Culture media composition influences patient-derived organoid ability to predict therapeutic responses in gastrointestinal cancers

Abstract

Background: A patient-derived organoid (PDO) platform may serve as a promising tool for translational cancer research. In this study, we evaluated PDO's ability to predict clinical response to gastrointestinal (GI) cancers. Methods:We generated PDOs from primary and metastatic lesions of patients with GI cancers, including pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, and cholangiocarcinoma. We compared PDO response with the observed clinical response for donor patients to the same treatments. Results:We reported an approximately 80% concordance rate between PDO and donor tumor response.Importantly, we found a profound influence of culture media on PDO phenotype, where we showed significant difference in response to standard of care chemotherapies, distinct morphologies, and transcriptomes between media within the same PDOs cultures. Conclusion:While we demonstrate a high concordance rate between donor tumor and PDO, these studies also showed the important role of culture media when using PDOs to inform treatment selection and predict response across a spectrum of GI cancers.

Translational relevance of SOS1 targeting for KRAS‐mutant colorectal cancer

“…This observation was supported by that fact that expressions of the 9 KRAS effector genes in the 3 BI3406‐sensitive CRC PDOs after treatment with BI3406 for 24 h did not show significant difference (Figure 1E) despite suppression of some enriched gene sets such as E2F and MYC Targets (Figure 1F). Finally, given the functional role of RAS pathway activation by EGF in CRC and recently report on the effect of culture media composition on the predictive ability to treatment response by PDOs of gastrointestinal cancers, 31 we looked at the effect of human EGF, routinely present in the culture media, on SOS1 inhibitor sensitivity in a sensitive and resistant CRC PDO (Figure 1G). We found no significant effect of human EGF on SOS1 inhibitor sensitivity.…”

The impact of extracellular matrix on the precision medicine utility of pancreatic cancer patient-derived organoids

“…The predictive power of PDOs to mirror patient genetics, transcriptomics, and drug response in retrospective studies prompted the onset of several clinical trials to use PDOs to inform treatment decisions. However, previous studies demonstrated the plasticity of PDOs in response to varying culture conditions and potential impact on PDO drug response (10,11). With multi-institutional clinical trials underway, the need to investigate factors that impact the robustness of PDO genetics, transcriptomics, and drug testing is imperative.…”

“…As the use of organoids has expanded and become more accessible, variations in culture conditions have been introduced to optimize PDA PDO generation and growth. A number of studies have delineated the impact of media composition on organoid phenotype, transcriptome, and drug response ( 10, 11 ). Commercial products to support organoid studies have become more widespread, including a wide variety of basement membrane extracts (BME), which serve as 3D scaffolds.…”

Constructing 3D In Vitro Models of Heterocellular Solid Tumors and Stromal Tissues Using Extrusion-Based Bioprinting

“…In the practical setting, signaling molecules are often deployed alongside the cell culture medium. It has been demonstrated that cell culture medium formulation dictates cell behavior in cancer organoids . We must figure out the optimal way of administering relevant oxygen levels, pressure conditions, vitamins, GFs, hormones, and cytokines while considering their effectiveness in medium.…”