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Autophagy Differentially Regulates Distinct Breast Cancer Stem-like Cells in Murine Models via EGFR/Stat3 and Tgf?/Smad Signaling.

ABSTRACT: Cancer stem-like cells contribute to tumor heterogeneity and have been implicated in disease relapse and drug resistance. Here we show the coexistence of distinct breast cancer stem-like cells (BCSC) as identified by ALDH(+) and CD29(hi)CD61(+) markers, respectively, in murine models of breast cancer. While both BCSC exhibit enhanced tumor-initiating potential, CD29(hi)CD61(+) BCSC displayed increased invasive abilities and higher expression of epithelial-to-mesenchymal transition and mammary stem cell-associated genes, whereas ALDH(+) BCSC were more closely associated with luminal progenitors. Attenuating the autophagy regulator FIP200 diminished the tumor-initiating properties of both ALDH(+) and CD29(hi)CD61(+) BCSC, as achieved by impairing either the Stat3 or TGF?/Smad pathways, respectively. Furthermore, combining the Stat3 inhibitor Stattic and the Tgf?-R1 inhibitor LY-2157299 inhibited the formation of both epithelial and mesenchymal BCSC colonies. In vivo, this combination treatment was sufficient to limit tumor growth and reduce BCSC number. Overall, our findings reveal a differential dependence of heterogeneous BCSC populations on divergent signaling pathways, with implications on how to tailor drug combinations to improve therapeutic efficacy. Cancer Res; 76(11); 3397-410. ©2016 AACR.

SUBMITTER: Yeo SK

PROVIDER: S-EPMC4990205 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Autophagy Differentially Regulates Distinct Breast Cancer Stem-like Cells in Murine Models via EGFR/Stat3 and Tgfβ/Smad Signaling.

Yeo Syn Kok SK Wen Jian J Chen Song S Guan Jun-Lin JL

Cancer research 20160413 11

Cancer stem-like cells contribute to tumor heterogeneity and have been implicated in disease relapse and drug resistance. Here we show the coexistence of distinct breast cancer stem-like cells (BCSC) as identified by ALDH(+) and CD29(hi)CD61(+) markers, respectively, in murine models of breast cancer. While both BCSC exhibit enhanced tumor-initiating potential, CD29(hi)CD61(+) BCSC displayed increased invasive abilities and higher expression of epithelial-to-mesenchymal transition and mammary st ...[more]

PMID: 27197172

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Project description:BackgroundGlioblastoma multiforme (GBM) is characterized by lethal aggressiveness and patients with GBM are in urgent need for new therapeutic avenues to improve quality of life. Current studies on tumor invasion focused on roles of cytokines in tumor microenvironment and numerous evidence suggests that TGF-β2 is abundant in glioma microenvironment and vital for glioma invasion. Autopagy is also emerging as a critical factor in aggressive behaviors of cancer cells; however, the relationship between TGF-β2 and autophagy in glioma has been poorly understood.MethodsU251, T98 and U87 GBM cell lines as well as GBM cells from a primary human specimen were used in vitro and in vivo to evaluate the effect of TGF-β2 on autophagy. Western blot, qPCR, immunofluorescence and transmission-electron microscope were used to detect target molecular expression. Lentivirus and siRNA vehicle were introduced to establish cell lines, as well as mitotracker and seahorse experiment to study the metabolic process in glioma. Preclinical therapeutic efficacy was evaluated in orthotopic xenograft mouse models.ResultsHere we demonstrated that TGF-β2 activated autophagy in human glioma cell lines and knockdown of Smad2 or inhibition of c-Jun NH2-terminal kinase, attenuated TGF-β2-induced autophagy. TGF-β2-induced autophagy is important for glioma invasion due to the alteration of epithelial-mesenchymal transition and metabolism conversion, particularly influencing mitochondria trafficking and membrane potential (△Ψm). Autopaghy also initiated a feedback on TGF-β2 in glioma by keeping its autocrine loop and affecting Smad2/3/7 expression. A xenograft model provided additional confirmation on combination of TGF-β inhibitor (Galunisertib) and autophagy inhibitor (CQ) to better "turn off" tumor growth.ConclusionOur findings elucidated a potential mechanism of autophagy-associated glioma invasion that TGF-β2 could initiate autophagy via Smad and non-Smad pathway to promote glioma cells' invasion.

Dataset Information

Autophagy Differentially Regulates Distinct Breast Cancer Stem-like Cells in Murine Models via EGFR/Stat3 and Tgf?/Smad Signaling.

Publications

Autophagy Differentially Regulates Distinct Breast Cancer Stem-like Cells in Murine Models via EGFR/Stat3 and Tgfβ/Smad Signaling.

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