Patient-derived xenografts (PDXs) are an important and powerful tool to study many types of cancer and provide valuable insight into potential drug response and development of resistance. Due to the differences in tissue lineage PDXs also allow the dissection of stromal contribution to the tumor that is not easily obtainable from examination of the original tumor itself. We have applied mass-spectrometry enabled proteomics, phosphoproteomics, and RNAseq to compare primary metastasis, and PDXs derived from several metastatic sites from the same original tumor which was a colorectal adenocarcinoma.
Comparing our results with a large-scale proteomic characterization of tumors performed under the clinical tumor analysis consortium (CPTAC) shows that the original metastasis, and PDXs from different sites, are significantly similar, regardless of metastasis site. Proteomic profiles of these samples are enriched in proteins expressed in the tissue of origin, rather than the site of metastasis. Pathway analysis from proteomics revealed enrichment in complement cascade, extracellular matrix receptors, and focal adhesion. These were different than the pathways indicated by the transcriptomics, which included cell cycle, focal adhesion, and MAP signaling, but not complement or extracellular matrix.
We found in the case of complement and focal adhesion the original metastasis sample was very different from the PDX samples, if we only considered human protein contributions. Considering mouse proteins we found that the mouse stromal contribution complemented the human tumor contribution in the PDXs, aligning the functional analysis in both types of samples. Combining these results with subsequent analysis of driver mutations revealed that the proteomic contribution of stroma was as high as 40%. We have extended these observations to additional pairs of clinical tumor specimens and paired PDXs, including different tumor types. In all cases, there is greater similarity among the same sample type (resected tumor, metastatic lesion, or PDX) than between different sample types from the same patient.
Citation Format: Jason E. McDermott, Tao Liu, Vladislav Petyuk, Richard Smith, Karin Rodland. Proteomic characterization of stromal contribution to tumor using patient-derived xenografts. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A31.
