Matched Fibroblasts Reduce Chemotherapy Sensitivity in Lung Cancer Organoids
Patient-matched lung adenocarcinoma organoids and fibroblasts connected a stromal cell state with drug resistance. The study implicated a PLAU–CXCL5–CLGN signaling relationship.
Adding Patient-Matched Stroma
An academic research collaboration in China established lung adenocarcinoma organoids paired with cancer-associated fibroblasts from treatment-naïve tumors. Adding the matched fibroblasts reduced the organoids' sensitivity to chemotherapy, providing a way to investigate how the tumor's own stroma affects drug response.
The researchers identified a fibroblast state marked by plasminogen activator urokinase, or PLAU. This state was associated with chemotherapy resistance and poor survival in patients with lung adenocarcinoma. Tumor cells also promoted polarization of fibroblasts toward the PLAU-positive state.
Following the Signal into the Tumor Cells
PLAU-positive fibroblasts secreted CXCL5, which increased the endoplasmic-reticulum chaperone calmegin, encoded by CLGN, in tumor cells. Removing CLGN restored drug sensitivity in the reported experiments. CLGN expression was also elevated in chemotherapy-resistant tumors and associated with pathological progression.
The paired system linked a functional drug-response comparison with a candidate stromal-to-tumor signaling mechanism. For preclinical studies, the work supports examining chemotherapy response in the presence of the matched fibroblast population, alongside the tumor-only model.