Lab research

Cancer Cell-Autonomous Regulation of Tumor Progression and Metastasis

Epithelial-mesenchymal plasticity (EMP)

The epithelial-to-mesenchymal transition (EMT) program creates cells residing in a spectrum of states ranging between epithelial and mesenchymal; cells can interconvert between these alternative states, indicating phenotypic plasticity. While cancer cells undergo EMT to disseminate from the primary tumor, intravasate into the circulation, and subsequently extravasate into the parenchyma of secondary organs, it is becoming increasingly apparent that after extravasation, such cancer cells may need to revert to a partially or fully epithelial state, i.e., undergo a mesenchymal-to-epithelial transition (MET) to enable metastatic colonization – the outgrowth of macroscopic metastatic colonies. Recent research in the lab has identified various molecular determinants of the residence of breast carcinoma cells in these states and how they affect their capacity to metastasize, i.e., disseminate from the primary tumor and colonize distant tissues (Pattabiraman et al., 2016Bierie et al., 2017Fröse et al., 2018, Kroger et al., 2019, Zhang et al., 2022).

Cancer stemness and tumor-or metastasis-initiating ability

The lab has previously demonstrated an overlap between EMP and stemness in cancer cells ( Mani et al., 2008, Scheel et al., 2011Guo et al., 2012Chaffer et al., 2013). We have also shown that unique combinations of EMT-related transcription factors (EMT-TFs) and well-known stemness factors coordinate to drive stemness programs in normal and neoplastic mammary epithelial cells (Ye et al., 2015). More recently, we have observed that the extreme epithelial or mesenchymal states are largely incompatible with cancer stemness, i.e., tumor or metastasis-initiating ability. Rather, it is the residence of cancer cells within a quasi-mesenchymal (qM) state, having undergone a partial EMT or MET that seems to be the primary determinant of cancer stemness (Kroger et al., 2019Zhang et al., 2022). We are currently identifying key transcription factors (such as p63) that could be drivers of cancer stemness and consequently, metastatic colonization.