Abstract

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Effective cancer therapy relies heavily on robust drug combinations. Our previous studies establish the advantage of 3D co-culture model systems to study cancer-promoting mechanisms. Here, we describe a model combining primary breast epithelial cells, HMEC, with a highly metastatic breast epithelial cell line, MDA-MB-231. We have identified a mode of communication between these cell types through thin cytoskeletal projections called tunneling nanotubes (TNTs). TNTs may promote cancer progression through rapid and specific transfer of cytoplasmic contents to neighboring cell populations resulting in transformation of previously healthy cells. TNTs form quickly (~1.5hrs) mediating transfer of intercellular contents to 35% (p<0.0001) of the primary cell population after 24hr co-culture. The TNTs are composed of cytoskeletal components and are inhibited by low dose actin and tubulin small molecule inhibitors. Combination of 500pM Docetaxel with 30nM Latrunculin A or 50nM Cytoclasin D resulted in a 3× (p< 0.01) disruption of TNT structures, reducing TNT-mediated communication by 33.14% (p<0.001) and 61.96% (p<0.0001), respectively. In conclusion, TNTs present a novel mechanism for breast cancer progression, inhibited by actin-tubulin small molecule inhibitors. Therefore, low dose dual combination actin tubulin inhibitors are strong candidates for breast cancer therapies. Supported by DoD BCRP.