Lab research

Microenvironmental Regulation of Tumor Progression and Metastasis

Immunomodulation of the tumor microenvironment (TME) governed by TME governed by epithelial vs. mesenchymal phenotypes of cancer cells

Interestingly, we have observed that the residence of carcinoma cells in epithelial or quasi-mesenchymal states can differentially modulate the TME of breast cancer cells. For example, carcinoma cell-induced immune-suppression of cells in the TME is associated with increased polarization/abundance of pro-tumorigenic M2-like macrophages in the vicinity of tumors containing quasi-mesenchymal (qM) carcinoma cells (Dongre et al., 2017). Intriguingly, minority populations of qM cells within a tumor can cross-protect their more epithelial neighbors from immune attack, making tumors resistant to immune-checkpoint (anti-CTLA4) blockade (ICB) therapy. We identified several factors produced by qM cells that can drive immunosuppression, including CD73, which encodes an ecto-enzyme that converts extracellular ATP to immunosuppressive adenosine (Dongre et al., 2020).

Effects of localized and systemic inflammation, wound healing, and fibrosis on metastatic colonization

Previous work from our lab demonstrated that experimental induction of inflammation using the bacterial endotoxin lipopolysaccharide (LPS) can facilitate the colonization of the lungs by disseminated murine breast cancer cells, and that such cancer cells concomitantly underwent an E-to-M transition. Additionally, the ectopic overexpression of EMT-TFs, such as Snail and Zeb1 phenocopied LPS-induced metastatic colonization of the lungs (De Cock et al., 2016). More recently, we observed that surgery-induced tissue injury and consequent inflammation can trigger the outgrowth of breast cancer metastases in mice, which can be suppressed by the administration of non-steroidal anti-inflammatory drugs (NSAIDs) (Krall et al., 2018). Currently, we are exploring how dormant disseminated cells lodged in the lungs can be provoked to enter proliferation and spawn macroscopic metastases in the lungs, liver, and in future work, in other tissue sites of dissemination.