Regulation of Collective Metastasis by Nanolumenal Signaling

Wrenn, Emma D.; Yamamoto, Ami; Moore, Breanna M.; Huang, Yin; McBirney, Margaux; Thomas, Aaron J.; Greenwood, Erin; Rabena, Yuri F.; Rahbar, Habib; Partridge, Savannah C.; Cheung, Kevin

doi:10.1016/j.cell.2020.08.045

Cited by 59 publications

(60 citation statements)

References 82 publications

(82 reference statements)

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“…This finding was consistent with a previous study that correlated spheroid compaction with resistance to drug treatment [ 24 ]. A recent study discovered the presence of “nanolumina” between clustered breast cancer cells [ 40 ]. These nanolumina are very small, impermeable intercellular spaces bound by cell junctions in compacted tumor cell clusters.…”

Section: Discussionmentioning

confidence: 99%

“…These nanolumina are very small, impermeable intercellular spaces bound by cell junctions in compacted tumor cell clusters. Nanolumina promote high local concentration of pro-growth signals, which contributed to increased metastasis by tumor cells organized in clusters [ 40 ]. It is possible that nanolumina compartments between cells within compact spheres promote signaling that renders the tight clusters more resistant to chemotherapy than the more loosely connected spheres.…”

Section: Discussionmentioning

confidence: 99%

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PLEKHA7, an Apical Adherens Junction Protein, Suppresses Inflammatory Breast Cancer in the Context of High E-Cadherin and p120-Catenin Expression

Pence

Kourtidis

Feathers

et al. 2021

IJMS

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Inflammatory breast cancer is a highly aggressive form of breast cancer that forms clusters of tumor emboli in dermal lymphatics and readily metastasizes. These cancers express high levels of E-cadherin, the major mediator of adherens junctions, which enhances formation of tumor emboli. Previous studies suggest that E-cadherin promotes cancer when the balance between apical and basolateral cadherin complexes is disrupted. Here, we used immunohistochemistry of inflammatory breast cancer patient samples and analysis of cell lines to determine the expression of PLEKHA7, an apical adherens junction protein. We used viral transduction to re-express PLEKHA7 in inflammatory breast cancer cells and examined their aggressiveness in 2D and 3D cultures and in vivo. We determined that PLEKHA7 was deregulated in inflammatory breast cancer, demonstrating improper localization or lost expression in most patient samples and very low expression in cell lines. Re-expressing PLEKHA7 suppressed proliferation, anchorage independent growth, spheroid viability, and tumor growth in vivo. The data indicate that PLEKHA7 is frequently deregulated and acts to suppress inflammatory breast cancer. The data also promote the need for future inquiry into the imbalance between apical and basolateral cadherin complexes as driving forces in inflammatory breast cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

PLEKHA7, an Apical Adherens Junction Protein, Suppresses Inflammatory Breast Cancer in the Context of High E-Cadherin and p120-Catenin Expression

Pence

Kourtidis

Feathers

et al. 2021

IJMS

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“…Moreover, by revealing a large-scale cooperation during differentiation, our work provides a basis for and shows that it would be possible to tune long-range communication and cooperation ( 71 ) to build a completely synthetic, macroscopic structure - one without an in vivo analogue that consists of spatially disconnected cells spanning many centimeters and coherently functioning as a single entity. Such structures, together with our systematic approach for determining spatial range of cell-cell communication, may provide new testing grounds in synthetic biology for quantitatively understanding how microscopic cells can bridge vast length-scales to perform a coherent, biological function as well as help in elucidating physical principles that underlie multicellular systems ( 21,72-78 ).…”

Section: Discussionmentioning

confidence: 99%

Centimeter-scale quorum sensing dictates collective survival of differentiating embryonic stem cells

Daneshpour

Bersselaar

Youk

2020

Preprint

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SUMMARY“Community effect” conventionally describes differentiation occurring only when enough cells help their local (micrometers-scale) neighbors differentiate. Although new community effects are being uncovered for myriad differentiations, macroscopic-scale community effects - fates of millions of cells all entangled across centimeters - remain elusive. We found that differentiating mouse Embryonic Stem (ES) cells that are scattered as individuals over many centimeters form one macroscopic entity via long-range communications. The macroscopic population avoids extinction only if its centimeter-scale density is above a threshold value. Single-cell-level measurements, transcriptomics, and mathematical modeling revealed that this “global community effect” occurs because differentiating ES-cell populations secrete, accumulate, and sense survival-promoting factors, including FGF4, that diffuse over many millimeters and activate Yap1-induced survival mechanisms. Only above-threshold-density populations accumulate above-threshold-concentrations of factors required to survive. We thus uncovered a previously overlooked, large-scale cooperation that underlies ES-cell differentiation. Tuning such large-scale cooperation may enable constructions of macroscopic, synthetic multicellular structures.

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“…MMTV-PyMT transgenic mice were also utilized to uncover collective tumor cell interactions during invasion, ultimately responsible for oligoclonal metastasis (78). Follow-up studies further implicated nanolumenal signaling between tumor cell clusters via the molecule epigen during oligoclonal metastasis (79). To more accurately depict breast cancer subtype, the TP53-null syngeneic transplant model of mammary tumorigenesis comprises a biobank of tumors that reflect heterogeneity of human breast cancers at the molecular and histological levels (80)(81)(82).…”

Section: Genetically Engineered Mouse Models and Syngeneic In Vivo Trmentioning

confidence: 99%

Laboratory Models for Investigating Breast Cancer Therapy Resistance and Metastasis

Roarty

Echeverria

2021

Front. Oncol.

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While numerous therapies are highly efficacious in early-stage breast cancers and in particular subsets of breast cancers, therapeutic resistance and metastasis unfortunately arise in many patients. In many cases, tumors that are resistant to standard of care therapies, as well as tumors that have metastasized, are treatable but incurable with existing clinical strategies. Both therapy resistance and metastasis are multi-step processes during which tumor cells must overcome diverse environmental and selective hurdles. Mechanisms by which tumor cells achieve this are numerous and include acquisition of invasive and migratory capabilities, cell-intrinsic genetic and/or epigenetic adaptations, clonal selection, immune evasion, interactions with stromal cells, entering a state of dormancy or senescence, and maintaining self-renewal capacity. To overcome therapy resistance and metastasis in breast cancer, the ability to effectively model each of these mechanisms in the laboratory is essential. Herein we review historic and the current state-of-the-art laboratory model systems and experimental approaches used to investigate breast cancer metastasis and resistance to standard of care therapeutics. While each model system has inherent limitations, they have provided invaluable insights, many of which have translated into regimens undergoing clinical evaluation. We will discuss the limitations and advantages of a variety of model systems that have been used to investigate breast cancer metastasis and therapy resistance and outline potential strategies to improve experimental modeling to further our knowledge of these processes, which will be crucial for the continued development of effective breast cancer treatments.

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Regulation of Collective Metastasis by Nanolumenal Signaling

Cited by 59 publications

References 82 publications

PLEKHA7, an Apical Adherens Junction Protein, Suppresses Inflammatory Breast Cancer in the Context of High E-Cadherin and p120-Catenin Expression

PLEKHA7, an Apical Adherens Junction Protein, Suppresses Inflammatory Breast Cancer in the Context of High E-Cadherin and p120-Catenin Expression

Centimeter-scale quorum sensing dictates collective survival of differentiating embryonic stem cells

Laboratory Models for Investigating Breast Cancer Therapy Resistance and Metastasis

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