| dc.description.abstract | Epithelial-mesenchymal transition (EMT) is a developmental program hijacked by cancer cells to facilitate metastasis —a multi-step process involving the spread of cancer cells from the primary tumor site and culminating in the formation of secondary tumors at distant anatomical sites. Majority of cancer-associated deaths are due to metastasis; however, currently, there is a dearth of effective treatment once the tumors have metastasized. A better comprehension of the molecular players that govern the process of EMT will aid in the development of effective therapeutic strategies. AMP-activated protein kinase (AMPK) —an evolutionarily conserved energy-sensing kinase— is known to be activated by pathophysiological cues that induce EMT, such as hypoxia and TGFβ. Thus, the role of AMPK in the regulation of EMT was investigated. Activation of AMPK induced EMT in multiple solid tumor cell lines, as observed by enhanced expression of mesenchymal markers, decrease in epithelial markers, and an increase in migration and invasion. In contrast, inhibition or depletion of AMPK resulted in the reversal of EMT. Notably, AMPK activity was necessary for the induction of EMT by pathophysiological cues such as hypoxia and TGFβ treatment. Mechanistically, AMPK mediated EMT activation via multi-factorial regulation of the EMT-transcription factor Twist1. The present study identifies AMPK as a critical regulator of the EMT program, thus suggesting that strategies targeting AMPK might provide novel approaches to curb the spread of cancer.
Cancer is increasingly being viewed as an “ecosystem” that enables cellular interactions between cancer cells and neighboring cancer-associated cells. Furthermore, intra-tumoral heterogeneity arising from the presence of functionally distinct cancer cells is being recognized as a major player in cancer progression and therapy failure. Reversible EMT changes, serving as a source of intra-tumoral epithelial-mesenchymal (EM) heterogeneity, could generate heterogeneous cancer cells with functional differences in migration, invasion, stemness, immune evasion, and drug response. In this study, we investigated the effect of cellular interactions between epithelial and mesenchymal cancer cells within a tumor population in the outcome of chemotherapeutic drug treatment. Epithelial (E) and mesenchymal (M) subpopulations were segregated from the parental A549 cell line that exhibits inherent EM heterogeneity. Contrary to the prevalent notion in the field, mesenchymal (M) cells segregated from within the parental heterogeneous population displayed enhanced susceptibility to DNA-damaging chemotherapies, such as doxorubicin and mitoxantrone, compared to epithelial (E) cells. More importantly, E cell-derived exosomes transmitted chemoresistance to the sensitive M cells. Blockade of exosome production impairs the survival advantage conferred during the coculture of E and M cells, revealing ‘intercellular’ cooperation between epithelial and mesenchymal cancer cells in overcoming chemotherapeutic challenges. Mechanistically, exosome proteomics identified several proteins as potential candidates responsible for conferring chemoresistance. Furthermore, a novel role for AMPK in regulating exosome biogenesis was identified. AMPK inhibition reduced the number of exosomes released by the donor E cells and altered the exosomal protein cargo, suggesting that AMPK-targeted therapeutics might sabotage the cooperative survival advantage established by heterogeneous epithelial and mesenchymal cancer cells. | en_US |
