E-Poster Presentation 34th Lorne Cancer Conference 2022

Single-cell RNAseq analysis of IL11-dependent pathways in Triple Negative Breast Cancer (#111)

Sarah Bennett 1 2 , Yang Liao 1 2 , Bhupinder Pal 1 2 , Wei Shi 1 2 , Matthias Ernst 1 2 , Ashwini Chand 1 2
  1. Olivia Newton John Cancer Research Institute, Heidelberg, VIC, Australia
  2. School of Cancer Medicine, LaTrobe University, Heidelberg, VIC, Australia

Triple-negative breast cancer (TNBC) accounts for ~15-20% of all breast cancer. It is characterised by a lack of oestrogen receptor, progesterone receptor and epidermal growth factor receptor 2 (HER2), making it impervious to endocrine or HER2-directed therapies routinely used for other breast cancer subtypes. There is an urgent clinical need to identify cellular mechanisms driving progression and metastasis so improved treatments can be developed.  Evidence supports the role of transcription factor Signal Transducer and Activator of Transcription 3 (STAT3) in promoting TNBC “cancer hallmark capabilities” including proliferation, survival, and invasion. Analysis of TCGA datasets show an enrichment of STAT3 activation signatures in TNBC, correlated with reduced metastasis-free survival. Binding of the cytokine Interleukin-11 (IL11) to a heterotrimeric complex including its receptor IL11RA and the GP130 receptor is one of the upstream events leading to STAT3 activation. Our analysis shows IL11 mRNA transcripts in TCGA datasets are elevated in breast cancer compared to normal adjacent tissue. High IL11 levels are positively correlated with TNBC progression, recurrent disease and metastasis. To investigate the role of IL11 signaling on tumour growth and metastasis, we implanted 4T1 mammary tumour cells into the mammary fat pad of wildtype and IL11RA knockout mice. Tumour and metastatic burden was reduced in the IL11ra-/- mice compared to wildtype animals. Transcriptomic analysis by single-cell RNAseq revealed the importance of IL11 signaling in regulating macrophage maturation, activation of T-cells and glycolysis within cell types of the tumour microenvironment, highlighting the importance of host IL11 signaling on local immune cell function. Populations of T-cells, B-cells, macrophages and dendritic cells were increased in IL11ra-/- mice, and these populations also displayed the highest number of differentially expressed genes. Taken together, these results indicate a pronounced role for IL11 signaling in driving TNBC primary tumour growth and metastasis. Therapeutic manipulation of IL11 signaling would present a promising avenue for TNBC treatment research.