Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Acquired resistance to anticancer treatments significantly increases cancer morbidity and mortality.
• The tumor microenvironment (TME) plays a crucial role in influencing cancer cell phenotypes and treatment responses.
• Understanding resistance mechanisms is vital for developing more effective cancer therapies.

Purpose of the Study:

• To identify secreted factors from the TME that contribute to acquired resistance to genotoxic cancer therapies.
• To elucidate the signaling pathway through which these TME factors mediate resistance.
• To investigate the role of WNT16B in mediating chemotherapy resistance in prostate cancer.

Main Methods:

• Genome-wide transcriptional analysis of cellular responses to genotoxic stress.
• Identification and characterization of secreted proteins in the TME.
• Investigation of NF-κB signaling pathway activation following DNA damage.
• In vivo studies using prostate cancer models to assess the impact of WNT16B on chemotherapy efficacy.

Main Results:

• A secreted protein, wingless-type MMTV integration site family member 16B (WNT16B), was identified as a key TME-derived factor.
• WNT16B expression is induced by DNA damage via NF-κB signaling.
• WNT16B acts in a paracrine manner to activate the canonical Wnt pathway in tumor cells.
• WNT16B expression in the TME attenuated chemotherapy effects, promoting tumor cell survival and progression in vivo.

Conclusions:

• Genotoxic therapies can paradoxically enhance treatment resistance through TME-mediated paracrine signaling.
• WNT16B is a critical mediator of this resistance, highlighting a novel therapeutic target.
• Targeting WNT16B or its signaling pathway may overcome acquired resistance to chemotherapy.