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MetSearch: A screening platform for the discovery of genes implicated in metastatic dormancy and reactivation

ABSTRACT: We have developed a screening platform for the isolation of genetic entities involved in metastatic reactivation. Retroviral libraries encoding cDNAs from highly metastatic breast cancer cells or pooled microRNAs were transduced into breast cancer cells that become dormant upon infiltrating the lung. Upon inoculation in the tail vein of mice, the cells that had acquired the ability to undergo reactivation generated metastatic lesions. Integrated retroviral vectors were recovered from these lesions, sequenced, and subjected to a second round of validation. By using this strategy, we identified canonical genes and microRNAs that mediate metastatic reactivation in the lung. To identify genes that oppose reactivation, we screened an expression library encoding shRNAs and we identified target genes that encode potential enforcers of dormancy. Our screening strategy enables the identification and rapid biological validation of single genetic entities that are necessary to maintain dormancy or to induce reactivation. This technology should facilitate the elucidation of the molecular underpinnings of these processes.

ORGANISM(S): Mus musculus

PROVIDER: GSE43483 | GEO | 2015/11/24

SECONDARY ACCESSION(S): PRJNA186550

REPOSITORIES: GEO

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MetSearch: A screening platform for the discovery of genes implicated in metastatic dormancy and reactivation

Project description:We have developed a screening platform for the isolation of genetic entities involved in metastatic reactivation. Retroviral libraries encoding cDNAs from highly metastatic breast cancer cells or pooled microRNAs were transduced into breast cancer cells that become dormant upon infiltrating the lung. Upon inoculation in the tail vein of mice, the cells that had acquired the ability to undergo reactivation generated metastatic lesions. Integrated retroviral vectors were recovered from these lesions, sequenced, and subjected to a second round of validation. By using this strategy, we identified canonical genes and microRNAs that mediate metastatic reactivation in the lung. To identify genes that oppose reactivation, we screened an expression library encoding shRNAs and we identified target genes that encode potential enforcers of dormancy. Our screening strategy enables the identification and rapid biological validation of single genetic entities that are necessary to maintain dormancy or to induce reactivation. This technology should facilitate the elucidation of the molecular underpinnings of these processes. We conducte miRNA microarray analysis (Agilent Technologies) as a complementary technique to examine miRNA expression profiles in our tumor progression series model, comparing the non-metastatic cells lines (67NR, 168FARN, 4TO7) with that of the metastatic cell line (4T1). By studying these profiles, we can identify sets of miRNAs that regulate the different steps of metastasis, namely intravasation, survival in the circulatory system and at distant sites, and extravasation and metastases formation, as represented by the different cell lines.

2015-11-24 | E-GEOD-43483 | biostudies-arrayexpress

Mus musculus

Project description:MetSearch: A screening platform for the discovery of genes implicated in metastatic dormancy and reactivation

| PRJNA186550 | ENA

Stromal Changes in The Aged Lung Induce an Emergence From Melanoma Dormancy

Project description:Disseminated cancer cells (DCCs) that escape the primary site can seed in distal tissues, but may take several years, or even decades to grow out into overt metastases, a phenomenon termed tumor dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully model or characterize dormancy within melanoma. Here, we show that age-related changes in the lung microenvironment facilitate a permissive niche for efficient outgrowth of disseminated dormant tumor cells, in contrast to the aged skin, where age-related changes suppress melanoma growth but drive dissemination. A model of melanoma progression that addresses these microenvironmental complexities is the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state1-3. We have previously shown that dermal fibroblasts are key orchestrators of promoting phenotype switching in primary melanoma tumors via changes in the secretion of soluble factors during aging4-8. Our new data identifies Wnt5A as a master regulator of activating melanoma DCC dormancy within the lung, which initially enables efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of the soluble Wnt antagonist sFRP1, which inhibits Wnt5A, enabling efficient metastatic outgrowth. Further, we have identified the tyrosine kinase receptors AXL and MER as promoting a dormancy-toreactivation axis respectively. Overall, we find that age-induced changes in distal metastatic microenvironments promotes efficient reactivation of dormant melanoma cells in the lung.

2022-03-03 | MSV000088977 | MassIVE

MSK1 regulates luminal cell differentiation and metastatic dormancy in breast cancer

Project description:For many breast cancer (BCa) patients, symptomatic bone metastases appear after years or even decades of latency. How metastatic cells disseminate, and how micrometastatic lesions remain dormant and undetectable yet initiate colonization, are major questions in cancer research. Here we identify and functionally analyse a molecular mechanism involved in bone metastatic latency of estrogen receptor–positive (ER)+ BCa. We developed an in vivo loss-of-function, genome-wide shRNA screening to identify genes relevant for long-latent relapse in BCa. This screen revealed the kinase MSK1 as an important regulator of metastatic dormancy. Importantly, low MSK1 expression associates with early metastasis in ER+ BCa patients. Reduced MSK1 levels impaired cellular differentiation and increased the bone homing and growth capacity of metastatic cells. MSK1 modulates chromatin status at promoters to regulate the expression of luminal differentiation genes, including those for the GATA-3 and FOXA1 transcription factors, which prevent the progression of ER+ BCa towards metastasis. Our results identify the regulation of luminal cell differentiation by MSK1 via modulation of chromatin remodelling to be a key mechanism for controlling metastatic dormancy in BCa. We propose that MSK1 could be a useful marker for stratifying BCa patients as high- or low-risk for early relapse, allowing patients to receive appropriate treatments.

2017-11-13 | GSE100306 | GEO

RNA sequencing of MMTV-Neu early lesion (EL) and primary tumor (PT) spheres

Project description:Cancer cells can disseminate from early-evolved primary lesions. It is thought that a state of early disseminated cancer cell (early DCC) dormancy would precede genetic maturation of DCCs and metastasis initiation. Here we reveal at single cell resolution a previously unrecognized role of mesenchymal- and pluripotency-like programs in coordinating early cancer cell spread and a long-lived dormancy program in early DCCs. We identify in early lesions and early DCCs, the transcription factor ZFP281 as an inducer of mesenchymal- and primed pluripotency-like programs, which is absent in advanced primary tumors and overt metastasis. ZFP281 not only controls the early spread of cancer cells but also locks early DCCs in a prolonged dormancy state by preventing the acquisition of an epithelial-like proliferative program. Thus, ZFP281-driven dormancy of early DCCs may be a rate-limiting step in metastatic progression functioning as a first barrier that DCCs must overcome to then undergo genetic maturation.

2021-01-26 | GSE165431 | GEO

Profiling the proteome of Mycobacterium tuberculosis during dormancy and reactivation

Project description:Tuberculosis, caused by Mycobacterium tuberculosis, still remains a major global health problem. The main obstacle in eradicating this disease is the ability of this pathogen to remain dormant in macrophages, and to get reactivated later under immuno-compromised conditions. The physiology of hypoxic nonreplicating M. tuberculosis is well studied using many in vitro dormancy models. However, the physiological changes that take place during the shift from dormancy to aerobic growth (reactivation) have rarely been subjected to a detailed investigation. In this study, we developed an in vitro reactivation system by re-aerating bacteria that were made dormant employing Wayne’s dormancy model, and compared the proteome profiles of dormant and reactivated bacteria using label-free one-dimensional LC/MS/MS analysis.

2015-06-01 | PXD001158 | Pride

scRNAseq of MMTV-Neu lung cancer cells in early and late stage

2021-01-26 | GSE165459 | GEO

scRNAseq of MMTV-Neu primary site and lung cancer cells in early and late stage

2021-01-26 | GSE165456 | GEO

ZFP281 ChIP-sequencing of MMTV-Neu early lesion (EL) and primary tumor (PT) spheres

2021-01-26 | GSE165444 | GEO

Comparative label-free lipidomic analysis of Mycobacterium tuberculosis during dormancy and reactivation

Project description:Mycobacterium tuberculosis employs several strategies to combat and adapt to adverse conditions encountered inside the host. The non-replicative dormant state of the bacterium is linked to drug resistance and slower response to anti-tubercular therapy. It is known that alterations in lipid content allow dormant bacteria to acclimatize to cellular stress. Employing comparative lipidomic analysis we profiled the changes in lipid metabolism in M. tuberculosis using a modified Wayne's model of hypoxia-induced dormancy. Further we subjected the dormant bacteria to resuscitation, and analyzed their lipidomes until the lipid profile was similar to that of normoxially grown bacteria. An enhanced degradation of cell wall-associated and cytoplasmic lipids during dormancy, and their gradual restoration during reactivation, were clearly evident. This study throws light on distinct lipid metabolic patterns that M. tuberculosis undergoes to maintain its cellular energetics during dormancy and reactivation.

2018-10-22 | MTBLS304 | MetaboLights

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