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Inter- and intratumor heterogeneity are key factors associated with patient outcomes. Adrenocortical carcinoma (ACC) is an exceedingly rare tumor associated with poor survival. Its clinical prognosis is highly variable, but the contributions of tumor metabolic heterogeneity have not been investigated thus far to our knowledge. An in-depth understanding of tumor heterogeneity requires molecular feature-based identification of tumor subpopulations associated with tumor aggressiveness. Here, using spatial metabolomics by high\u2013mass resolution MALDI Fourier transform ion cyclotron resonance mass spectrometry imaging, we assessed metabolic heterogeneity by de novo discovery of metabolic subpopulations and Simpson\u2019s diversity index. After identification of tumor subpopulations in 72 patients with ACC, we additionally performed a comparison with 25 tissue sections of normal adrenal cortex to identify their common and unique metabolic subpopulations. We observed variability of ACC tumor heterogeneity and correlation of high metabolic heterogeneity with worse clinical outcome. Moreover, we identified tumor subpopulations that served as independent prognostic factors and, furthermore, discovered 4 associated anticancer drug action pathways. Our research may facilitate comprehensive understanding of the biological implications of tumor subpopulations in ACC and showed that metabolic heterogeneity might impact chemotherapy.<\/jats:p>","DOI":"10.1172\/jci.insight.167007","type":"journal-article","created":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T14:01:04Z","timestamp":1692626464000},"source":"Crossref","is-referenced-by-count":14,"title":["Metabolic heterogeneity in adrenocortical carcinoma impacts patient outcomes"],"prefix":"10.1172","volume":"8","author":[{"given":"Qian","family":"Wang","sequence":"first","affiliation":[{"name":"Research Unit Analytical Pathology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0155-1763","authenticated-orcid":true,"given":"Na","family":"Sun","sequence":"additional","affiliation":[{"name":"Research Unit Analytical Pathology 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