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Analyzing different tumor regions by next generation sequencing allows the assessment of intratumor genetic heterogeneity (ITGH), a phenomenon that has been studied widely in some tumor types but has been less well explored in endometrial carcinoma (EC). In this study, we sought to characterize the spatial and temporal heterogeneity of 9 different ECs using whole-exome sequencing, and by performing targeted sequencing validation of the 42 primary tumor regions and 30 metastatic samples analyzed. In addition, copy number alterations of serous carcinomas were assessed by comparative genomic hybridization arrays. From the somatic mutations, identified by whole-exome sequencing, 532 were validated by targeted sequencing. Based on these data, the phylogenetic tree reconstructed for each case allowed us to establish the tumors’ evolution and correlate this to tumor progression, prognosis, and the presence of recurrent disease. Moreover, we studied the genetic landscape of an ambiguous EC and the molecular profile obtained was used to guide the selection of a potential personalized therapy for this patient, which was subsequently validated by preclinical testing in patient-derived xenograft models. Overall, our study reveals the impact of analyzing different tumor regions to decipher the ITGH in ECs, which could help make the best treatment decision., Tissue samples were obtained with the support of the MD Anderson Foundation Biobank (record number B.0000745, ISCIII National Biobank Record), the “Xarxa Catalana de Bancs de Tumors” and “Plataforma de Biobancos” ISCIII (PT13/0010/0014, B.000609). This study has been supported by the Spanish Ministry of Economy and Innovation (PID2019-104644RB-I00 (GMB), the Instituto de Salud Carlos III (ISCIII, CIBERONC, CB16/12/00295 - GMB-, CB16/12/00328 -EC, AGM- and CB16/12/00231 -XMG- [all partly supported by FEDER funds]) and by the AECC Scientific Foundation (FC_AECC PROYE19036MOR -GMB- and Coordinated groups 2018 -XMG, AGM, GMB-). SO is funded by an AECC-postdoctoral grant (2020). JSR-F and BW are funded in part by the Breast Cancer Research Foundation and in part by the NIH/NCI P50 CA247749 01 grant. Research reported in this publication was supported in part by a Cancer Center Support Grant of the NIH/NCI (Grant No. P30CA008748; MSK).

BACKGROUND: Remodeling targeted tissues for reception of tumor cells metastasizing from primary lesions is a consequence of communication between the tumor and the environment that governs metastasis. This study describes a novel approach that aims to disrupt the process of metastasis by interfering with this intense dialogue. METHODS: Proteomics and adhesion assays identified exosomes purified from the ascitic fluid of ovarian cancer patients (n = 9) as intermediaries of tumor cell attachment. A novel tumor cell capture device was fabricated by embedding exosomes onto a 3D scaffold (metastatic trap [M-Trap]). Murine models of ovarian metastasis (n = 3 to 34 mice per group) were used to demonstrate the efficacy of M-Trap to capture metastatic cells disseminating in the peritoneal cavity. Kaplan-Meier survival curves were used to estimate cumulative survival probabilities. All statistical tests were two-sided. RESULTS: The exosome-based M-Trap device promoted tumor cell adhesion with a nonpharmacological mode of action. M-Trap served as a preferential site for metastasis formation and completely remodeled the pattern of peritoneal metastasis in clinically relevant models of ovarian cancer. Most importantly, M-Trap demonstrated a statistically significant benefit in survival outcomes, with mean survival increasing from 117.5 to 198.8 days in the presence of M-Trap; removal of the device upon tumor cell capture further improved survival to a mean of 309.4 days (P < .001). CONCLUSIONS: A potent artificial premetastatic niche based on exosomes is an effective approach to impair the crosstalk between metastatic cells and their environment. In the clinical setting, the capacity to modulate the pattern of dissemination represents an opportunity to control the process of metastasis. In summary, M-Trap transforms a systemic, fatal disease into a focalized disease where proven therapeutic approaches such as surgery can extend survival.