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Influence of the Hippo-YAP signalling pathway on tumor associated macrophages (TAMs) and its implications on cancer immunosuppressive microenvironment.

ABSTRACT: A large number of immune cells are present in the tumour microenvironment (TME), of which, tumour-associated macrophages (TAMs) are among the most important and highly infiltrated cells, and mainly include the M1 type classically activated and M2 type alternatively activated TAMs. Both cell types are known to play an important role in tumour initiation and proliferation. It has recently been confirmed that the TAMs in tumours tend to be dominated by the M2 type. However, the precise mechanism underlying TAM recruitment and polarization in the immune microenvironment remains to be elucidated. The Hippo-Yes-associated protein (YAP) signalling pathway is one of the most extensively discussed mechanism for the regulation of tumour proliferation, migration, angiogenesis, and invasion in recent years. To date, several studies have revealed that YAP is involved in the interrelating interactions between tumour and immune cells, particularly the TAMs. In this review, we have summarized the mechanism by which the YAP regulates the activity of TAMs and its impact on the TME.

SUBMITTER: Yang W

PROVIDER: S-EPMC7186717 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Influence of the Hippo-YAP signalling pathway on tumor associated macrophages (TAMs) and its implications on cancer immunosuppressive microenvironment.

Yang Wenjie W Yang Shikun S Zhang Feng F Cheng Feng F Wang Xuehao X Rao Jianhua J

Annals of translational medicine 20200301 6

A large number of immune cells are present in the tumour microenvironment (TME), of which, tumour-associated macrophages (TAMs) are among the most important and highly infiltrated cells, and mainly include the M1 type classically activated and M2 type alternatively activated TAMs. Both cell types are known to play an important role in tumour initiation and proliferation. It has recently been confirmed that the TAMs in tumours tend to be dominated by the M2 type. However, the precise mechanism un ...[more]

PMID: 32355843

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Project description:Background and aimsLiver regeneration retardation post partial hepatectomy (PH) is a common clinical problem after liver transplantation. Identification of key regulators in liver regeneration post PH may be beneficial for clinically improving the prognosis of patients after liver transplantation. This study aimed to clarify the function of junctional protein-associated with coronary artery disease (JCAD) in liver regeneration post PH and to reveal the underlying mechanisms.MethodsJCAD knockout (JCAD-KO), liver-specific JCAD-KO (Jcad△Hep) mice and their control group were subjected to 70% PH. RNA sequencing was conducted to unravel the related signalling pathways. Primary hepatocytes from KO mice were treated with epidermal growth factor (EGF) to evaluate DNA replication. Fluorescent ubiquitination-based cell cycle indicator (FUCCI) live-imaging system was used to visualise the phases of cell cycle.ResultsBoth global and liver-specific JCAD deficiency postponed liver regeneration after PH as indicated by reduced gene expression of cell cycle transition and DNA replication. Prolonged retention in G1 phase and failure to transition over the cell cycle checkpoint in JCAD-KO cell line was indicated by a FUCCI live-imaging system as well as pharmacologic blockage. JCAD replenishment by adenovirus reversed the impaired DNA synthesis in JCAD-KO primary hepatocyte in exposure to EGF, which was abrogated by a Yes-associated protein (YAP) inhibitor, verteporfin. Mechanistically, JCAD competed with large tumour suppressor 2 (LATS2) for WWC1 interaction, leading to LATS2 inhibition and thereafter YAP activation, and enhanced expression of cell cycle-associated genes.ConclusionJCAD deficiency led to delayed regeneration after PH as a result of blockage in cell cycle progression through the Hippo-YAP signalling pathway. These findings uncovered novel functions of JCAD and suggested a potential strategy for improving graft growth and function post liver transplantation.Key pointsJCAD deficiency leads to an impaired liver growth after PH due to cell division blockage. JCAD competes with LATS2 for WWC1 interaction, resulting in LATS2 inhibition, YAP activation and enhanced expression of cell cycle-associated genes. Delineation of JCADHippoYAP signalling pathway would facilitate to improve prognosis of acute liver failure and graft growth in living-donor liver transplantation.

Project description:Fibroblasts turn into cancer associated fibroblasts (CAFs) in the tumour microenvironment. CAFs have recently attracted attention for their function as a regulator of immune cell recruitment and function in addition to their tumour-promoting roles. In this study, we aimed to determine the role of CAFs on monocyte recruitment and macrophage polarization in breast cancer. CAFs, which were α-SMA expressing fibroblasts in contrast to normal fibroblasts (NFs), effectively recruited monocytes. Recruitment of monocytes by CAFs might be mediated by monocyte chemotactic protein-1 (MCP-1) as well as stromal cell-derived factor-1 (SDF-1) cytokines. CAFs differentiated the recruited monocytes into M2-like macrophages which are capable of exerting their immunosuppressive roles via the PD-1 axis. CAF-educated monocytes exhibited strong immune suppression unlike NF-educated monocytes and enhanced the motility/invasion of breast cancer cells in addition to increasing the expressions of epithelial-mesenchymal transition (EMT)-related genes and vimentin protein in cancer cells. CAF-educated M1 macrophages displayed increased expression of M2 markers and production of anti-inflammatory cytokine IL-10 in contrast to decreased production of pro-inflammatory cytokine IL-12 compared with control M1 macrophages; suggesting that CAFs were also able to induce the trans-differentiation of M1 macrophages to M2 macrophages. We then investigated the relationship between the infiltration of CAFs and tumour associated macrophages (TAMs) using tissue samples obtained from breast cancer patients. High grade of CAFs significantly correlated with the number of TAMs in human breast cancer tissue samples. It was also associated with higher Ki-67 proliferation index, and higher tumour volume. This result is in line with our finding of increased breast cancer cell proliferation due to the effects of CAF-educated monocytes in vitro. Our results concluded that CAFs play pivotal roles in sculpturing the tumour microenvironment in breast cancer, and therapeutic strategies to reverse the CAF-mediated immunosuppressive microenvironment should be taken into consideration.

Dataset Information

Influence of the Hippo-YAP signalling pathway on tumor associated macrophages (TAMs) and its implications on cancer immunosuppressive microenvironment.

Publications

Influence of the Hippo-YAP signalling pathway on tumor associated macrophages (TAMs) and its implications on cancer immunosuppressive microenvironment.

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