Metastasis is the major cause of cancer-related deaths; therefore, the prevention and treatment of metastasis are fundamental to improving clinical outcomes Epithelial mesenchymal transition (EMT), an evolutionarily conserved developmental program, has been implicated in carcinogenesis and confers metastatic properties upon cancer cells by enhancing mobility, invasion, and resistance to apoptotic stimuli Furthermore, EMT-derived tumor cells acquire stem cell properties and exhibit marked therapeutic resistance Given these attributes, the complex biological process of EMT has been heralded as a key hallmark of carcinogenesis, and targeting EMT pathways constitutes an attractive strategy for cancer treatment However, demonstrating the necessity of EMT for metastasis in vivo has been technically challenging, and recent efforts to demonstrate a functional contribution of EMT to metastasis have yielded unexpected results Therefore, determining the functional role of EMT in metastasis remains an area of active investigation Studies using improved lineage tracing systems, dynamic in vivo imaging, and clinically relevant in vivo models have the potential to uncover the direct link between EMT and metastasis This review focuses primarily on recent advances in and emerging concepts of the biology of EMT in metastasis in vivo and discusses future directions in the context of novel diagnostic and therapeutic opportunities

Epithelial Mesenchymal Transition in Tumor Metastasis

Experimental evidence accumulated over decades has implicated epithelial–mesenchymal plasticity (EMP), which collectively encompasses epithelial–mesenchymal transition and the reverse process of mesenchymal–epithelial transition, in tumour metastasis, cancer stem cell generation and maintenance, and therapeutic resistance. However, the dynamic nature of EMP processes, the apparent need to reverse mesenchymal changes for the development of macrometastases and the likelihood that only minor cancer cell subpopulations exhibit EMP at any one time have made such evidence difficult to accrue in the clinical setting. In this Perspectives article, we outline the existing preclinical and clinical evidence for EMP and reflect on recent controversies, including the failure of initial lineage-tracing experiments to confirm a major role for EMP in dissemination, and discuss accumulating data suggesting that epithelial features and/or a hybrid epithelial–mesenchymal phenotype are important in metastasis. We also highlight strategies to address the complexities of therapeutically targeting the EMP process that give consideration to its spatially and temporally divergent roles in metastasis, with the view that this will yield a potent and broad class of therapeutic agents. In this Perspectives article, the authors outline the preclinical and clinical evidence for epithelial–mesenchymal plasticity (EMP) in cancer progression and metastasis, focusing on recent challenges and controversies, and highlight strategies to therapeutically target the EMP process.

/pdf/controversies-around-epithelial-mesenchymal-plasticity-in-4m9iqw2qup.pdf

Controversies around epithelial–mesenchymal plasticity in cancer metastasis

Myeloid-derived suppressor cells (MDSCs) are innate immune cells that acquire the capacity to suppress adaptive immune responses during cancer. It remains elusive how MDSCs differ from their normal myeloid counterparts, which limits our ability to specifically detect and therapeutically target MDSCs during cancer. Here, we sought to determine the molecular features of breast cancer-associated MDSCs using the widely studied mouse model based on the mouse mammary tumor virus (MMTV) promoter-driven expression of the polyomavirus middle T oncoprotein (MMTV-PyMT). To identify MDSCs in an unbiased manner, we used single-cell RNA sequencing to compare MDSC-containing splenic myeloid cells from breast tumor-bearing mice with wild-type controls. Our computational analysis of 14,646 single-cell transcriptomes revealed that MDSCs emerge through an aberrant neutrophil maturation trajectory in the spleen that confers them an immunosuppressive cell state. We establish the MDSC-specific gene signature and identify CD84 as a surface marker for improved detection and enrichment of MDSCs in breast cancers.

Defining the emergence of myeloid-derived suppressor cells in breast cancer using single-cell transcriptomics

https://www.cell.com/cell-reports/pdf/S2211-1247(16)30137-1.pdf

Plasticity between Epithelial and Mesenchymal States Unlinks EMT from Metastasis-Enhancing Stem Cell Capacity

Overactive phosphoinositide 3-kinase (PI3K) in cancer and immune dysregulation has spurred extensive efforts to develop therapeutic PI3K inhibitors. Although progress has been hampered by issues such as poor drug tolerance and drug resistance, several PI3K inhibitors have now received regulatory approval — the PI3Kα isoform-selective inhibitor alpelisib for the treatment of breast cancer and inhibitors mainly aimed at the leukocyte-enriched PI3Kδ in B cell malignancies. In addition to targeting cancer cell-intrinsic PI3K activity, emerging evidence highlights the potential of PI3K inhibitors in cancer immunotherapy. This Review summarizes key discoveries that aid the clinical translation of PI3Kα and PI3Kδ inhibitors, highlighting lessons learnt and future opportunities PI3K signalling is one of the most frequently aberrantly activated pathways in cancer. However, the development of therapeutic PI3K pathway inhibitors has faced challenges including poor drug tolerance and drug resistance. Here, Vanhaesebroeck et al. review efforts to understand and therapeutically exploit the biology of PI3Kα and PI3Kδ — the key targets of currently approved PI3K inhibitors, highlighting lessons learned and future opportunities.

PI3K inhibitors are finally coming of age.

An epithelial-mesenchymal transition (EMT) underlies malignant tumor progression and metastatic spread by enabling cancer cells to depart from the primary tumor, invade surrounding tissue, and disseminate to distant organs. EMT also enriches for cancer stem cells (CSC) and increases the capacity of cancer cells to initiate and propagate tumors upon transplantation into immune-deficient mice, a major hallmark of CSCs. However, the molecular mechanisms promoting the tumorigenicity of cancer cells undergoing an EMT and of CSCs have remained widely elusive. We here report that EMT confers efficient tumorigenicity to murine breast cancer cells by the upregulated expression of the proangiogenic factor VEGF-A and by increased tumor angiogenesis. On the basis of these data, we propose a novel interpretation of the features of CSCs with EMT-induced, VEGF-A-mediated angiogenesis as the connecting mechanism between cancer cell stemness and tumor initiation.

https://cancerres.aacrjournals.org/content/canres/74/5/1566.full.pdf

VEGF-Mediated Angiogenesis Links EMT-Induced Cancer Stemness to Tumor Initiation

The PI3K pathway is hyperactivated in many cancers, including 70 % of breast cancers. Pan- and isoform-specific inhibitors of the PI3K pathway are currently being evaluated in clinical trials. However, the clinical responses to PI3K inhibitors when used as single agents are not as efficient as expected. In order to anticipate potential molecular mechanisms of resistance to the p110α isoform-selective inhibitor BYL719, we developed resistant breast cancer cell lines, assessed the concomitant changes in cellular signaling pathways using unbiased phosphotyrosine proteomics and characterized the mechanism of resistance using pharmacological inhibitors. We found an increase in IGF1R, IRS1/IRS2 and p85 phosphorylation in the resistant lines. Co-immunoprecipitation experiments identified an IGF1R/IRS/p85/p110β complex that causes the activation of AKT/mTOR/S6K and stifles the effects of BYL719. Pharmacological inhibition of members of this complex reduced mTOR/S6K activation and restored sensitivity to BYL719. Our study demonstrates that the IGF1R/p110β/AKT/mTOR axis confers resistance to BYL719 in PIK3CA mutant breast cancers. This provides a rationale for the combined targeting of p110α with IGF1R or p110β in patients with breast tumors harboring PIK3CA mutations.

/pdf/activation-of-igf1r-p110b-akt-mtor-confers-resistance-to-a-2g0f9985g0.pdf

Activation of IGF1R/p110β/AKT/mTOR confers resistance to α-specific PI3K inhibition

is a figure showing that a combination of BYL719/AEW541 triggers apoptosis in BYL719-resistant cell lines. A Anti-cleaved PARP (T47D) or anti-PARP (MCF7) immunoblots of lysates from parental and resistant cells treated for 24 hours as indicated. BYL719 (IC90), AEW541 (1 μM). B Parental and resistant cells were treated with BYL719 (2 μM for T47D and 5 μM for MCF7), AEW541 (1 μM), or the combination BYL719/AEW541 for 72 hours. Percentage of apoptotic (Annexin V-positive and PI-negative) and necrotic cells (Annexin V and PI-positive) are indicated. (PDF 158 kb)

Additional file 4: of Activation of IGF1R/p110β/AKT/mTOR confers resistance to α-specific PI3K inhibition

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VEGF-Mediated Angiogenesis Links EMT-Induced Cancer Stemness to Tumor Initiation

Activation of IGF1R/p110β/AKT/mTOR confers resistance to α-specific PI3K inhibition

Additional file 4: of Activation of IGF1R/p110β/AKT/mTOR confers resistance to α-specific PI3K inhibition