Basal‐like mammary carcinomas stimulate cancer stem cell properties through AXL‐signaling to induce chemotherapy resistance

Abstract

Abstract 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.

What's new? Basal‐like breast cancer (BLBC) is the most aggressive breast cancer subtype, and it often develops resistance to chemotherapy. Here, the authors used high‐throughput mRNA sequencing to identify transcriptional changes that allowed the tumor cells to withstand chemotherapy. After only one round of combination chemotherapy (Cyclophosphamide, Adriamycin and 5‐Fluorouracil) the tumor cells had begun a massive gene expression reprogramming, becoming more like cancer stem cells by activating Axl and its ligand Pros1. They also showed that inhibition of AXL made the cells susceptible to cytotoxic treatment in vitro, suggesting AXL may be a potential therapeutic target.

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