Abstract:<\/p>\n
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-\u03b2 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-na\u00efve tumors. Tumors with high AXL, TGF-\u03b2 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-na\u00efve lung tumors, coupled with ex vivo testing of PDOs, identifies continuous AXL, TGF-\u03b2 and JAK1-STAT3 signal activation in select tumors that may be targeted by combined AXL-JAK1 inhibition.<\/p>\n
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Taverna JA<\/strong>, Hung CN, DeArmond DT, Chen M, Lin CL, Osmulski PA<\/strong>, Gaczynska ME<\/strong>, Wang CM, Lucio ND, Chou CW, Chen CL<\/strong>, Nazarullah A, Lampkin SR, Qiu L, Bearss DJ, Warner S, Whatcott CJ, Mouritsen L, Wade M, Weitman S, Mesa RA, Kirma N<\/strong>, Chao WT, and Huang T<\/strong>. Single-cell proteomic profiling identifies combined AXL and JAK1 inhibition as a novel therapeutic strategy for lung cancer. Cancer Research<\/em>. 2020. In Press.<\/p>\n <\/p>\n <\/p>\n <\/p>\n","protected":false},"excerpt":{"rendered":" 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 […]<\/p>\n","protected":false},"author":264,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[3,14],"class_list":["post-1170","post","type-post","status-publish","format-standard","hentry","category-highimpactpublication","category-news"],"yoast_head":"\n