (IDDF2024-ABS-0220-Figure 2 (A)), and its mRNA expressions were positively correlated to C26 levels (IDDF2024-ABS-0220-Figure 2 (B)). Genetically modification of CERS3 also influenced the proliferation of human CRC organoids (IDDF2024-ABS-0220-Figure 2 (C,D)). In terms of mechanism, C26 was found to activate PI3K/AKT signaling pathway as a ligand of EGFR to promote CRC (IDDF2024-ABS-0220-Figure 3 (A-C)). Patient-derived CRC organoids were established with 32 patients for anti-EGFR therapy response screening (IDDF2024-ABS-0220-Figure 3 (D-E)), and CERS3 was proved to act as a biomarker in the evaluation of response to anti-EGFR therapy (IDDF2024-ABS-0220-Figure 3 (F)).
Conclusions This study highlights that C26 produced by its synthetase CERS3 activates EGFR directly as a ligand, and acts as a potential targets for treating CRC and predicting the patient response to anti-EGFR therapies.