Notch signaling can have either an oncogenic or tumor suppressive function in cancer depending on the cancer type and cellular context. While Notch can be oncogenic in early prostate cancer, we identified significant downregulation of the Notch pathway during prostate cancer progression from adenocarcinoma to neuroendocrine prostate cancer where it functions as a tumor suppressor. Activation of Notch in neuroendocrine and Rb1/Trp53-deficient prostate cancer models led to phenotypic conversion towards a more indolent non-neuroendocrine state with glandular features and expression of luminal lineage markers. This was accompanied by up-regulation of MHC and type I interferon and immune cell infiltration. Overall, these data support Notch signaling as a suppressor of neuroendocrine differentiation in advanced prostate cancer and provides insights into how Notch signaling influences lineage plasticity and the tumor microenvironment.
The Journal of clinical investigation. 2024 Jul 18 [Epub ahead of print]
Sheng-Yu Ku, Yanqing Wang, Maria Mica Garcia, Yasutaka Yamada, Kei Mizuno, Mark D Long, Spencer Rosario, Meenalakshmi Chinnam, Majd Al Assaad, Loredana Puca, Min Jin Kim, Martin K Bakht, Varadha Balaji Venkadakrishnan, Brian D Robinson, Andrés M Acosta, Kristine M Wadosky, Juan Miguel Mosquera, David W Goodrich, Himisha Beltran
Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America., Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America., Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, United States of America., Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America., Medicine, Weill Cornell Medicine, New York, United States of America., Pathology, Brigham and Women's Hospital, Boston, United States of America.