Patient-derived Organoids and Xenografts Uncover Therapeutic Vulnerabilities in Colorectal Signet Ring Cell Carcinomas

Abstract Purpose: Identifying therapeutic targets for Signet Ring Cell Carcinoma (SRCC) of the colon and rectum is a clinical challenge due to the lack of Patient-Derived Organoids (PDO) or Xenografts (PDX). We present a robust method to establish PDO and PDX models to answer address this unmet need. We demonstrate that these models identify novel therapeutic strategies targeting therapy resistance and peritoneal metastasis. Experimental Design: We derived nine PDO and PDX models from colorectal SRCC patients. Detailed histopathological characterization confirmed the fidelity of these models to the original tumors. Drug sensitivity assays were conducted in-vitro and in-vivo to assess therapeutic efficacy and impact on peritoneal metastasis. An RNA-seq analysis was performed to identify critical pathways contributing to therapy resistance and metastatic progression. Results: We successfully developed and characterized PDO and PDX models from nine SRCC patients. The SRCC PDO and PDX models exhibited histopathological features consistent with the original tumors, including high mucin content and eccentric nuclei. They demonstrated increased sensitivity to FOLFIRI combined with Paclitaxel or vincristine, reducing peritoneal metastasis. RNA-seq analysis revealed the upregulation of autophagy genes in SRCC. Treatment with Chloroquine alone resulted in decreased tumor growth and peritoneal metastasis. Conclusions: Our study establishes PDO and PDX models as robust platforms for studying SRCC and identifying potential therapeutic strategies. Combining FOLFIRI with paclitaxel/ vincristine or Chloroquine alone inhibits tumor growth and prevents peritoneal metastasis, showing promise for clinical translation. These findings suggest that combining FOLFIRI with IP paclitaxel warrants further investigation in Phase-I clinical trials for SRCC patients.