An Orthotopic Patient-Derived Xenograft (PDX) Model Allows the Analysis of Metastasis-Associated Features in Colorectal Cancer

Maria Laura De Angelis; Federica Francescangeli; Chiara Nicolazzo; Eljona Xhelili; Filippo La Torre; Lidia Colace; Alessandro Bruselles; Daniele Macchia; Sara Vitale; Paola Gazzaniga; Marta Baiocchi; Ann Zeuner

doi:10.3389/fonc.2022.869485

An Orthotopic Patient-Derived Xenograft (PDX) Model Allows the Analysis of Metastasis-Associated Features in Colorectal Cancer

Front Oncol. 2022 Jun 28:12:869485. doi: 10.3389/fonc.2022.869485. eCollection 2022.

Affiliations

¹ Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
² Department of Molecular Medicine, Liquid Biopsy Unit, Sapienza University, Rome, Italy.
³ Surgical Sciences and Emergency Department, Policlinico Umberto I/Sapienza University of Rome, Rome, Italy.
⁴ Department of Surgical Sciences, Policlinico Umberto I/Sapienza University of Rome, Rome, Italy.
⁵ Center of Animal research and Welfare, Istituto Superiore di Sanità, Rome, Italy.
⁶ Department of Medicine and Traslational Surgery, Università Cattolica del Sacro Cuore, Rome, Italy.

Abstract

Metastasis is the primary cause of death in patients with colorectal cancer (CRC), urging the need for preclinical models that recapitulate the metastatic process at the individual patient level. We used an orthotopic patient-derived xenograft (PDX) obtained through the direct implantation of freshly dissociated CRC cells in the colon of immunocompromised mice to model the metastatic process. Ortho-PDX engraftment was associated to a specific set of molecular features of the parental tumor, such as epithelial-to-mesenchymal transition (EMT), TGF-β pathway activation, increased expression of stemness-associated factors and higher numbers of circulating tumor cells (CTCs) clusters expressing the metastatic marker CD44v6. A parallel analysis of orthotopic/metastatic xenografts and organoids showed that tumor cells underwent mesenchymal-to-epithelial transition at the metastatic site and that metastasis-derived organoids had increased chemotherapy resistance. These observations support the usefulness of ortho-PDX as a preclinical model to study metastasis-related features and provide preliminary evidence that EMT/stemness properties of primary colorectal tumors may be crucial for orthotopic tumor engraftment.

Keywords: colorectal cancer (CRC); epithelial-to-mesenchymal transition (EMT); metastasis; organoids; patient-derived xenograft (PDX).