Notch signaling suppresses neuroendocrine differentiation and alters the immune microenvironment in advanced prostate cancer
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
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
View: Text | PDF
Research Article Oncology

Notch signaling suppresses neuroendocrine differentiation and alters the immune microenvironment in advanced prostate cancer

Abstract

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 (NE) prostate cancer, where it functions as a tumor suppressor. Activation of Notch in NE and Rb1/Trp53-deficient prostate cancer models led to phenotypic conversion toward a more indolent, non-NE state with glandular features and expression of luminal lineage markers. This was accompanied by upregulation of MHC and type I IFN and immune cell infiltration. Overall, these data support Notch signaling as a suppressor of NE differentiation in advanced prostate cancer and provide insights into how Notch signaling influences lineage plasticity and the tumor microenvironment (TME).

Authors

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

×

Figure 5

AR signaling in the WCM154-CMV-fNICD2 model.

Options: View larger image (or click on image) Download as PowerPoint
AR signaling in the WCM154-CMV-fNICD2 model. (A) AR signature scores wer...
(A) AR signature scores were calculated in DEST tumor and NE, transitional, and luminal lineages of fNICD2-#1 tumors. *P < 0.05 and ***P < 0.001, by 1-way ANOVA. (B) DEST and fNICD2-#1 tumors were assessed for AR and SYP expression. Mouse prostate epithelial cells were used as an internal control to indicate positive nuclear AR staining and negative SYP staining. Scale bars: 50 μm. (C) DEST and fNICD2-#1 tumors were subcutaneously implanted into male mice. When tumor size reached approximately 100 mm3, half of the mice were surgically castrated. Tumor size was measured on the indicated days (n = 4–5 per group). A 2-way ANOVA was performed to test for significant differences between intact (AS) and castrated (Cx) mice for both DEST and fNICD2-#1. (D) Histology of intact and castrated DEST and fNICD2-#1 tumors. Scale bars: 100 μm.