Basal-like mammary carcinomas stimulate cancer stem cell properties through AXL-signaling to induce chemotherapy resistance.
Garyfallia Pantelaiou-ProkakiOliver ReinhardtNadine S GeorgesDavid J AgorkuOlaf T HardtEvangelos ProkakisIga K MieczkowskaWolfgang DeppertFlorian WegwitzFrauke AlvesPublished in: International journal of cancer (2023)
Basal-like breast cancer (BLBC) is the most aggressive and heterogeneous breast cancer (BC) subtype. Conventional chemotherapies represent next to surgery the most frequently employed treatment options. Unfortunately, resistant tumor phenotypes often develop, resulting in therapeutic failure. To identify the early events occurring upon the first drug application and initiating chemotherapy resistance in BLBC, we leveraged the WAP-T syngeneic mammary carcinoma mouse model and we developed a strategy combining magnetic-activated cell sorting (MACS)-based tumor cell enrichment with high-throughput transcriptome analyses. We discovered that chemotherapy induced a massive gene expression reprogramming toward stemness acquisition to tolerate and survive the cytotoxic treatment in vitro and in vivo. Retransplantation experiments revealed that one single cycle of cytotoxic drug combination therapy (Cyclophosphamide, Adriamycin and 5-Fluorouracil) suffices to induce resistant tumor cell phenotypes in vivo. We identified Axl and its ligand Pros1 as highly induced genes driving cancer stem cell (CSC) properties upon chemotherapy in vivo and in vitro. Furthermore, from our analysis of BLBC patient datasets, we found that AXL expression is also strongly correlated with CSC-gene signatures, a poor response to conventional therapies and worse survival outcomes in those patients. Finally, we demonstrate that AXL inhibition sensitized BLBC-cells to cytotoxic treatment in vitro. Together, our data support AXL as a promising therapeutic target to optimize the efficiency of conventional cytotoxic therapies in BLBC.
Keyphrases
- single cell
- cancer stem cells
- combination therapy
- tyrosine kinase
- gene expression
- chemotherapy induced
- high throughput
- rna seq
- genome wide
- mouse model
- cell therapy
- end stage renal disease
- stem cells
- dna methylation
- locally advanced
- epithelial mesenchymal transition
- minimally invasive
- chronic kidney disease
- newly diagnosed
- low dose
- prognostic factors
- emergency department
- peritoneal dialysis
- squamous cell carcinoma
- radiation therapy
- machine learning
- young adults
- coronary artery disease
- binding protein
- oxidative stress
- induced apoptosis
- patient reported outcomes
- artificial intelligence
- high grade
- cell proliferation
- drug induced
- high dose
- case report
- diabetic rats
- big data
- percutaneous coronary intervention
- data analysis
- transcription factor
- electronic health record
- replacement therapy
- simultaneous determination