Carcinomas typically invade as a cohesive multicellular unit, a process termed collective invasion. It remains unclear how different subpopulations of cancer cells contribute to this process. We ...developed three-dimensional (3D) organoid assays to identify the most invasive cancer cells in primary breast tumors. Collective invasion was led by specialized cancer cells that were defined by their expression of basal epithelial genes, such as cytokeratin-14 (K14) and p63. Furthermore, K14+ cells led collective invasion in the major human breast cancer subtypes. Importantly, luminal cancer cells were observed to convert phenotypically to invasive leaders following induction of basal epithelial genes. Although only a minority of cells within luminal tumors expressed basal epithelial genes, knockdown of either K14 or p63 was sufficient to block collective invasion. Our data reveal that heterotypic interactions between epithelial subpopulations are critical to collective invasion. We suggest that targeting the basal invasive program could limit metastatic progression.
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•Molecularly distinct tumor cells lead collective invasion in breast cancer•Keratin-14+ cells lead collective invasion across major subtypes of breast cancer•Invasive leader cells are generated by induction of a basal epithelial program•Basal epithelial gene expression is required for collective invasion
Collective invasion in breast cancer is led by specialized cancer cells defined by their expression of basal epithelial genes. Targeting the basal epithelial program is sufficient to disrupt the invasive process.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Despite decades of study, there are still many unanswered questions about metastasis, the process by which a localized cancer becomes a systemic disease. One of these questions is the nature of the ...tumor cells that give rise to metastases. Although conventional models suggest that metastases are seeded by single cells from the primary tumor, there is growing evidence that seeding requires the collective action of tumor cells traveling together in clusters. Here, we review this evidence, which comes from analysis of both experimental models and patient samples. We present a model of metastatic dissemination that highlights the activities of clusters of tumor cells that retain and require their epithelial properties.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
Recent genomic studies challenge the conventional model that each metastasis must arise from a single tumor cell and instead reveal that metastases can be composed of multiple genetically distinct ...clones. These intriguing observations raise the question: How do polyclonal metastases emerge from the primary tumor? In this study, we used multicolor lineage tracing to demonstrate that polyclonal seeding by cell clusters is a frequent mechanism in a common mouse model of breast cancer, accounting for >90% of metastases. We directly observed multicolored tumor cell clusters across major stages of metastasis, including collective invasion, local dissemination, intravascular emboli, circulating tumor cell clusters, and micrometastases. Experimentally aggregating tumor cells into clusters induced a >15-fold increase in colony formation ex vivo and a >100-fold increase in metastasis formation in vivo. Intriguingly, locally disseminated clusters, circulating tumor cell clusters, and lung micrometastases frequently expressed the epithelial cytoskeletal protein, keratin 14 (K14). RNA-seq analysis revealed that K14⁺ cells were enriched for desmosome and hemidesmosome adhesion complex genes, and were depleted for MHC class II genes. Depletion of K14 expression abrogated distant metastases and disrupted expression of multiple metastasis effectors, including Tenascin C (Tnc), Jagged1 (Jag1), and Epiregulin (Ereg). Taken together, our findings reveal K14 as a key regulator of metastasis and establish the concept that K14⁺ epithelial tumor cell clusters disseminate collectively to colonize distant organs.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Highlights • Cancer invasion is accomplished through interactions among distinct cell types. • Both epithelial–epithelial and epithelial–stromal interactions regulate invasion. • Metastasis can occur ...without a molecular epithelial to mesenchymal transition. • Multiple different mechanisms have been identified to promote invasion.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Breast cancer progression involves genetic changes and changes in the extracellular matrix (ECM). To test the importance of the ECM in tumor cell dissemination, we cultured epithelium from primary ...human breast carcinomas in different ECM gels. We used basement membrane gels to model the normal microenvironment and collagen I to model the stromal ECM. In basement membrane gels, malignant epithelium either was indolent or grew collectively, without protrusions. In collagen I, epithelium from the same tumor invaded with protrusions and disseminated cells. Importantly, collagen I induced a similar initial response of protrusions and dissemination in both normal and malignant mammary epithelium. However, dissemination of normal cells into collagen I was transient and ceased as laminin 111 localized to the basal surface, whereas dissemination of carcinoma cells was sustained throughout culture, and laminin 111 was not detected. Despite the large impact of ECM on migration strategy, transcriptome analysis of our 3D cultures revealed few ECM-dependent changes in RNA expression. However, we observed many differences between normal and malignant epithelium, including reduced expression of cell-adhesion genes in tumors. Therefore, we tested whether deletion of an adhesion gene could induce sustained dissemination of nontransformed cells into collagen I. We found that deletion of P-cadherin was sufficient for sustained dissemination, but exclusively into collagen I. Our data reveal that metastatic tumors preferentially disseminate in specific ECM microenvironments. Furthermore, these data suggest that breaks in the basement membrane could induce invasion and dissemination via the resulting direct contact between cancer cells and collagen I.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania
The inositol 1,4,5-trisphosphate (InsP 3 ) receptors (InsP 3 Rs) are a family of Ca 2+ release channels localized ...predominately in the endoplasmic reticulum of all cell types. They function to release Ca 2+ into the cytoplasm in response to InsP 3 produced by diverse stimuli, generating complex local and global Ca 2+ signals that regulate numerous cell physiological processes ranging from gene transcription to secretion to learning and memory. The InsP 3 R is a calcium-selective cation channel whose gating is regulated not only by InsP 3 , but by other ligands as well, in particular cytoplasmic Ca 2+ . Over the last decade, detailed quantitative studies of InsP 3 R channel function and its regulation by ligands and interacting proteins have provided new insights into a remarkable richness of channel regulation and of the structural aspects that underlie signal transduction and permeation. Here, we focus on these developments and review and synthesize the literature regarding the structure and single-channel properties of the InsP 3 R.
Collective metastasis is defined as the cohesive migration and metastasis of multicellular tumor cell clusters. Disrupting various cell adhesion genes markedly reduces cluster formation and ...colonization efficiency, yet the downstream signals transmitted by clustering remain largely unknown. Here, we use mouse and human breast cancer models to identify a collective signal generated by tumor cell clusters supporting metastatic colonization. We show that tumor cell clusters produce the growth factor epigen and concentrate it within nanolumina—intercellular compartments sealed by cell-cell junctions and lined with microvilli-like protrusions. Epigen knockdown profoundly reduces metastatic outgrowth and switches clusters from a proliferative to a collective migratory state. Tumor cell clusters from basal-like 2, but not mesenchymal-like, triple-negative breast cancer cell lines have increased epigen expression, sealed nanolumina, and impaired outgrowth upon nanolumenal junction disruption. We propose that nanolumenal signaling could offer a therapeutic target for aggressive metastatic breast cancers.
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•Breast tumor cell clusters contain nanolumina—sealed, intercellular cavities•Clusters produce the growth factor epigen and concentrate it in nanolumina•Epigen is regulated during metastasis, and its suppression reduces outgrowth•Basal-like 2 breast cancer clusters highly express epigen and form nanolumina
Nanolumina encased within clusters of tumor cells harbor signaling molecules that promote metastasis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mitochondrial permeability transition is a phenomenon in which the mitochondrial permeability transition pore (PTP) abruptly opens, resulting in mitochondrial membrane potential (ΔΨm) dissipation, ...loss of ATP production, and cell death. Several genetic candidates have been proposed to form the PTP complex, however, the core component is unknown. We identified a necessary and conserved role for spastic paraplegia 7 (SPG7) in Ca2+- and ROS-induced PTP opening using RNAi-based screening. Loss of SPG7 resulted in higher mitochondrial Ca2+ retention, similar to cyclophilin D (CypD, PPIF) knockdown with sustained ΔΨm during both Ca2+ and ROS stress. Biochemical analyses revealed that the PTP is a heterooligomeric complex composed of VDAC, SPG7, and CypD. Silencing or disruption of SPG7-CypD binding prevented Ca2+- and ROS-induced ΔΨm depolarization and cell death. This study identifies an ubiquitously expressed IMM integral protein, SPG7, as a core component of the PTP at the OMM and IMM contact site.
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•Mitochondrial SPG7 is essential for the PTP complex formation in multiple cell types•SPG7 interacts with CypD and VDAC at the IMM and OMM contact site•C terminus of SPG7 and CsA-binding region of CypD are necessary for PTP formation•Loss of SPG7 protects mitochondria from Ca2+- and ROS-induced PTP-dependent necrosis
Using an RNAi-based screen, Shanmughapriya et al. identify mitochondrial spastic paraplegia 7 as essential for the PTP complex formation. They show that SPG7 interacts with CypD and VDAC1 at the IMM and OMM contact site, and loss of SPG7 protects mitochondria from Ca2+- and ROS-induced PTP-dependent necrosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Tropical cyclones and climate change Walsh, Kevin J.E.; McBride, John L.; Klotzbach, Philip J. ...
Wiley interdisciplinary reviews. Climate change,
January/February 2016, Volume:
7, Issue:
1
Journal Article
Peer reviewed
Open access
Recent research has strengthened the understanding of the links between climate and tropical cyclones (TCs) on various timescales. Geological records of past climates have shown century‐long ...variations in TC numbers. While no significant trends have been identified in the Atlantic since the late 19th century, significant observed trends in TC numbers and intensities have occurred in this basin over the past few decades, and trends in other basins are increasingly being identified. However, understanding of the causes of these trends is incomplete, and confidence in these trends continues to be hampered by a lack of consistent observations in some basins. A theoretical basis for maximum TC intensity appears now to be well established, but a climate theory of TC formation remains elusive. Climate models mostly continue to predict future decreases in global TC numbers, projected increases in the intensities of the strongest storms and increased rainfall rates. Sea level rise will likely contribute toward increased storm surge risk. Against the background of global climate change and sea level rise, it is important to carry out quantitative assessments on the potential risk of TC‐induced storm surge and flooding to densely populated cities and river deltas. Several climate models are now able to generate a good distribution of both TC numbers and intensities in the current climate. Inconsistent TC projection results emerge from modeling studies due to different downscaling methodologies and warming scenarios, inconsistencies in projected changes of large‐scale conditions, and differences in model physics and tracking algorithms. WIREs Clim Change 2016, 7:65–89. doi: 10.1002/wcc.371
This article is categorized under:
Paleoclimates and Current Trends > Earth System Behavior
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Metastatic dissemination has lethal consequences for cancer patients. Accruing evidence supports the hypothesis that tumor cells can migrate and metastasize as clusters of cells while maintaining ...contacts with one another. Collective metastasis enables tumor cells to colonize secondary sites more efficiently, resist cell death, and evade the immune system. On the other hand, tumor cell clusters face unique challenges for dissemination particularly during systemic dissemination. Here, we review recent progress toward understanding how tumor cell clusters overcome these disadvantages as well as mechanisms they utilize to gain advantages throughout the metastatic process. We consider useful models for studying collective metastasis and reflect on how the study of collective metastasis suggests new opportunities for eradicating and preventing metastatic disease.
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