Kavli Affiliate: Denis Wirtz
| Authors: André Forjaz, Vasco Queiroga, Yajuan Li, Alfredo Hernandez, Ashleigh Crawford, Xiaoyu Qin, Mei Zhong, Margarita Tsapatsis, Saurabh Joshi, Donald Kramer, Oliver Nizet, Habin Bea, Yuhan Li, Shuo Qin, Robert O Flynn, Mingder Yang, Britanny Pratt, Fan Wu, Paul Gensbigler, Max Blecher, Pei-Hsun Wu, Luciane Tsukamoto Kagohara, Ie Ming Shih, David Zwicker, Mark A. Atkinson, Lingyan Shi, Rong Fan, Ashley L Kiemen and Denis Wirtz
| Summary:
Uncovering the spatial and molecular landscape of precancerous lesions is essential for developing meaningful cancer prevention and early detection strategies. High-Grade Serous Carcinoma (HGSC), the most lethal gynecologic malignancy, often originates from Serous Tubal Intraepithelial Carcinomas (STICs) in the fallopian tubes, yet their minute size and our historical reliance on standard 2D histology contribute to their underreporting. Here, we present a spatially resolved, multi-omics framework that integrates whole-organ 3D imaging at cellular resolution with targeted proteomic, metabolomic, and transcriptomic profiling to detect and characterize microscopic tubal lesions. Using this platform, we identified a total of 99 STICs and their presumed precursors that harbor TP53 mutations in morphologically unremarkable tubal epithelium in all five specimens obtained from cancer-free organ donors with average-risk of developing ovarian cancer. Although these lesions comprised only 0.2% of the epithelial compartment, they displayed geographic diversity, immune exclusion, metabolic rewiring, and DNA copy number changes among lesions and normal fallopian tube epithelium discovered alterations in STIC-associated genes and the pathways they control. In sum, this platform provides a comprehensive 3D atlas of early neoplastic transformation, yielding mechanistic insights into tumor initiation and informing clinical screening strategies for detecting cancer precursors in whole organs at cellular resolution.