Abstract
BackgroundsCancer-related mortality in patients with colorectal cancer (CRC) is predominantly caused by development of colorectal liver metastases (CLMs). How to screen the sensitive chemotherapy and targeted therapy is the key element to improve the prognosis of CLMs patients. The study aims to develop patient-derived organoids-based xenografted liver metastases (PDOX-LM) model of CRC, to recapitulate the clinical drug response.MethodsWe transplanted human CRC primary tumor derived organoids in murine spleen to obtain xenografted liver metastases in murine liver. Immunohistochemistry (IHC) staining, whole-exome and RNA sequencing, and drug response testing were utilized to identify the homogeneity in biological and genetic characteristics, and drug response between the PDOX-LM models and donor liver metastases.ResultsWe successfully established PDOX-LM models from patients with CLMs. IHC staining showed that positive expression of CEA, Ki67, VEGF, FGFR2 in donor liver metastases were also well preserved in matched xenografted liver metastases. Whole-exon sequencing and transcriptome analysis showed that both xenografted and donor liver metastases were highly concordant in somatic variants (≥ 0.90 frequency of concordance) and co-expression of driver genes (Pearson’s correlation coefficient reach up to 0.99, P = 0.001). Furthermore, drug response testing showed that the PDOX-LM models can closely recapitulated the clinical response to mFOLFOX6 regiments.ConclusionsThis PDOX-LM model provides a more convenient and informative platform for preclinical testing of individual tumors by retaining the histologic and genetic features of donor liver metastases. This technology holds great promise to predict treatment sensitivity for patients with CLMs undergoing chemotherapy.
Highlights
Colorectal cancer (CRC) represents the third leading cause of cancer-related deaths worldwide [1]
Protocol of establishment and analysis of a PDOX‐liver metastases (LM) model Here we presented a detailed description of the procedure for the patient-derived organoids-based xenografted liver metastases (PDOX-LM) model (Additional file 1: Figure S1)
By immunohistochemical (IHC) staining, whole-exome and RNA sequence, and drug response testing, we verified that the xenografted liver metastases formed by organoids of primary tumor recapitulated similar mutations, gene expression and drug response of the donor liver metastases
Summary
Colorectal cancer (CRC) represents the third leading cause of cancer-related deaths worldwide [1]. The pre-clinical animal models play critical roles in precision medicine, by elucidating biomarkers that predict drug response and identify patients who are most likely to benefit from a specific treatment [4, 5]. PDX models have advantages in replicating the characteristics and genetic diversity of the donor tumor, and these models provide platform for pre-clinical drug response testing. The GEMMs are popular in the research of carcinogenic progress and the mechanisms of specific cancer-related genes. They usually cannot fully reproduce the genetic complexity of human tumors in the clinical practice
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