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

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

  • bioRxiv. 2025 Feb 22:2025.02.17.638725. doi: 10.1101/2025.02.17.638725.
Ahmed Mahmoud 1 2,  Philip H Choi 2 3,  Christine Sukhwa 2,  Jura Pintar 2,  Henry Walch 4 5 6,  Nan Zhao 7,  Jonathan Bermeo 2,  Sebastian Chung 2 8,  Manisha Raghavan 2 7,  Samhita Bapat 2,  Qingwen Jiang 2,  Georgios Karagkounis 2 8,  Julia Meredith 2,  Michael Giarrizzo 2 8,  Canan Firat 9,  Andrea Cercek 3,  Michael B Foote 3,  Nikolaus Schultz 1 2 3 4 5 6 7 8 10 9,  Walid K Chatila 4,  Garrett M Nash 8,  Jinru Shia 9,  Francisco Sanchez-Vega 6 8,  Steven Larson 2,  Arvin C Dar 7,  Neal Rosen 2 3,  Karuna Ganesh 2 3
Affiliations

Affiliations

  • 1 Pharmacology Program, Weill Cornell Graduate School, New York, NY, USA.
  • 2 Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 3 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 4 Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 5 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 6 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 7 Program in Chemical Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 8 Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 9 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA.
  • 10 Louis V. Gerstner Jr Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
PMID: 40027618 DOI: 10.1101/2025.02.17.638725
Abstract

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 KRASMULTI-ON inhibitor RMC-7977 and Wnt-targeting tyrosine kinase inhibitor WNTinib as novel, clinically actionable strategies to target AC-PC more effectively.

Figures
Products