Evolution of Cancer Stem-like Cells in Endocrine-Resistant Metastatic Breast Cancers Is Mediated by Stromal Microvesicles.

TitleEvolution of Cancer Stem-like Cells in Endocrine-Resistant Metastatic Breast Cancers Is Mediated by Stromal Microvesicles.
Publication TypeJournal Article
Year of Publication2017
AuthorsSansone P, Berishaj M, Rajasekhar VK, Ceccarelli C, Chang Q, Strillacci A, Savini C, Shapiro L, Bowman RL, Mastroleo C, De Carolis S, Daly LA, Benito-Martin A, Perna F, Fabbri N, Healey JH, Spisni E, Cricca M, Lyden DC, Bonafé M, Bromberg JF
JournalCancer Res
Date Published2017 04 15
KeywordsAnimals, Antineoplastic Agents, Hormonal, Breast Neoplasms, Cancer-Associated Fibroblasts, Case-Control Studies, Cell-Derived Microparticles, Drug Resistance, Neoplasm, Estradiol, Female, Fulvestrant, HeLa Cells, Heterografts, Humans, Interleukin-6, MCF-7 Cells, Mice, Mice, Inbred NOD, Mice, SCID, MicroRNAs, Neoplasms, Hormone-Dependent, Neoplastic Stem Cells, STAT3 Transcription Factor, Stromal Cells

The hypothesis that microvesicle-mediated miRNA transfer converts noncancer stem cells into cancer stem cells (CSC) leading to therapy resistance remains poorly investigated. Here we provide direct evidence supporting this hypothesis, by demonstrating how microvesicles derived from cancer-associated fibroblasts (CAF) transfer miR-221 to promote hormonal therapy resistance (HTR) in models of luminal breast cancer. We determined that CAF-derived microvesicles horizontally transferred miR-221 to tumor cells and, in combination with hormone therapy, activated an ER/Notch feed-forward loop responsible for the generation of CD133 CSCs. Importantly, microvesicles from patients with HTR metastatic disease expressed high levels of miR-221. We further determined that the IL6-pStat3 pathway promoted the biogenesis of onco-miR-221 CAF microvesicles and established stromal CSC niches in experimental and patient-derived breast cancer models. Coinjection of patient-derived CAFs from bone metastases led to HTR tumors, which was reversed with IL6R blockade. Finally, we generated patient-derived xenograft (PDX) models from patient-derived HTR bone metastases and analyzed tumor cells, stroma, and microvesicles. Murine and human CAFs were enriched in HTR tumors expressing high levels of CD133 cells. Depletion of murine CAFs from PDX restored sensitivity to HT, with a concurrent reduction of CD133 CSCs. Conversely, in models of CD133, HT-sensitive cancer cells, both murine and human CAFs promoted HT resistance via the generation of CD133 CSCs that expressed low levels of estrogen receptor alpha. Overall, our results illuminate how microvesicle-mediated horizontal transfer of genetic material from host stromal cells to cancer cells triggers the evolution of therapy-resistant metastases, with potentially broad implications for their control. .

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Alternate JournalCancer Res.
PubMed ID28202520
PubMed Central IDPMC5392366
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
R01 CA087637 / CA / NCI NIH HHS / United States
R01 CA169416 / CA / NCI NIH HHS / United States
U01 CA169538 / CA / NCI NIH HHS / United States

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