The role and spatiotemporal dynamics of TREM2+ macrophages in liver metastases of pancreatic ductal adenocarcinoma

Abstract public domain (NIH RePORTER)

Project summary The goal of the proposed 5-year training and research plan for the Mentored Clinical Scientist Development Award is to support the transition of Dr. Liang-I Kang (PI) to an independent research career as a physician scientist. Dr. Kang has research background in liver biology and digestive system malignancies, with a focus on pancreatic ductal adenocarcinoma (PDAC). She is also a board-certified anatomic pathologist with subspecialty training in Hepatobiliary, Pancreatic, and Gastrointestinal Pathology. Dr. Kang’s long term goal is to lead an independently funded basic science and translational research program to study the tumor microenvironment (TME) in liver metastases. To achieve this goal, Dr. Kang proposes to gain new expertise in advanced tumor immunology and transcriptomics, through a combination of didactic training and a research project under the mentorship of Dr. David DeNardo, an expert on the TME in PDAC, and a committee of scientific advisors with expertise in pancreatic cancer, innate immunology, and genomics/bioinformatics. The research will be performed at Washington University School of Medicine, a leading institution in pancreatic cancer research, immunology, cancer genomics/transcriptomics, and physician scientist training. There is an unmet need for effective treatment strategies for metastatic PDAC, which has a 5-year survival rate of less than 5%. The liver is the most common solid organ site for PDAC metastasis and is associated with a worse prognosis. Better understanding of the liver TME may provide insight to candidate treatment targets. Our preliminary data show that, in mouse models of PDAC liver metastases and human PDAC liver metastases, there is an enrichment of metastasis-associated macrophages (MAMs) that express the TREM2 receptor and other immunosuppressive markers. Liver metastatic tumor burden is significantly decreased in mice when MAMs lack TREM2, suggesting a key role for TREM2-positive MAMs in liver metastases. The central hypothesis of this proposed study is that TREM2 expression and signaling in MAMs drive a tumor-promoting phenotype in the setting of PDAC liver metastases in mice and humans. To investigate, Dr. Kang will use advanced tools such as metastatic niche-labeling technology, genetically engineered mouse models, ex vivo functional assays, singlecell RNA sequencing and spatial transcriptomic analysis. Mouse models are necessary, as there are currently no in vitro models that adequately recapitulate the complete TME of metastastic PDAC; however, in addition to mouse models, Dr. Kang will use curated human PDAC liver metastases samples from clinical and autopsy cases to confirm human relevance. With these tools, she will determine cellular and molecular mechanisms by which TREM2-expressing MAMs may promote tumor growth and their spatiotemporal dynamics in human PDAC liver metastasis. This work will provide greater insight into the metastatic TME that can be leveraged for potential metastatic-targeted therapies. The training, mentorship, and professional development during the award period will provide the PI with the skills needed to achieve her goal of becoming an independent investigator.

Public health relevance public domain (NIH RePORTER)

Project Narrative Pancreatic cancer is a highly lethal disease in which most patients are diagnosed with or eventually develop distant metastases; however, there are currently no effective therapies for metastatic pancreatic cancer. This project aims to identify candidate treatment targets for metastatic pancreatic cancer by studying the cells that interact with and support tumor growth in liver metastasis. The findings of this study could contribute to the development of new treatments to improve outcomes in metastatic pancreatic cancer patients, but also could benefit patients with metastatic cancer of other types as well.