Role of Exosome Signaling in Cancer Cell Dedifferentiation and Chemo-Resistance 

JI Program: Cancer & Precision Health

Intratumor heterogeneity, which favors the selection of drug-resistant tumor cells with cancer stem cell (CSC) properties, constitutes one of the greatest challenges in cancer treatment. Two prevailing models of chemo-resistance arise in tumor cells: the enrichment of pre-existing CSCs and stress-induced dedifferentiation of differentiated bulk cancer cells (DCCs) into CSC-like phenotypes. However, to what extent and how DCC dedifferentiation occurs in response to therapeutic stress remain largely elusive. Exosomes are extracellular vesicles of 50-140 nm in size containing proteins, RNA/DNA, lipids, and metabolites, which mediate juxtracrine/paracrine signaling to promote cancer cell plasticity and metastatic progression. We hypothesize that, exosome communications between CSCs and DCCs are augmented by chemotherapy-induced stress, promoting the dedifferentiation of DCCs into chemo-resistant CSCs. Specific Aims of  this pilot grant include: 1) Using CSC epithelial (E) and mesenchymal (M) fluorescent reporters established in different breast cancer cell lines to assess the extent of dedifferentiation from DCCs when treated with or without chemotherapeutics, and determine if exosome secretion from CSCs is enhanced by chemotherapy to promote DCC dedifferentiation;  2) Using zebrafish embryo and mouse xenograft models, we will examine if CSC E/M reporter expression and tumorigenic/metastatic capacity of DCCs are induced when pre-treated with exosomes derived from various CSC states; 3) We will investigate if chemotherapy-induced exosome secretion from breast cancer patient CSCs facilitates the dedifferentiation of DCCs, and define the molecular mechanisms of exosome communications between CSCs and DCCs elicited by therapeutic stress. These studies will result in the development of innovative imaging technologies and animal models to trace tumor cell dedifferentiation at single-cell resolution and provide mechanistic insights to overcome chemo-resistance in advanced breast cancer with the potential to improve patient outcome.