Basic Research

The omentum, a large sheet of fat tissue lining the peritoneal cavity in the abdomen, is a preferred early site of ovarian cancer metastasis. Disseminated ovarian cancer cells preferentially localize to specialized structures known as milky spots within the omentum. These physiologic structures enable the migration of immune cells into and out of the peritoneal cavity. Depletion of omental adipose tissue macrophages (ATMs) disrupts ovarian cancer metastatic colonization of the omentum, suggesting that resident ATMs within the omentum play a role in metastasis formation. Factors secreted by omental ATMs have an enhanced ability to promote ovarian cancer migration compared to factors secreted by other fat tissues.

We are investigating the cause of these properties of ATMs that make the omentum a preferred site for metastasis. The goal of this research is to develop therapies that interfere with ovarian cancer dissemination and provide patients with a better chance to respond to chemotherapy.

We are searching for innovative therapies to treat ovarian cancer by targeting the tumor microenvironment. Large numbers of tumor-associated immune cells called macrophages are associated with poor patient prognosis. Normal and tumor-associated macrophages can differentiate into two types, M1 and M2, depending on the molecular cues prevalent in the local environment. M1 macrophages promote an anti-tumor immune response, while M2 macrophages promote tumor invasiveness and metastasis.

We are developing a genetic reporter system to screen drug compounds on a large scale that can convert M2 macrophages into anti-tumor M1 macrophages.

Our research to date on ovarian tumor associated macrophages led us to the hypothesis that these macrophages harbor a set of genes that is unique to the disease compared to macrophages in normal tissues. To explore this idea, we are isolating macrophages from primary tumors, metastatic tumors and ascites from ovarian cancer patients, and then performing a detailed analysis of the gene expression for single macrophages. This technique is called “single-cell RNA sequencing,” which allows a greater degree of precision in classifying different gene expression signatures. We will also analyze the gene expression signatures of macrophages found in benign conditions at the single cell level as an experimental control.

By comparing the benign and malignant macrophage populations using computational methods, we can derive in-depth knowledge about the diversity of ovarian cancer macrophages, their role in ovarian cancer growth, and ultimately design new and more effective therapies.

Cisplatin is an effective and widely used chemotherapeutic agent against ovarian cancer. Despite its great efficacy at treating ovarian cancer, the major limitation of cisplatin treatment is the development of resistance in responsive ovarian cancer.

We are studying what cellular signaling pathways can give rise to platinum resistance, both intrinsic pathways that lead to cell survival as well as extrinsic factors such as tumor associated macrophages. Macrophages associated with tumors have been shown to promote resistance to chemotherapies, but the mechanism(s) involved are a mystery.

Macrophage colony-stimulating factor (M-CSF) is a potent growth factor promoting the differentiation, proliferation, and migration of macrophages via signaling through its receptor CSF1R. M-CSF and CSF1R have been reported to be upregulated in several solid cancers, including ovarian cancer, implicating this pathway in ovarian cancer progression.

To investigate this important topic of inflammatory modulation of cancer progression, we are using both small molecules and antibodies that selectively blocks CSF1R. We recently showed that tumor associated macrophages (TAMs) are dependent on M-CSF/CSF1R signaling for recruitment into the tumor; (ii) they play critical roles in tumoral angiogenesis, immune suppression and tissue remodeling; and (iii) blocking the recruitment of TAMs by CSF1R inhibition greatly augmented the efficacy of an anti-angiogenic therapy.