Paired primary-metastasis patient-derived organoids and mouse models identify phenotypic evolution and druggable dependencies of peritoneal metastasis from appendiceal cancer.

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Tác giả: Samhita Bapat, Jonathan Bermeo, Andrea Cercek, Walid K Chatila, Philip H Choi, Sebastian Chung, Arvin C Dar, Canan Firat, Michael B Foote, Karuna Ganesh, Michael Giarrizzo, Qingwen Jiang, Georgios Karagkounis, Steven Larson, Ahmed Mahmoud, Julia Meredith, Garrett M Nash, Jura Pintar, Manisha Raghavan, Neal Rosen, Francisco Sanchez-Vega, Nikolaus Schultz, Jinru Shia, Christine Sukhwa, Henry Walch, Nan Zhao

Ngôn ngữ: eng

Ký hiệu phân loại: 665.82 Gases derived from liquefaction and fractionation of air

Thông tin xuất bản: United States : bioRxiv : the preprint server for biology , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 692433

Peritoneal carcinomatosis is a common yet deadly manifestation of gastrointestinal cancers, with few effective treatments. To identify targetable determinants of peritoneal metastasis, we focused on appendiceal adenocarcinoma (AC), a gastrointestinal cancer that metastasizes almost exclusively to the peritoneum. Current treatments are extrapolated from colorectal cancer (CRC), yet AC has distinct genomic alterations, mucinous morphology and peritoneum restricted metastatic pattern. Further, no stable preclinical models of AC exist, limiting drug discovery and representing an unmet clinical need. We establish a first-in-class stable biobank of 16 long-term cultured AC patient-derived organoids (PDOs), including 3 matched, simultaneously resected primary AC-peritoneal carcinomatosis (AC-PC) pairs. By enriching for cancer cells, AC PDOs enable accurate genomic characterization relative to paucicellular AC tissue. We establish an organoid orthotopic intraperitoneal xenograft model that recapitulates diffuse peritoneal carcinomatosis and show that PC-organoids retain increased metastatic capacity, decreased growth factor dependency and sensitivity to standard of care chemotherapy relative to matched primary AC organoids. Single cell profiling of AC-PC pairs reveals dedifferentiation from mucinous differentiated states in primary AC into intestinal stem cell and fetal progenitor states in AC-PC, with upregulation of oncogenic signaling pathways. Through hypothesis-driven drug testing, we identify KRAS
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