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
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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

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Figure 8

Notch-mediated prostate cancer lineage state influences the tumor immune microenvironment.

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Notch-mediated prostate cancer lineage state influences the tumor immune...
(A) Prostate tissue from SKO (n = 3; 18,622 cells), TKO (n = 6; 19,485 cells), and TKO-Nicd1 (n = 4; 19,253 cells) GEMMs or TKO (TKO.TrPl, n = 2; 11,918 cells) and TKO-Nicd1 (TKO-Nicd1.TrPl, n = 2; 11,691 cells) transplant tumors were analyzed by scRNA-Seq, and the cells were clustered by transcriptional profile. The clusters are color coded on the basis of cell type as determined by the expression of cell-type–specific gene expression markers. UMAP, uniform manifold approximation and projection; prolif., proliferating. (B) The cell-type clusters are displayed for each genotype to compare relative cell-type composition of the samples. (C) Normalized expression of IFN/inflammatory (Ifitm1, Ckap4) and MHC genes (B2m, H2-K1) in neoplastic cells from TKO and TKO-Nicd1 GEMMs was determined by scRNA-Seq (Supplemental Figure 15D). Wilcox tests were used to assess differences between genotypes, and the P values are shown. (D) The proportion of immune cell subtypes detected within TKO and TKO-Nicd1 prostate tissue was calculated from scRNA-Seq data. A 2-tailed t test was used to assess the differences observed, the P values are shown. (E) Volcano plots depicting genes differentially expressed between NE and non-NE lineages developing in fNICD2-#1 transplant tumors. MHC-I genes (HLA-A, -B, -E, and -F) and B2M are highlighted, showing upregulation in non-NE cells. (F) A fNICD2-#1 transplant tumor section immunostained for HLA-ABC demonstrates upregulation at the protein level in cells with a non-NE lineage phenotype. Scale bar: 100 μm. (G) GSEA was performed using the spatial transcriptomics data in the luminal lineage, and type I IFN responses were identified. (H) Schematic of Notch signaling in NEPC. Notch signaling suppresses NE differentiation, drives non-NE lineage differentiation, and influences the immune microenvironment. Mon, monocytes; Mac, macrophages.