Epithelial to Mesenchymal Transition Contributes to Drug Resistance in Pancreatic Cancer

By Thiruvengadam Arumugam, V. Ramachandran, K. Fournier, Huamin Wang, L. Marquis, J. Abbruzzese, G. Gallick, C. Logsdon, D. McConkey, W. Choi. Cancer Research, 2009

864 citations recorded by the source corpus.

A better understanding of drug resistance mechanisms is required to improve outcomes in patients with pancreatic cancer. Here we characterized patterns of sensitivity and resistance to three conventional chemotherapeutic agents with divergent mechanisms of action (gemcitabine, 5-fluorouracil, and cisplatin) in pancreatic cancer cells. Four (L3.6pl, BxPC-3, CFPAC-1, SU86.86) were sensitive and five (PANC-1, Hs766T, AsPC-1, MIAPaCa-2, Mpanc96) were resistant to all 3 agents based on GI50 (50% growth inhibition). Gene expression profiling and unsupervised hierarchical clustering revealed that the sensitive and resistant cells formed two distinct groups and differed in expression of specific genes including several features of “epithelial-mesenchymal transition” (EMT). Interestingly, an inverse correlation between E-cadherin and its transcriptional suppressor, Zeb-1 was observed in the gene expression data and was confirmed by real time PCR. Independent validation experiment using 5 new pancreatic cancer cell lines confirmed that an inverse correlation between E-cadherin and Zeb-1 correlated closely with resistance to gemcitabine, 5-fluorouracil, and cisplatin. Silencing Zeb-1 in the mesenchymal lines not only increased the expression of E-cadherin but also other epithelial markers such as EVA1 and MAL2 and restored drug sensitivity. Importantly, immunohistochemical analysis of E-cadherin and Zeb-1 in primary tumors confirmed that expression of the two proteins was mutually exclusive (p=0.012). Therefore, our results suggest that Zeb-1 and other regulators of EMT may maintain drug resistance in human pancreatic cancer cells, and therapeutic strategies to inhibit Zeb-1 and reverse EMT should be evaluated.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/0f4dab9ae085a3d22bc7db5d1ad1298ed9c30bc8

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Citations in the corpus

Epithelial-mesenchymal transition spectrum quantification and its efficacy in deciphering survival and drug responses of cancer patients (2014, critical): “Although many reports have associated the EMT status with survival (Witta et al , 2006; Arumugam et al , 2009; Hrstka et al , 2010; Sethi et al , 2010; Loboda et al , 2011; Cieply et al , 2012; Byers et al , 2013; Marchini et al , 2013), our EMT scoring does not wholly support these findings.”
Phenotype and Genotype of Pancreatic Cancer Cell Lines (2010, background): “Examples of studies that capitalized on phenotypic differences in PA cell lines have provided mechanistic insight through linkage of differential expression of specific proteins to tumor growth, invasion and metastasis,(4,5) and chemotherapeutic drug resistance.(6) Choosing cell lines for specific p”
The ZEB/miR‐200 feedback loop—a motor of cellular plasticity in development and cancer? (2010, background): “It is now known that EMT activation is also associated with the maintenance of stem-cell properties”
Targeting Epithelial–Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer (2016, background): “It has been increasingly recognized that cancer drug resistance is frequently accompanied with EMT in diverse cancer, including pancreatic cancer [25], bladder cancer [26] and breast cancer [27].”
Epithelial-mesenchymal plasticity in cancer progression and metastasis (2019, background): “A) Genetic deletion of EMT-TFs Snai1 and Twist1 does not reduce metastasis in KPC model of mouse pancreatic cancer.”
Cisplatin Resistance: A Cellular Self-Defense Mechanism Resulting from Multiple Epigenetic and Genetic Changes (2012, background): “Arumugam et al. (2009) found an inverse correlation between levels of E-cadherin and Zeb-1 and resistance to cisplatin, gemcitabine, and fluorouracil, suggesting that the EMT pathway may contribute to drug resistance in pancreatic cancer CP-r cells.”