Ki-67 promotes circulating tumor cell intravasation and metastasis in breast cancer
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE303593 | GEO | 2026/04/13
REPOSITORIES: GEO
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Project description:Hematogenous dissemination by circulating tumor cells (CTCs) drives metastatic spread. However, the molecular features that empower these cells to colonize distant organs remain unclear. We profiled single CTCs and CTC clusters from three breast cancer xenograft models by single-cell RNA sequencing and uncovered a shared transcriptional program marked by broad upregulation of cell-cycle genes. A targeted CRISPR loss-of-function screen identified MKI67 as an essential regulator of CTC abundance, particularly of cluster abundance, and metastatic progression. MKI67 disruption markedly reduced CTC numbers and decreased the fraction ofCTC clusters, leading to diminished lung metastases. CRISPRa-mediated re-expression of downstream adhesion genes CD47 and KLF4 restored both cluster prevalence and metastatic burden. Our findings link cell-cycle upregulation to enhanced metastatic capacity and position MKI67-dependent adhesion signals as tractable targpendent adhesion signals as tractable targets against metastatic spread.
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Project description:Hematogenous dissemination by circulating tumor cells (CTCs) drives metastatic spread. However, the molecular features that empower these cells to colonize distant organs remain unclear. We profiled single CTCs and CTC clusters from three breast cancer xenograft models by single-cell RNA sequencing and uncovered a shared transcriptional program marked by broad upregulation of cell-cycle genes. A targeted CRISPR loss-of-function screen identified MKI67 as an essential regulator of CTC abundance, particularly of cluster abundance, and metastatic progression. MKI67 disruption markedly reduced CTC numbers and decreased the fraction ofCTC clusters, leading to diminished lung metastases. CRISPRa-mediated re-expression of downstream adhesion genes CD47 and KLF4 restored both cluster prevalence and metastatic burden. Our findings link cell-cycle upregulation to enhanced metastatic capacity and position MKI67-dependent adhesion signals as tractable targpendent adhesion signals as tractable targets against metastatic spread.
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Project description:Background: Circulating tumor cells (CTCs) play a key role in cancer progression, and in vitro CTC models are essential for studying their biology. This study examined extracellular vesicles (EVs) from CTC lines of a metastatic colorectal cancer (mCRC) patient who progressed despite therapy. Methods and results: EVs from different CTC lines showed size and morphological variations. Proteomic analysis revealed an enrichment of proteins linked to stemness, endosomal biogenesis, and mCRC prognosis. Integrins were notably enriched in EVs from post-therapy CTC lines. In vivo, EVs accumulated in the liver, lungs, kidneys, and bones, though their influence on CTC organotropism was unclear. Conclusions: This study highlights therapy-related changes in EVs from mCRC CTCs and their role in cancer spread. These findings suggest the utility of CTC-derived EVs in understanding cancer dissemination, though further validation in mCRC patients is needed.
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Project description:Circulating tumor cells (CTCs) are critical in the development of distant organ tumor metastasis, and are associated with advanced cancer stage and poor patient outcome. Here, we present the first genome-wide nucleotide-level characterization of CTCs. Our single-nucleotide polymorphism (SNP) analysis in patients with melanoma involved: 1) global comparative genomic analysis of CTCs and matched regional metastases, 2) identification of key genomic aberrations in CTCs, 3) verification of these target genes in aggressive distant tumor metastases, and 4) evidence of selective expression and functional consequence of CTC-associated genes in melanomas. We report 131 aberrant loci in CTCs that are potentially pro-metastatic, and show that such expression of a 5-marker gene panel (CSMD2, CNTNAP5, FLJ14051, ADAM6, TRPM2) in melanomas confers prognostic utility. Successful treatment of melanoma requires understanding of the metastatic process and identification of patients with tumors most likely to develop aggressive metastatic disease. Melanomas are heterogeneous, and CTCs have long been recognized as vehicles for cancer spread, representing particularly aggressive tumor clones that can evolve into successful clinical metastases. Elucidation of genomic aberrations in CTCs will aid in the development of prognostic biomarkers and therapeutic strategies to target CTCs to prevent or control distant cancer spread. This study provides the first detailed genomic confirmation of the close relation between CTCs and tumor metastases, and illustrates how CTCs can be utilized as a novel approach and rational source for identification of pro-metastatic genes in cancer research. Three individual patient cohorts were utilized in the study. CNV and LOH loci were evaluated initially in metastatic melanoma patients (n=13) in a discovery cohort. SNP loci that harbored CNV/LOH in CTCs were then separately verified for: (a) presence in distant organ metastasis (AJCC Stage IV melanoma) (n=27), and (b) relevance to prognosis in regional melanoma metastasis (AJCC Stage III melanoma) (n=35). The first discovery patient cohort group was utilized for capture of CTCs, and consisted of peripheral blood mononuclear cell (PBMC) and tumor specimens from metastatic melanoma patients (n=13). CTC-related loci were verified in a second cohort of patients with Stage IV distant organ metastases (n=27), including 15 brain, 4 lung, and 8 gastrointestinal (bowel, liver) metastases. The third patient cohort consisted of early passage (<12) established melanoma cell lines derived from 35 regional melanoma metastases (Stage III) for evaluation of the prognostic utility of the CTC-associated aberrant loci.
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Project description:The presence of circulating tumor cell (CTC) clusters is associated with disease progression, new metastasis formation and reduced survival in a variety of cancer types. In breast cancer, pre-clinical studies showed that inhibitors of the Na+/K+-ATPase can suppress CTC clusters shedding and block metastasis. Here, we conducted a prospective, open-label, phase I study in patients with metastatic breast cancer, where the primary endpoint was to determine whether a short (one week) treatment with the Na+/K+-ATPase inhibitor digoxin could reduce mean CTC cluster size. Mechanistically, transcriptome profiling of CTCs highlighted downregulation of cell-cell adhesion and cell cycle-related genes upon treatment with digoxin, in line with its cluster-dissolution activity. ClinicalTrials.gov identifier: NCT03928210.
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Project description:Circulating Tumor Cells (CTCs) are shed from primary tumors into the bloodstream, mediating the hematogenous spread of cancer to distant organs. To determine the relevance of ECM protein expression to human disease, CTCs were isolated from the blood of metastatic PDAC patients and subjected to single cell RNA-sequencing. Analysis of 7 pancreatic CTCs from 3 patients revealed that the majority expressed keratins defining their epithelial origin. A total of 13 of 60 extracellular protein genes enriched in mouse CTCs (see GEO GSE51372) were expressed at high levels (>100 rpm) in at least one human pancreatic CTC. Human SPARC was the only gene found at high levels in all human pancreatic CTCs. To achieve a deep RNA sequencing profile of CTCs at the single cell level, we applied a novel inertial focusing-enhanced device, the CTC-iChip, which allows high efficiency negative depletion of normal blood cells, leaving unattached CTCs in solution where they can be selected and analyzed as single cells (Pubmed ID 23552373). CTCs were then subjected to single cell RNA-sequencing (Pubmed ID 20203668).
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Project description:Circulating tumor cells (CTCs) are shed from solid cancers in the form of single or clustered cells, with the latter displaying an extraordinary ability to initiate metastasis. Yet, the biological phenomena that trigger the intravasation of CTC clusters are largely unknown. Here, we compare gene expression of hypoxic and normoxic CTC clusters to identify genes that are not only upregulated as a consequence to hypoxia, but that may also play a pivotal role in promoting CTC clusters generation and metastasis.
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Project description:Melanoma is an invasive malignancy with a high frequency of blood-borne metastases, but circulating tumor cells (CTCs) have not been readily isolated. We adapted microfluidic CTC capture to a tamoxifen-driven B-RAF/PTEN mouse melanoma model. CTCs were detected in all tumor-bearing mice, rapidly declining after B-RAF inhibitor treatment. CTCs were shed early from localized tumors and a short course of B-RAF inhibition following surgical resection was sufficient to dramatically suppress distant metastases. The large number of CTCs in melanoma-bearing mice enabled comparison of RNA sequencing profiles with the matched primary tumor. A mouse melanoma CTC-derived signature correlated with invasiveness and cellular motility in human melanoma. In patients with metastatic melanoma, CTCs were detected in smaller numbers in patients with metastatic melanoma and declined with successful B-RAF targeted therapy. Together, the capture of CTCs and their molecular characterization provide insight into the hematogenous spread of melanoma.
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Project description:The immune ecosystem, particularly T cells, is central to maintaining effective anti-tumor responses. However, how immune cells in the periphery blood interact with circulating tumor cells (CTCs) - critical mediators of metastatic spread 1-8 – remains largely unexplored. Here, our analysis of the blood specimens from patients with advanced breast cancer (N=1,529) revealed that over 75% of the CTC-positive blood specimens contained heterotypic CTC clusters with CD45+ white blood cells (WBCs). These CTC-WBC clusters correlate with breast cancer subtypes (triple negative and luminal B), racial groups (Black), and unfavorable clinical outcomes. Using flow cytometry and ImageStream, we characterized the diverse WBC composition in these heterotypic clusters, such as overrepresented T cells and underrepresented neutrophils. Most strikingly, a rare subset of CD4 and CD8 double positive T (DPT) cells showed an up to 140-fold enrichment in the CTC clusters (~14.2%) versus its frequency in WBCs (0.1%). DPT cells shared part of profiles with CD4+ T cells and others with CD8+ T cells but exhibited unique features of T cell exhaustion and immune suppression (TIM-3 and PD-1). Single-cell RNA sequencing further identified distinct cell adhesion profiles of DPT cells and CTCs. CRISPR/Cas9-mediated gene depletion pinpointed the integrin VLA4 (β1/α4) in DPT and its ligand VCAM1 in tumor cells as essential mediators of heterotypic CTC clusters. Anti-α4 (VLA4) neutralizing antibodies markedly reduced CTC–DPT cell clustering and blocked metastatic lesion formation in murine models in vivo. These findings uncover a pivotal role for a rare T cell subset in fostering cancer dissemination through heterotypic CTC cluster interactions. It lays a foundation for innovative therapeutic strategies aimed at preventing and targeting metastasis of breast cancer, thus benefiting Black and non-Black patients.
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Project description:Clusters of circulating tumor cells (CTC-clusters) are present in the blood of patients with cancer but their contribution to metastasis is not well defined. Here, we first use mouse models to demonstrate that breast cancer cells injected intravascularly as clusters are more prone to survive and colonize the lungs than single cells. Primary mammary tumors comprised of tagged cells give rise to oligoclonal CTC-clusters, with 50-fold increased metastatic potential, compared with single CTCs. Using intravital imaging and in vivo flow cytometry, CTC-clusters are visualized in the tumor circulation, and they demonstrate rapid clearance in peripheral vessels. In patients with breast cancer, presence of CTC-clusters is correlated with decreased progression-free survival. RNA sequencing identifies the cell junction protein plakoglobin as most differentially expressed between clusters and single human breast CTCs. Expression of plakoglobin is required for efficient CTC-cluster formation and breast cancer metastasis in mice, while its expression is associated with diminished metastasis-free survival in breast cancer patients. Together, these observations suggest that plakoglobin-enriched primary tumor cells break off into the vasculature as CTC-clusters, with greatly enhanced metastasis propensity. RNA-seq from 29 samples (15 pools of single CTCs and 14 CTC-clusters) isolated from 10 breast cancer patients
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