Recently, a team led by Prof. David Wai Chan from the School of Medicine at The Chinese University of Hong Kong, Shenzhen, in collaboration with The Chinese University of Hong Kong, Sir Run Run Shaw Hospital affiliated with the Zhejiang University School of Medicine, and Ruijin Hospital affiliated with the Shanghai Jiao Tong University School of Medicine, published a significant research paper in the international academic journal "Experimental Hematology & Oncology". The paper, titled "Polyunsaturated fatty acids promote M2-like TAM deposition via dampening RhoA/YAP1 signaling in the ovarian cancer microenvironment".

The research delves into a previously uncharted territory by demonstrating how polyunsaturated fatty acids can induce a more benign M2-like phenotype in tumor-associated macrophages (TAMs) within the hostile milieu of malignant ascites, a common feature in metastatic ovarian cancer. By attenuating the RhoA/YAP1 signaling pathway, the study suggests a promising new avenue for therapeutic intervention. Specifically, the activation of YAP1 with the novel agent XMU-MP1 has shown potent efficacy in reprogramming TAMs, thereby hindering the metastatic progression of ovarian epithelial cancer. This discovery opens up potential for innovative treatments that target the intricate interplay between cancer cells and their microenvironment, marking a significant step forward in the fight against this aggressive disease.

Tumor immunotherapy is an innovative yet challenging treatment for peritoneal metastasis in advanced ovarian cancer due to its limited efficacy. Macrophages, highly plastic in function and phenotype, are influenced by the tumor microenvironment (TME) and are crucial in the resistance to cancer therapies. Prof. Chan's team has uncovered a pivotal role of polyunsaturated fatty acids (PUFAs) in driving the polarization of M2-like tumor-associated macrophages (TAMs) in the ascites of metastatic ovarian cancer patients, contributing to an immunosuppressive TME and aiding cancer spread.

 Researchers firstly used multiplex immunohistochemistry (m-IHC) to study macrophage diversity in epithelial ovarian cancer (EOC) progression, evaluating their distribution and activity in patient samples. They found that malignant ascites indicates peritoneal metastasis and forms a tumor-promoting microenvironment linked to poor prognosis. The study confirmed that pro-tumoral M2-like tumor-associated macrophages (TAMs) accumulate in metastatic regions, as evidenced by m-IHC and immunofluorescence analyses.

To clarify the molecular mechanisms that promote tumor-associated macrophage (TAM) polarization in malignant ascites, transcriptomic and Reactome pathway analyses indicated that polyunsaturated fatty acids (PUFAs) in malignant ascites promote pro-tumoral M2-like TAM polarization by inhibiting RhoA GTPase activity, which in turn suppresses the RhoA-YAP1 signaling pathway through the MST1/2-YAP1 independent cascade.

Further investigation revealed that the downregulation of RhoA mediated by polyunsaturated fatty acids (PUFAs) leads to the loss of YAP1, prompting macrophages (MФs) to polarize towards pro-tumoral M2-like TAMs. This shift reduces the infiltration of cytotoxic CD8+ T cells, facilitating metastatic progression. Conversely, targeting MST1/2 (Hippo pathway) with the specific inhibitor XMU-MP1 can increase nuclear YAP1 expression, driving TAMs to switch from an M2 to an M1 phenotype. This change results in the re-recruitment and reactivation of cytotoxic CD8+ T cells, thereby inhibiting the metastatic progression of epithelial ovarian cancer (EOC).

Their research found that YAP1 acts like a key "controller" within macrophages (MФs), regulating anti-tumor immune responses and cell infiltration in a peritoneal microenvironment rich in PUFAs. The study shows that the expression levels of YAP1 differ between M1 and M2 type macrophages: it is lower in M2 and higher in M1 types. They further confirm that a reduction in nuclear YAP1 promotes polarization towards the M2 type, while the restoration of YAP1 drives macrophages towards a phenotype capable of tumor killing. Additionally, macrophages lacking Yap1 make mice more prone to tumor growth and metastasis, which is related to an increased ratio of M2 to M1 type macrophages and a decrease in CD8+ T cell infiltration, highlighting the decisive role of TAMs in peritoneal metastasis. This finding offers a promising new direction for treating advanced ovarian cancer.

CHAN, Wai David

Associate Professor (Teaching)

Research Field: Tumor microenvironment, Epigenetics and human cancers, Cancer cell metabolism, Lipid Metabolism, Onco-immunology, Chemoresistance

Prof. David Wai Chan received his Ph.D. from Monash University, Australia, in 2002. He had worked at Peter MacCallum Cancer Centre, Australia, and did his Postdoctoral training at The University of Hong Kong from 2003 to 2006. He served as a Research Assistant Professor, Assistant Professor, and Scientific Officer undertaking administration, postgraduate supervision, laboratory management, teaching, PBL tutorial and academic advisor for MBBS students at the LKS Faculty of Medicine, HKU, from 2007 to 2021. He then joined an international biotech company as a Senior Vice-President for the scientific development and GMP manufacturing of cell therapies, and worked as a Research Associate in School of Biomedical Sciences of CUHK before joining the School of Medicine, CUHK-Shenzhen as an Associate Professor for pre-clinical teaching in 2022. 

Prof. Chan’s research areas include genetic and epigenetic alterations in tumor development, tumor microenvironment impact on chemoresistance and metastatic progression, and precision cancer medicine. His research mainly utilizes clinical data and cellular and animal models combined with bioinformatics to decipher signaling pathways of tumor-stromal interactions, onco-immunology, and cancer cell metabolism in the metastatic progression. His team has successfully established an omental conditioned media model to imitate the ascites microenvironment to study peritoneal metastases of ovarian cancer and therapeutic translational research. He has identified MAP30 bioactive protein from bitter melon playing as a natural AMPK activator in enhancing the efficancy of platinum-based chemotherapy in ovarian cancer. His recent research mainly focuses on nano-based drug delivery, genomic analysis and organoid-drug screening systems in targeted therapy. The research outcomes were granted patents and published in more than 78 peer-reviewed papers receiving >12,380 citations (Google Scholar). His works have also attracted not only academic centers from Hong Kong, mainland China, and USA/UK but also pharmaceutical companies in seeking collaborations and funding supports such as RGC-GRF, HMRF, and ITF of Hong Kong, NSFC and SZ-NSF of mainland China. In academic society, he now serves as an Associate Editor of Journal of Ovarian Research (JCR Q1 in Reproductive Biology) and Frontiers in Pharmacology (JCR Q1 in Pharmacology & Pharmacy), as well as a Guest editor of International Journal of Molecular Sciences (JCR Q1 in Biochemistry & Molecular Biology), and Frontiers in Oncology (JCR Q2 in Oncology).