Single-cell proteomic profiling identifies combined AXL and JAK1 inhibition as a novel therapeutic strategy for lung cancer

Josephine A. Taverna, Chia Nung Hung, Daniel T. DeArmond, Meizhen Chen, Chun Lin Lin, Pawel A. Osmulski, Maria E. Gaczynska, Chiou Miin Wang, Nicholas D. Lucio, Chih Wei Chou, Chun Liang Chen, Alia Nazarullah, Shellye R. Lampkin, Lianqun Qiu, David J. Bearss, Steven Warner, Clifford J. Whatcott, Lars Mouritsen, Mark Wade, Steven WeitmanRuben A. Mesa, Nameer B. Kirma, Wei Ting Chao, Tim H.M. Huang

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Cytometry by time-of-flight (CyTOF) simultaneously measures multiple cellular proteins at the single-cell level and is used to assess intertumor and intratumor 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/TGFβ 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, TGFβ, and JAK1 signaling concomitantly displayed CD133-mediated cancer stemness and hybrid epithelial-to-mesenchymal transition 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 (PDO) 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, TGFb, and JAK1–STAT3 signal activation in select tumors that may be targeted by combined AXL–JAK1 inhibition.

Original languageEnglish (US)
Pages (from-to)1551-1563
Number of pages13
JournalCancer Research
Volume80
Issue number7
DOIs
StatePublished - Apr 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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