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McCaffrey Lab

Cancer Cell Biology and Morphogenesis

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Epithelial Cell Biology

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Research

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Cell Polarity Signaling and Malignant Transformation

Loss of tissue organization and apical-basal polarity (i.e. the segregation of apical and basolateral membrane domains) are characteristics of epithelial cancers. A concept that we have championed is that loss of apical-basal polarity deregulates signaling pathways involved in epithelial homeostasis, which is a permissive step in the progression to a malignant state. Apical-basal membrane polarity demarcates distinct cellular membrane compartments, with an apical membrane that faces the lumen and a basolateral membrane that contacts adjacent cells and the extracellular matrix. Key regulators of apical-basal polarity control a wide range of cellular activities, including proliferation, survival, motility, and invasion that are important for breast cancer progression. This theme investigates novel mechanisms by which tissue organization and polarity are regulated during cancer progression. Read more

Characterizing Cell Heterogeneity in Early Breast Cancer Progression

Ductal Carcinoma In Situ (DCIS) is a non-obligate precursor for invasive cancer. This means that invasive cancer develops from DCIS, but not all DCIS will progress to invasive cancer. There are currently no established clinical, pathological, or genetic features that reliably predict progression of DCIS to invasive cancer. We envision that epithelial phenotypic diversity and plasticity contribute to progression of DCIS to invasive cancer by endowing cells the ability to adapt from a ductal environment to a stromal environment. The major objective of this theme is to elucidate the molecular mechanisms underlying early breast cancer development with the long-term goal of developing predictive biomarkers for DCIS. Read more

Overcoming Suppressive Microenvironments in Breast Cancer Progression

Ductal carcinoma in situ (DCIS) is characterized by a suppressive epithelial and and immune microenvironment that restricts cell invasion. Macrophages can exist in multiple states with diverse activities, including inflammation, immune regulation, angiogenesis, invasion, and metastasis. Increased numbers of tumor-associated macrophages are associated with poor outcome in breast cancer patients. Breast ducts are organized as a bilayer of luminal epithelial cells surrounded by a contractile myoepithelial layer. In early breast cancer progression, luminal cells acquire malignant properties and expand in number. Myoepithelial cells are hypothesized to be natural repressors of tumour progression by acting as a physical barrier to prevent luminal cells from invading into surrounding tissue. Loss of myoepithelial cells is a characteristic of the transition from DCIS to invasive cancer, however, the molecular mechanisms that disrupt the myoepithelial layer remain largely unknown. This theme investigates the mechanisms by which the suppressive immune microenvironment and myoepithelial cells are reprogrammed to permit invasive breast cancer Read more