Single-cell proteomic profiling identifies combined AXL and JAK1 inhibition as a novel therapeutic strategy for lung cancer
Abstract:
Cytometry by time-of-flight (CyTOF) simultaneously measures multiple cellular proteins at the single-cell level and is used to assess inter- and intra-tumor heterogeneity. This approach may be used to investigate the variability of individual tumor responses to treatments. Herein, we stratified lung tumor subpopulations based on AXL signaling as a potential targeting strategy. Integrative transcriptome analyses were used to investigate how TP-0903, an AXL kinase inhibitor, influences redundant oncogenic pathways in metastatic lung cancer cells. CyTOF profiling revealed that AXL inhibition suppressed SMAD4/TGF-β signaling and induced JAK1-STAT3 signaling to compensate for the loss of AXL. Interestingly, high JAK1-STAT3 was associated with increased levels of AXL in treatment-naïve tumors. Tumors with high AXL, TGF-β and JAK1 signaling concomitantly displayed CD133-mediated cancer stemness and hybrid EMT features in advanced stage patients, suggesting greater potential for distant dissemination. Diffusion pseudotime analysis revealed cell-fate trajectories among four different categories that were linked to clinicopathologic features for each patient. Patient-derived organoids (PDOs) obtained from tumors with high AXL and JAK1 were sensitive to TP-0903 and ruxolitinib (JAK inhibitor) treatments supporting the CyTOF findings. This study shows that single-cell proteomic profiling of treatment-naïve lung tumors, coupled with ex vivo testing of PDOs, identifies continuous AXL, TGF-β and JAK1-STAT3 signal activation in select tumors that may be targeted by combined AXL-JAK1 inhibition.
Taverna JA, Hung CN, DeArmond DT, Chen M, Lin CL, Osmulski PA, Gaczynska ME, Wang CM, Lucio ND, Chou CW, Chen CL, Nazarullah A, Lampkin SR, Qiu L, Bearss DJ, Warner S, Whatcott CJ, Mouritsen L, Wade M, Weitman S, Mesa RA, Kirma N, Chao WT, and Huang T. Single-cell proteomic profiling identifies combined AXL and JAK1 inhibition as a novel therapeutic strategy for lung cancer. Cancer Research. 2020. In Press.