Spatial Metabolomics Reveals Metabolic reprogramming dynamics during ductal carcinoma in situ progression to invasive ductal carcinoma

Elucidating the progression mechanism from ductal carcinoma in situ (DCIS), a non-obligate precursor of invasive ductal carcinoma (IDC), remains a critical challenge in oncology. Metabolic profiling of lesions with differential invasiveness may help reveal key drivers underlying DCIS progression. This study employed mass spectrometry imaging to delineate the small-molecule metabolic profiles of DCIS, DCIS with synchronous IDC, and IDC lesions. Key metabolic alterations driving DCIS-to-IDC progression were identified, including elevated fatty acid biosynthesis in tumor tissues. Comparative analyses revealed that IDC exhibited significantly higher accumulation of polyunsaturated fatty acids (PUFAs) than DCIS (P<0.05), consistent with immunohistochemical validation showing upregulated fatty acid desaturase 2 expression in IDC. DCIS lesions predominantly accumulated phosphatidylinositols with saturated/monounsaturated acyl chains, while IDC exhibited a marked enrichment of phosphatidylinositols with PUFA (P<0.01). Furthermore, IDC showed significantly reduced levels of antioxidant molecules (taurine, ascorbic acid, glutathione) and the detoxification enzyme glutathione S-transferase mu 2 compared to DCIS (P<0.05), indicating dysregulation of redox homeostasis. Strikingly, DCIS with synchronous IDC displayed metabolic signatures closely aligned with IDC, suggesting its role as a transitional state during malignant progression. These findings indicate that DCIS malignant progression exhibits metabolic dependency on PUFAs/phosphatidylinositols with PUFA and depletion of antioxidants. Therapeutic targeting of PUFA biosynthesis or redox homeostasis regulators may offer novel translational approaches for tracking and intercepting DCIS progression. This study included 5 IDC, 5 DCIS, 5 DCIS with coexisting IDC, 5 DCIS with microinvasion, and 5 distant surrounding tissues (DSTs; >5 cm from tumor bed). These samples were collected from West China Hospital, Sichuan University between November 2020 to December 2021. All patients had no evidence of distant metastasis and did not receive neoadjuvant therapy. *************************************************************** Raw files for human/patient samples were not submitted to GEO due to concerns about submitting personally identifiable sequence data for open access. ***************************************************************