ASCL1 is activated downstream of the ROR2/CREB signaling pathway to support lineage plasticity in prostate cancer
Nakisa Tabrizian,
Shaghayegh Nouruzi,
Cassandra Jingjing Cui,
Maxim Kobelev,
Takeshi Namekawa,
Ishana Lodhia,
Amina Talal,
Olena Sivak,
Dwaipayan Ganguli,
Amina Zoubeidi
Affiliations
Nakisa Tabrizian
Department of Urologic Sciences, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
Shaghayegh Nouruzi
Department of Urologic Sciences, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
Cassandra Jingjing Cui
Department of Urologic Sciences, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
Maxim Kobelev
Department of Urologic Sciences, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
Takeshi Namekawa
Department of Urologic Sciences, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
Ishana Lodhia
Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
Amina Talal
Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
Olena Sivak
Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
Dwaipayan Ganguli
Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
Amina Zoubeidi
Department of Urologic Sciences, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada; Corresponding author
Summary: Lineage plasticity is a form of therapy-induced drug resistance. In prostate cancer, androgen receptor (AR) pathway inhibitors potentially lead to the accretion of tumor relapse with loss of AR signaling and a shift from a luminal state to an alternate program. However, the molecular and signaling mechanisms orchestrating the development of lineage plasticity under the pressure of AR-targeted therapies are not fully understood. Here, a survey of receptor tyrosine kinases (RTKs) identifies ROR2 as the top upregulated RTK following AR pathway inhibition, which feeds into lineage plasticity by promoting stem-cell-like and neuronal networks. Mechanistically, ROR2 activates the ERK/CREB signaling pathway to modulate the expression of the lineage commitment transcription factor ASCL1. Collectively, our findings nominate ROR2 as a potential therapeutic target to reverse the ENZ-induced plastic phenotype and potentially re-sensitize tumors to AR pathway inhibitors.
