“Proteotranscriptomic analysis of advanced colorectal cancer patient derived organoids for drug sensitivity prediction”

Abstract

Background Patient-derived organoids (PDOs) from advanced colorectal cancer (CRC) patients could be a key platform to predict drug response and discover new biomarkers. We aimed to integrate PDO drug response with multi-omics characterization beyond genomics. Methods We generated 29 PDO lines from 22 advanced CRC patients and provided a morphologic, genomic, and transcriptomic characterization. We performed drug sensitivity assays with a panel of both standard and non-standard agents in five long-term cultures, and integrated drug response with a baseline proteomic and transcriptomic characterization by SWATH-MS and RNA-seq analysis, respectively. Results PDOs were successfully generated from heavily pre-treated patients, including a paired model of advanced MSI high CRC deriving from pre- and post-chemotherapy liver metastasis. Our PDOs faithfully reproduced genomic and phenotypic features of original tissue. Drug panel testing identified differential response among PDOs, particularly to oxaliplatin and palbociclib. Proteotranscriptomic analyses revealed that oxaliplatin non-responder PDOs present enrichment of the t-RNA aminoacylation process and showed a shift towards oxidative phosphorylation pathway dependence, while an exceptional response to palbociclib was detected in a PDO with activation of MYC and enrichment of chaperonin T-complex protein Ring Complex (TRiC), involved in proteome integrity. Proteotranscriptomic data fusion confirmed these results within a highly integrated network of functional processes involved in differential response to drugs. Conclusions Our strategy of integrating PDOs drug sensitivity with SWATH-mass spectrometry and RNA-seq allowed us to identify different baseline proteins and gene expression profiles with the potential to predict treatment response/resistance and to help in the development of effective and personalized cancer therapeutics.

Colorectal carcinoma peritoneal metastases-derived organoids: results and perspective of a model for tailoring hyperthermic intraperitoneal chemotherapy from bench-to-bedside

“…Overall, our data indicate that PDO models are able to reproduce the results observed in the patient, as also previously reported by Papaccio et al . [ 39 ], demonstrating the technical feasibility of performing HIPEC treatments with PDOs in a clinically relevant setting.…”

Pancreatic cancer environment: from patient-derived models to single-cell omics

“…37 The abundance of intra-tumor stromal cells and the inter-epithelial cancer cell heterogeneity causes challenges in the genetic sequencing of PC. 38 However, in comparison with the primary tumors, organoids that only comprise epithelial cells offer amplified signals, enabling the comprehensive sequencing of tumor cells and identification of mutations. Understanding PDO cellular state heterogeneity is pivotal for elucidating their potential as personalized models.…”

Organoids: The current status and biomedical applications

“…24 Tumoroids retain parental tumor heterogeneity and histopathological features and reserve their 3D structure after long-term culture 32,33,[205][206][207] (Table 1). Papaccio et al 208 reported that patient-derived colorectal tumoroids represented the morphology and immunohistochemistry characteristics and genomic and transcriptomic profile of corresponding tissues, and the response to anticancer drugs varied among these tumoroids derived from different patients. The role of mutations in genes or structures in tumor development is difficult to observe dynamically or to intervene.…”

“…Papaccio et al. 208 reported that patient‐derived colorectal tumoroids represented the morphology and immunohistochemistry characteristics and genomic and transcriptomic profile of corresponding tissues, and the response to anticancer drugs varied among these tumoroids derived from different patients.…”