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Molecular analysis of circulating tumor cells (CTCs) at single-cell resolution offers great promise for cancer diagnostics and therapeutics from simple liquid biopsy. Recent development of massively parallel single-cell RNA-sequencing (scRNA-seq) provides a powerful method to resolve the cellular heterogeneity from gene expression and pathway regulation analysis. However, the scarcity of CTCs and the massive contamination of blood cells limit the utility of currently available technologies. Here, we present Hydro-Seq, a scalable hydrodynamic scRNA-seq barcoding technique, for high-throughput CTC analysis. High cell-capture efficiency and contamination removal capability of Hydro-Seq enables successful scRNA-seq of 666 CTCs from 21 breast cancer patient samples at high throughput. We identify breast cancer drug targets for hormone and targeted therapies and tracked individual cells that express markers of cancer stem cells (CSCs) as well as of epithelial/mesenchymal cell state transitions. Transcriptome analysis of these cells provides insights into monitoring target therapeutics and processes underlying tumor metastasis. Transcriptome analysis of circulating tumor cells (CTCs) provides insights into monitoring target therapeutics and underlying tumor metastasis. Here the authors present Hydro-Seq, a contamination-free high-throughput hydrodynamic scRNA-seq barcoding technique for rare CTCs.

Many tumors, including breast cancer, are maintained by a subpopulation of cells that display stem cell properties, mediate metastasis, and contribute to treatment resistance. These cancer stem cells (CSCs) are regulated by complex interactions with the components of the tumor microenvironment - including mesenchymal stem cells, adipocytes, tumor associated fibroblasts, endothelial cells, and immune cells - through networks of cytokines and growth factors. Since these components have a direct influence on CSC properties, they represent attractive targets for therapeutic development.

Cancer has long been viewed as a disease of normal development gone awry. Cancer stem-like cells (CSCs), also termed as tumor-initiating cells (TICs), are increasingly recognized as a critical tumor cell population that drives not only tumorigenesis but also cancer progression, treatment resistance and metastatic relapse. The let-7 family of microRNAs (miRNAs), first identified in C. elegans but functionally conserved from worms to human, constitutes an important class of regulators for diverse cellular functions ranging from cell proliferation, differentiation and pluripotency to cancer development and progression. Here, we review the current state of knowledge regarding the roles of let-7 miRNAs in regulating cancer stemness. We outline several key RNA-binding proteins, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) involved in the regulation of let-7 biogenesis, maturation and function. We then highlight key gene targets and signaling pathways that are regulated or mutually regulated by the let-7 family of miRNAs to modulate CSC characteristics in various types of cancer. We also summarize the existing evidence indicating distinct metabolic pathways regulated by the let-7 miRNAs to impact CSC self-renewal, differentiation and treatment resistance. Lastly, we review current preclinical studies and discuss the clinical implications for developing let-7-based replacement strategies as potential cancer therapeutics that can be delivered through different platforms to target CSCs and reduce/overcome treatment resistance when applied alone or in combination with current chemo/radiation or molecularly targeted therapies. By specifically targeting CSCs, these strategies have the potential to significantly improve the efficacy of cancer therapies.

Antiangiogenic therapy has been thought to hold significant potential for the treatment of cancer. However, the efficacy of such treatments, especially in breast cancer patients, has been called into question, as recent clinical trials reveal only limited effectiveness of antiangiogenic agents in prolonging patient survival. New research using preclinical models further suggests that antiangiogenic agents actually increase invasive and metastatic properties of breast cancer cells. We demonstrate that by generating intratumoral hypoxia in human breast cancer xenografts, the antiangiogenic agents sunitinib and bevacizumab increase the population of cancer stem cells. In vitro studies revealed that hypoxia-driven stem/progenitor cell enrichment is primarily mediated by hypoxia-inducible factor 1α. We further show that the Akt/β-catenin cancer stem cell regulatory pathway is activated in breast cancer cells under hypoxic conditions in vitro and in sunitinib-treated mouse xenografts. These studies demonstrate that hypoxia-driven cancer stem cell stimulation limits the effectiveness of antiangiogenic agents, and suggest that to improve patient outcome, these agents might have to be combined with cancer stem cell-targeting drugs.

Key Points Chemokines regulate the infiltration of different immune cell subsets into tumours and, as such, these molecules affect tumour immunity and influence therapeutic outcomes in patients. Chemokines also target tumour cells and stromal cells, and they regulate tumour angiogenesis, stemness, proliferation and survival. Chemokine expression is regulated intrinsically by epigenetic and genetic pathways, and also extrinsically by hypoxia, metabolic cues and the microbiota. Targeting chemokine networks may alter tumour biological and immunological phenotypes, and increase antitumour immune responses. Therapies that target chemokines could synergize with existing cancer therapies, including current immunotherapies. This Review details how chemokines shape immune responses in the tumour microenvironment through their effects on immune cells, stromal cells and the tumour cells themselves. The authors discuss the potential of targeting chemokine networks for cancer therapy. The tumour microenvironment is the primary location in which tumour cells and the host immune system interact. Different immune cell subsets are recruited into the tumour microenvironment via interactions between chemokines and chemokine receptors, and these populations have distinct effects on tumour progression and therapeutic outcomes. In this Review, we focus on the main chemokines that are found in the human tumour microenvironment; we elaborate on their patterns of expression, their regulation and their roles in immune cell recruitment and in cancer and stromal cell biology, and we consider how they affect cancer immunity and tumorigenesis. We also discuss the potential of targeting chemokine networks, in combination with other immunotherapies, for the treatment of cancer.

Although clinically apparent metastasis is associated with late stages of cancer development, micro-metastatic dissemination may be an early event. However, the fate of these early disseminated tumor cells (DTC) remains elusive. We show that despite their capacity to disseminate into secondary organs, 4T1 tumor models develop overt metastasis while EMT6-tumor bearing mice clear DTCs shed from primary tumors as well as those introduced by intravenous (IV) injection. Following the surgical resection of primary EMT6 tumors, mice do not develop detectable metastasis and reject IV-injected tumor cells. In contrast, these cells readily grow and metastasize in immuno-deficient athymic or Rag2 −/− mice, an effect mimicked by CD8 + T-cell depletion in immunocompetent mice. Furthermore, recombinant G-CSF or adoptive transfer of granulocytic-MDSCs isolated from 4T1 tumor-bearing mice, induce metastasis by suppressing CD8 + T-cells in EMT6-primed mice. Our studies support the concept of immune surveillance providing molecular insights into the immune mechanisms during tumor progression. Dissemination of tumor cells from the primary site is an early event. Here, the authors show that the early disseminated tumor cells are actively cleared by the host cytotoxic T lymphocytes induced by the primary tumor and that infiltration of granulocytic myeloid-derived suppressor cells counteracts such immune protection and allow metastasis development.

Breast cancer stem cells (BCSCs) are thought to be responsible for tumor initiation, metastasis and relapse. Our group and others have described markers useful in isolating BCSCs just as aldehyde dehydrogenase positive (ALDH + ) or CD24 − CD44 + . In fact, cells which simultaneously express both sets of markers have the highest tumor initiating capacity. Although the transcriptomic profile of cells expressing each BCSC marker alone has been reported, the profile of the most tumorigenic population expressing both sets of markers has not. Here we used the biomarker combination of ALDH and CD24/CD44 to sort four populations isolated from triple-negative breast cancer (TNBC) patient-derived xenografts, and performed whole-transcriptome sequencing on each population. We systematically compared the profiles of the three states of BCSCs (ALDH + CD24 − CD44 + , ALDH + non-CD24 − CD44 + and ALDH − CD24 − CD44 + ) to that of the differentiated tumor cells (ALDH − non-CD24 − CD44 + ). For the first time, we compared the ALDH + CD24 − CD44 + BCSCs with the other two BCSC populations. In ALDH + CD24 − CD44 + BCSCs, we identified P4HA2 , PTGR1 and RAB40B as potential prognostic markers, which were virtually related to the status of BCSCs and tumor growth in TNBC cells.

Cancer stem cells (CSCs) possess capacity to both self-renew and generate all cells within a tumor, and are thought to drive tumor recurrence. Targeting the stem cell niche to eradicate CSCs represents an important area of therapeutic development. The complex nature of many interacting elements of the stem cell niche, including both intracellular signals and microenvironmental growth factors and cytokines, creates a challenge in choosing which elements to target, alone or in combination. Stochastic stimulation techniques allow for the careful study of complex systems in biology and medicine and are ideal for the investigation of strategies aimed at CSC eradication. We present a mathematical model of the breast cancer stem cell (BCSC) niche to predict population dynamics during carcinogenesis and in response to treatment. Using data from cell line and mouse xenograft experiments, we estimate rates of interconversion between mesenchymal and epithelial states in BCSCs and find that EMT/MET transitions occur frequently. We examine bulk tumor growth dynamics in response to alterations in the rate of symmetric self-renewal of BCSCs and find that small changes in BCSC behavior can give rise to the Gompertzian growth pattern observed in breast tumors. Finally, we examine stochastic reaction kinetic simulations in which elements of the breast cancer stem cell niche are inhibited individually and in combination. We find that slowing self-renewal and disrupting the positive feedback loop between IL-6, Stat3 activation, and NF-κB signaling by simultaneous inhibition of IL-6 and HER2 is the most effective combination to eliminate both mesenchymal and epithelial populations of BCSCs. Predictions from our model and simulations show excellent agreement with experimental data showing the efficacy of combined HER2 and Il-6 blockade in reducing BCSC populations. Our findings will be directly examined in a planned clinical trial of combined HER2 and IL-6 targeted therapy in HER2-positive breast cancer.

Cancer stem cells (CSCs) are a small group of tumor cells with the capacity to undergo self‐renewal and differentiation. These cells not only initiate and maintain tumor growth, but also confer resistance to current cancer therapies. CSCs display a high degree of plasticity and can be generated under therapeutic stress via dedifferentiation from non‐stem‐like tumor cells, suggesting the necessity simultaneously targeting CSCs and bulk tumor cells to achieve the best therapeutic effect. Despite the findings that therapeutic stress induces CSC plasticity, the mechanisms underpinning CSC formation and therapeutic resistance are not fully defined. Tumor cells display elevated levels of reactive oxygen species (ROS), contributed by rapid proliferation, enhanced metabolic demands and oncogenic signaling. CSCs achieve redox homeostasis partly by regulating redox‐sensitive transcription factors (TFs), including NRF2, HIF‐1α, BACH1, NF‐kB, FOXOs, AP‐1, and others. This review aims to summarize the roles and underlying mechanisms of these TFs in regulation of CSCs and tumor progression from the perspectives of stem cell maintenance, metabolic reprogramming, epithelial–mesenchymal transition (EMT) and angiogenesis. We also discuss the potentials of utilizing specific inhibitors for these TFs in suppressing drug resistance and metastasis by repressing CSC activity, an approach that may provide new targeted therapies for advanced cancer and improve patient outcome. Cancer stem cells (CSCs) in the tumor microenvironment achieve redox homeostasis by regulating redox‐sensitive transcription factors (TFs), especially NRF2, BACH1, and HIF‐1α. These TFs play crucial roles in stem cell maintenance, metabolic reprogramming, epithelial–mesenchymal transition (EMT), and angiogenesis. Targeting these TFs may offer novel therapeutic approaches to improve patient outcomes.

The contemporary use of nanomedicines for cancer treatment has been largely limited to serving as carriers for existing therapeutic agents. Here, we provide definitive evidence that, the metallofullerenol nanomaterial Gd@C 82 (OH) 22 , while essentially not toxic to normal mammary epithelial cells, possesses intrinsic inhibitory activity against triple-negative breast cancer cells. Gd@C 82 (OH) 22 blocks epithelial-to-mesenchymal transition with resultant efficient elimination of breast cancer stem cells (CSCs) resulting in abrogation of tumour initiation and metastasis. In normoxic conditions, Gd@C 82 (OH) 22 mediates these effects by blocking TGF-β signalling. Moreover, under hypoxic conditions found in the tumour microenvironment, cellular uptake of Gd@C 82 (OH) 22 is facilitated where it functions as a bi-potent inhibitor of HIF-1α and TGF-β activities, enhancing CSC elimination. These studies indicate that nanomaterials can be engineered to directly target CSCs. Thus, Gd-metallofullerenol is identified as a kind of non-toxic CSC specific inhibitors with significant therapeutic potential. A metallofullerenol nanomaterial, Gd@C 82 (OH) 22 , was shown to inhibit growth of several solid cancers in preclinical models and yet exhibit low toxicity. Herein the authors show that Gd@C 82 (OH) 22 functions as an inhibitor of breast cancer stem cell function via blocking TGF-β and HIF-1α signalling, while sparing normal tissue.