Abstract 4721: Epithelial to mesenchymal transition is not required for breast to lung metastasis but contributes to chemoresistance

Abstract

The role of epithelial to mesenchymal transition (EMT) in metastasis is a longstanding source of controversy, largely due to an inability to monitor transient and reversible EMT phenotypes in vivo. We have established a novel and unique EMT lineage tracing system in spontaneous breast to lung metastasis models. In these models, mesenchymal-specific Cre-mediated recombination initiates permanent switch of fluorescent markers in tumor cells undergoing EMT. This allows us to track EMT tumor cells in the primary tumor, circulation and distant organs following the trail of breast to lung metastasis in vivo. We confirmed that within a predominantly epithelial primary tumor, a small portion of tumor cells undergo EMT. Strikingly, lung metastases were mainly comprised of non-EMT tumor cells maintaining their epithelial phenotype. Inhibiting EMT by overexpressing miR-200 did not impact lung metastasis development. However, EMT cells significantly contribute to recurrent lung metastasis formation after chemotherapy. These cells survived cyclophosphamide treatment due to reduced proliferation, apoptotic tolerance, and elevated expression of chemoresistance-related genes. This study suggests the potential of an EMT-targeting strategy, in conjunction with conventional chemotherapies, in the treatment of breast cancer patients. Citation Format: Kari R. Fischer, Anna Durrans, Sharrell Lee, Jianting Sheng, Hyejin Choi, Fuhai Li, Stephen Wong, Nasser K. Altorki, Vivek Mittal, Dingcheng Gao. Epithelial to mesenchymal transition is not required for breast to lung metastasis but contributes to chemoresistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4721. doi:10.1158/1538-7445.AM2015-4721

ZEB1: A Critical Regulator of Cell Plasticity, DNA Damage Response, and Therapy Resistance

“…Indeed, the correlation between EMT, increased ZEB1/2dependent expression of MDR1 and ABCG2, and resistance to platinum-based drugs was confirmed by the whole transcriptome profiling of ovarian and lung cancer tissues (Zhou Y. et al, 2017;Wu et al, 2019a). Finally, several recent studies demonstrated decreased sensitivity to chemotherapy of primary and metastatic tumor cells in an EMT-dependent manner in both lung and pancreatic cancers (Fischer et al, 2015;Zheng et al, 2015). These reports provide convincing data linking EMT to chemoresistance.…”

“…Previous studies demonstrated that highly proliferative non-EMT breast cancer cells were sensitive to chemotherapy, while the emergence of recurrent EMT-derived metastases was associated with resistance to cyclophosphamide in vivo (Fischer et al, 2015). Also, miR-200 overexpression results in the switch toward cyclophosphamide sensitivity (Fischer et al, 2015). These results indicate potential relevance of EMT in the chemoresistance, as the main target of miR-200 is ZEB1, a crucial regulator of EMT that is capable of reversing the whole machinery (Bracken et al, 2014).…”

“…Thus, it remains unclear whether EMT by itself or specific EMT regulators are the main drivers of therapy resistance. Previous studies demonstrated that highly proliferative non-EMT breast cancer cells were sensitive to chemotherapy, while the emergence of recurrent EMT-derived metastases was associated with resistance to cyclophosphamide in vivo (Fischer et al, 2015). Also, miR-200 overexpression results in the switch toward cyclophosphamide sensitivity (Fischer et al, 2015).…”

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

“…options and therapeutic outcome. EMT is linked not only to increased metastasis (Yang et al, 2004;Mani et al, 2007;Ocana et al, 2012;Stankic et al, 2013) but also to chemoresistance (Singh and Settleman, 2010;Haslehurst et al, 2012;Ren et al, 2013;Fischer et al, 2015;Zheng et al, 2015;Li H. et al, 2019;Li N. et al, 2019). EMT in cancer is associated with the acquisition of a more stem-cell-like character.…”

“…EMT in cancer is associated with the acquisition of a more stem-cell-like character. Accordingly, Fisher et al found that the cyclophosphamide resistance of tumor cells that acquired a mesenchymal character could be attributed to reduced proliferation and increased expression of drug efflux pumps (ABCC1, ABCB1) and of enzymes involved in drug metabolism, like cytochrome p450s (Fischer et al, 2015), traits that are characteristic for stem and progenitor populations.…”