ABSTRACT
The purpose of ex vivo drug screening in the context of precision oncology is to serve as a functional diagnostic method for therapy efficacy modeling directly on patient-derived tumor cells. Here, we report a case study using integrated multiomics ex vivo drug screening approach to assess therapy efficacy in a rare metastatic squamous cell carcinoma of the parotid gland. Tumor cells isolated from lymph node metastasis and distal subcutaneous metastasis were used for imaging-based single-cell resolution drug screening and reverse-phase protein array-based drug screening assays to inform the treatment strategy after standard therapeutic options had been exhausted. The drug targets discovered on the basis of the ex vivo measured drug efficacy were validated with histopathology, genomic profiling, and in vitro cell biology methods, and targeted treatments with durable clinical responses were achieved. These results demonstrate the use of serial ex vivo drug screening to inform adjuvant therapy options prior to and during treatment and highlight HER2 as a potential therapy target also in metastatic squamous cell carcinoma of the salivary glands.
ABSTRACT
Colorectal cancer (CRC) and cachexia are associated with the gut microbiota and microbial surface molecules. We characterized the CRC-associated microbiota and investigated whether cachexia affects the microbiota composition. Further, we examined the possible relationship between the microbial surface molecule flagellin and CRC. CRC cells (C26) were inoculated into mice. Activin receptor (ACVR) ligands were blocked, either before tumor formation or before and after, to increase muscle mass and prevent muscle loss. The effects of flagellin on C26-cells were studied in vitro. The occurrence of similar phenomena were studied in murine and human tumors. Cancer modulated the gut microbiota without consistent effects of blocking the ACVR ligands. However, continued treatment for muscle loss modified the association between microbiota and weight loss. Several abundant microbial taxa in cancer were flagellated. Exposure of C26-cells to flagellin increased IL6 and CCL2/MCP-1 mRNA and IL6 excretion. Murine C26 tumors expressed more IL6 and CCL2/MCP-1 mRNA than C26-cells, and human CRC tumors expressed more CCL2/MCP-1 than healthy colon sites. Additionally, flagellin decreased caspase-1 activity and the production of reactive oxygen species, and increased cytotoxicity in C26-cells. Conditioned media from flagellin-treated C26-cells deteriorated C2C12-myotubes and decreased their number. In conclusion, cancer increased flagellated microbes that may promote CRC survival and cachexia by inducing inflammatory proteins such as MCP-1. Cancer-associated gut microbiota could not be rescued by blocking ACVR ligands.
