Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast

By C. Scheel, E. Eaton, S. Li, Christine L. Chaffer, Ferenc Reinhardt, Kong J Kah, George W. Bell, Wenjun Guo, J. Rubin, A. Richardson and 1 more. Cell, 2011

899 citations recorded by the source corpus.

Summary The epithelial-mesenchymal transition (EMT) has been associated with the acquisition of motility, invasiveness and self-renewal traits. During both normal development and tumor pathogenesis this change in cell phenotype is induced by contextual signals that epithelial cells receive from their microenvironment. The signals that are responsible for inducing an EMT and maintaining the resulting cellular state have been unclear. We describe three signaling pathways, involving Transforming Growth Factor (TGF)-β as well as canonical and non-canonical Wnt signaling, that collaborate to induce activation of the EMT program and thereafter function in an autocrine fashion to maintain the resulting mesenchymal state. Downregulation of endogenously synthesized inhibitors of autocrine signals in epithelial cells enables the induction of the EMT program. Conversely, disruption of autocrine signaling by added inhibitors of these pathways inhibits migration and self-renewal in primary mammary epithelial cells, and inhibits tumorigenicity and metastasis by their transformed derivatives.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/c2f2bd3d8fb7260c598f3ed63c8025c8c7704637

How researchers see this paper

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In Molecular Biology

1. R. Weinberg
2. M. Nieto
3. Thomas Brabletz
4. Zena Werb
5. Simone Brabletz
6. X. Ye
7. V. Plaks
8. J. Medema

In Oncology

1. R. Weinberg
2. M. Nieto
3. Thomas Brabletz
4. Zena Werb
5. V. Plaks
6. Simone Brabletz
7. X. Ye
8. J. Medema

Citations in the corpus

• The ins and outs of the epithelial to mesenchymal transition in health and disease. (2011, background): “Later on, the maintenance of the mesenchymal phenotype is ensured by the activation of the same signals in an autocrine manner, essentially to maintain the expression of the transcription factors known as EMT inducers (Scheel et al. 2011).”
• Dynamic EMT: a multi‐tool for tumor progression (2021, positive): “…of secreted negative regulators of the pathways, like DKK 1 or SFRP 1 can promote reduction in migration and invasion, whereas inhibition of SFRP 1 , and thus elevated WNT signaling, can support an EMT phenotype and sensitize to TGF b -induced EMT (Gauger et al , 2011 ; Scheel et al , 2011 ).”
• Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA (2016, background): “In addition, HIF-1α is required for hypoxia-induced epithelial-mesenchymal transition (24), which is also linked to the BCSC phenotype (25).”
• ISMARA: automated modeling of genomic signals as a democracy of regulatory motifs (2014, methodology): “…the induction of XBP1’s activity occurs at the same time that the NFKB1/REL/RELA activity stops increasing, which is in line with studies showing that the UPR can attenuate the induction of inflammation as mediated by TFs of the NFkappaB family (Kaser et al. 2008; Kitamura 2011; Li et al. 2011).”
• Slug and Sox9 Cooperatively Determine the Mammary Stem Cell State (2012, background): “We calculated the frequency of mammary gland-reconstituting cells to be 1/250 in the SlugYFP-positive cells versus 1/6,000 in the Slug-YFP-negative cells (Figure 1D).”
• The Cancer Stem Cell Niche: How Essential is the Niche in Regulating Stemness of Tumor Cells? (2015, positive): “Activation of TGF-b as well as WNT signaling pathways by hypoxia induces stemness by promoting an undifferentiated state in tumor cells (Anido et al., 2010; Scheel et al., 2011).”
• Epithelial-Mesenchymal Plasticity: A central regulator of cancer progression (2015, background): “These metastable, partial mesenchymal states arising in a diverse array of carcinomas are likely controlled by multiple alternative variants of the core EMT program, which differ from one another in EMT-TF usage, epigenetic and metabolic programming, and the paracrine and autocrine signals that are ”
• Cancer stem cells: impact, heterogeneity, and uncertainty. (2012, background): “EMT has been proposed as a requisite step for breast cancer metastasis (Yang et al., 2004) and induction of an EMT also confers upon cultured cells a surface marker phenotype (CD44+CD24 ) similar to tumorigenic breast cancer cells (Mani et al., 2008; Scheel et al., 2011).”