Cells of origin in hormone-related cancers

Mammary gland transplantationWe are using several complementary approaches in genetically modified mice, including Cre-loxP genetic marking and in vivo cell fate mapping, as well as cell sorting coupled with transplantation, to study how cells of origin contribute to the heterogeneity of hormone-related cancers (e.g., breast cancer, ovarian cancer, prostate cancer). We also study whether the cellular origin confers a unique vulnerability to the corresponding cancer, which can be explored therapeutically.

Clonal evolution of premalignant and cancer cells

scRNA-seqBy applying lineage-tracing approaches in mouse models, we follow clonal evolution of normal cells (i.e., cells of origin) to premalignant cells, and eventually to cancer cells. By using flow cytometry, single cell profiling, and other molecular and cellular approaches (e.g., organoid culture), we aim to identify and validate key mutations, epigenetic changes, changes in the microenvironment (e.g., immune cells), and their corresponding deregulated pathways, at different stages of cancer progression, leading to the formation of cancer stem cells/tumor-initiating cells or metastatic cancer cells.

Epigenetic regulation and immune mechanism in breast cancer metastasis

Lung metastasisCancer genomics studies so far have not identified consistent genetic drivers unique to metastasis, raising a possibility that epigenetic mechanisms may play a more important role in driving cancer cell metastasis. By studying LSD1, a key epigenetic regulator, we aim to gain a detailed mechanistic understanding of how epigenetic programs intersect with cell type-specific transcriptional programs and/or modulate the tumor immune microenvironment to promote or suppress metastatic progression, under the setting of breast cancer.

Modeling breast cancers in mice

Intraductal injectionWe have a long-standing interest in making novel mouse models for human breast cancers. One approach we have developed is based on intraductal injection of Cre-expressing adenovirus (Ad-Cre) under the control of cell type-specific promoters [e.g., an Ad-Cre under the control of the Keratin 8 promoter (Ad-K8-Cre) to target luminal mammary epithelial cells (MECs), which may be cells of origin of most breast cancers]. Based on this approach, we have generated triple-negative breast cancer mouse models based on induced loss of p53 and/or BRCA1. We are currently generating a new mouse model for estrogen receptor (ER)+ breast cancer based on loss of RUNX1 function in luminal MECs.