A comprehensive study on tumor suppressor cooperation in prostate cancer progression
Prostate cancer remains a leading cause of cancer-related mortality in men worldwide, with treatment resistance and metastasis representing major clinical challenges . Lineage plasticity, the ability of cancer cells to alter their differentiation state, has emerged as a key mechanism driving therapeutic resistance and disease progression .
New prostate cancer cases annually in the US
Annual prostate cancer deaths in the US
The tumor suppressors Rb1 and Trp53 are frequently altered in advanced prostate cancer, but their cooperative functions in suppressing lineage plasticity and metastasis remain incompletely understood . This study investigates the molecular mechanisms through which these two critical tumor suppressors interact to constrain prostate cancer progression.
Rb1 and Trp53 cooperate to maintain luminal differentiation and prevent epithelial-to-mesenchymal transition (EMT) in prostate cancer cells .
Dual loss of Rb1 and Trp53 promotes invasive phenotypes and facilitates metastatic dissemination through altered cell adhesion and motility .
Co-deletion of Rb1 and Trp53 enables bypass of androgen receptor signaling blockade, leading to antiandrogen resistance .
Combined Rb1/Trp53 loss induces a stem-like transcriptional program that drives plasticity and treatment evasion .
"The simultaneous loss of Rb1 and Trp53 in prostate epithelium resulted in accelerated tumor progression, increased metastasis, and universal antiandrogen resistance, highlighting their critical cooperative tumor suppressive functions."
Conditional knockout mouse models with prostate-specific deletion of Rb1, Trp53, or both genes were generated to study tumor progression .
Lineage tracing experiments revealed that dual Rb1/Trp53 loss promoted basal-like differentiation and luminal-to-basal plasticity .
Antiandrogen treatment experiments demonstrated that Rb1/Trp53 co-deleted tumors were completely resistant to enzalutamide and abiraterone .
RNA sequencing and chromatin accessibility analyses identified key transcriptional programs activated upon Rb1/Trp53 loss .
The findings from this study have significant implications for prostate cancer treatment strategies :
This study establishes that Rb1 and Trp53 cooperate as critical barriers to prostate cancer progression by suppressing lineage plasticity, metastasis, and antiandrogen resistance . The dual loss of these tumor suppressors activates a stem-like program that drives therapeutic resistance and disease aggression.
Future research should focus on identifying vulnerabilities in Rb1/Trp53-deficient prostate cancers and developing targeted therapies that can overcome the resistance mechanisms driven by lineage plasticity .
Similar cooperative effects observed in other cancer types including lung and breast cancers .
Emerging evidence for plasticity as a resistance mechanism across multiple cancer types .