Inflammatory Breast Cancer: a model for investigating cluster-based dissemination

Jolly, Mohit Kumar; Boareto, Marcelo; Debeb, Bisrat G.; Aceto, Nicola; Farach‐Carson, Mary C.; Woodward, Wendy A.; Levine, Herbert

doi:10.1101/119479

Cited by 12 publications

(17 citation statements)

References 92 publications

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“…Tumor buds weakly expressing membrane E‐cad expression are also positive for partial EMT markers, as exemplified by ZEB1 at the invasive front of human pancreatic tumors . Furthermore, E‐cad‐expressing tumor emboli and CTC clusters with mesenchymal traits have been detected in circulating peripheral blood from various cancer patients . The partial EMT program also reportedly plays roles in regulating collective invasion and the dissemination of various carcinoma cell clusters .…”

Section: Discussionmentioning

confidence: 99%

Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state

Mizukoshi

Okazawa

Haeno

et al. 2019

Intl Journal of Cancer

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Emerging evidence supports the theory that tumor cell clusters efficiently metastasize to distant organs. However, the roles of epithelial‐to‐mesenchymal transition (EMT) in metastasizing tumor cell clusters have not yet been fully elucidated. To investigate this issue, tumor fragments were dissected from 40 colorectal cancer (CRC) patients and implanted subcutaneously into immunodeficient mice. We observed that tumors developed from the tumor fragments obtained from 28 of the 40 CRC patients. The tumors were then dissociated into cell suspensions to be orthotopically injected into secondary mice. The tumors from 13 of the 28 patients progressed. Furthermore, metastases formed spontaneously in the liver and lungs from the tumor fragments obtained from 8 of these 13 patients. Moreover, employing a mathematical analysis, we showed that tumor cell clusters seeded these metastases significantly more often than did single tumor cells. Membrane E‐cadherin‐ and nuclear ZEB1‐positive tumor cells indicating the hybrid epithelial/mesenchymal state were also detected in primary tumors of various CRC patients, and in the corresponding patient‐derived xenografts (PDXs) and circulating tumor cell clusters in the bloodstreams of mice. In contrast, ZEB1 staining was barely detectable in the patient‐matched liver metastases presumably developing through mesenchymal‐to‐epithelial transition. Inhibition of E‐cadherin or ZEB1 expression by shRNA notably prevented the PDX‐derived tumor organoids from colonizing the liver, when injected intrasplenically into mice, indicating E‐cadherin and ZEB1 expressions to be required for their metastatic colonization. Taken together, these findings suggest that the epithelial/mesenchymal state mediates metastatic seeding of human CRC cell clusters into distant organs.

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Section: Discussionmentioning

confidence: 99%

Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state

Mizukoshi

Okazawa

Haeno

et al. 2019

Intl Journal of Cancer

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“…These clusters of circulating tumor cells (CTCs) retain their epithelial traits, at least partially, and act as primary harbingers of metastasis (Cheung and Ewald, ; Grigore et al ., ; Jolly et al ., ). Differential gene expression signatures of leader vs. follower cells in collective migration and invasion during metastasis has highlighted JAG1 as a key player (Cheung et al ., ; Jolly et al ., ), thereby reminiscent of the involvement of Notch signaling in regulating leader vs. follower phenotypes in multiple contexts of collective cell migration (Blanco and Gerhardt, ; Boareto et al ., ; Riahi et al ., ).…”

Section: How Can Mathematical Models Connect Signaling Aspects To Celmentioning

confidence: 99%

Epithelial/mesenchymal plasticity: how have quantitative mathematical models helped improve our understanding?

et al. 2017

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Phenotypic plasticity, the ability of cells to reversibly alter their phenotypes in response to signals, presents a significant clinical challenge to treating solid tumors. Tumor cells utilize phenotypic plasticity to evade therapies, metastasize, and colonize distant organs. As a result, phenotypic plasticity can accelerate tumor progression. A well‐studied example of phenotypic plasticity is the bidirectional conversions among epithelial, mesenchymal, and hybrid epithelial/mesenchymal (E/M) phenotype(s). These conversions can alter a repertoire of cellular traits associated with multiple hallmarks of cancer, such as metabolism, immune evasion, invasion, and metastasis. To tackle the complexity and heterogeneity of these transitions, mathematical models have been developed that seek to capture the experimentally verified molecular mechanisms and act as ‘hypothesis‐generating machines’. Here, we discuss how these quantitative mathematical models have helped us explain existing experimental data, guided further experiments, and provided an improved conceptual framework for understanding how multiple intracellular and extracellular signals can drive E/M plasticity at both the single‐cell and population levels. We also discuss the implications of this plasticity in driving multiple aggressive facets of tumor progression.

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“…Even though NFATc extended the range of SNAIL values enabling a hybrid E/M state, the hybrid E/M state always co-existed with epithelial and/or mesenchymal states ({E, H, M} and {H, M} phases in Fig 1B); no monostable regime ({H}) for a hybrid E/M state was seen in the case of NFATc, as observed with GRHL2, OVOL1/2, ΔNP63α, NUMB and NRF2 (17)(18)(19)(20)(21)34). Similarly, compared to the other PSFs, the presence of NFATc does not increase the absolute value of MRT for a hybrid E/M phenotype as compared to the case without NFATc .…”

Section: Nfatc Does Not Increase the Mean Residence Time Of The Hybrimentioning

confidence: 86%

NFATc acts as a non-canonical phenotypic stability factor for a hybrid epithelial/mesenchymal phenotype

Subbalakshmi

Kundnani²,

Biswas

et al. 2020

Preprint

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Metastasis remains the cause of over 90% of cancer-related deaths. Cells undergoing metastasis use phenotypic plasticity to adapt to their changing environmental conditions and avoid therapy and immune response. Reversible transitions between epithelial and mesenchymal phenotypes -Epithelial-Mesenchymal Transition (EMT) and its reverse Mesenchymal-Epithelial Transition (MET) -form a key axis of phenotypic plasticity during metastasis and therapy resistance. Recent studies have shown that the cells undergoing EMT/MET can attain one or more hybrid epithelial/mesenchymal (E/M) phenotypes, the process of which is termed as partial EMT/MET. Cells in hybrid E/M phenotype(s) can be more aggressive than those in either epithelial or mesenchymal state. Thus, it is crucial to identify the factors and regulatory networks enabling such hybrid E/M phenotypes. Here, employing an integrated computational-experimental approach, we show that the transcription factor NFATc can inhibit the process of complete EMT, thus stabilizing the hybrid E/M phenotype. It increases the range of parameters enabling the existence of a hybrid E/M phenotype, thus behaving as a phenotypic stability factor (PSF). However, unlike previously identified PSFs, it does not increase the mean residence time of the cells in hybrid E/M phenotypes, as shown by stochastic simulations; rather it enables the coexistence of epithelial, mesenchymal and hybrid E/M phenotypes and transitions among them. Clinical data suggests the effect of NFATc on patient survival in a tissue-specific or contextdependent manner. Together, our results indicate that NFATc behaves as a non-canonical phenotypic stability factor for a hybrid E/M phenotype.

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Inflammatory Breast Cancer: a model for investigating cluster-based dissemination

Cited by 12 publications

References 92 publications

Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state

Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state

Epithelial/mesenchymal plasticity: how have quantitative mathematical models helped improve our understanding?

NFATc acts as a non-canonical phenotypic stability factor for a hybrid epithelial/mesenchymal phenotype

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