The CD44-RANK-AKT Crosstalk in Breast Cancer and Stemness

Relapse and metastasis in cancer are driven by cancer stem cells (CSC) which self-renew, give rise to tumor cell heterogeneity and are more resistant to chemotherapy. The RANK signalling pathway is implicated in a number of cancers and notably in breast carcinogenesis and metastasis.

Inhibition of this pathway reduces CSCs decreasing both recurrenceRelapse and metastasis in cancer are driven by cancer stem cells (CSC) which self-renew, give rise to tumor cell heterogeneity and are more resistant to chemotherapy. The RANK signalling pathway is implicated in a number of cancers and notably in breast carcinogenesis and metastasis.

Inhibition of this pathway reduces CSCs decreasing both recurrence and metastasis.

RANKL inhibitors are used in breast cancer clinical trials and studies focused on RANK signalling in carcinogenesis are needed to identify patients who would benefit from treatment.

RANK mediates many of its effects on cell survival, migration and chemoresistance via the PI3K/AKT pathway, activation of which confers enhanced proliferation, survival, metastatic potential and resistance to therapy in cancer. AKT is a central node in PI3K signalling and AKT isoforms play important and differential roles in carcinogenesis.

RANK is also regulated by CD44, a marker of stemness and a key player in cell migration, proliferation, differentiation, survival, stem cell maintenance and chemoresistance. CD44 alternative splicing plays a pivotal role in cancer development in breast and other tissues. However, the role of CD44 and AKT isoforms in cancer is not clearly defined.

In this MSCA project, I will investigate the role of the CD44-RANK-AKT crosstalk in tumorigenesis and identify CD44 and AKT isoforms regulating cancer stemness, metastasis and resistance to therapy.

I hypothesize that the interplay between CD44, RANK and AKT regulates cancer stemness and the metastatic potential of breast tumor cells, and specific CD44 and AKT isoforms have vital roles in this process.