Introduction

Cancer metastasis remains a major contributor to cancer-related mortality, making it a central focus of cancer research. CTCs, as precursors of metastasis, offer a valuable perspective for studying the metastatic process[1]. In the context of cancer prognosis, a burgeoning body of evidence highlights the significance of CTC count as a potent predictor. Investigations into breast cancer, colorectal cancer, lung cancer, and esophageal cancer have yielded compelling findings. The assessment of CTCs emerges as a prospective tool, offering invaluable prognostic insights for cancer patients across various stages of the disease spectrum, whether it be in the early phases, advanced stages, or spanning the critical phases before and after therapeutic interventions[2,3,5,6,7]. Hence, valuable information regarding potential factors leading to unfavorable patient prognoses should be found within CTCs. In cancer research, the direct and pivotal approach to unveiling the molecular characteristics of CTCs is through sequencing. In a single-cell sequencing research focused on CTCs in non-small cell lung cancer, it was discovered that CTCs harbor genetic mutations from both the primary tumor and metastatic lesions, encompassing mutations specific to both the primary tumor and metastatic sites [8]. Therefore, considering CTCs as an alternative subject of study for solid tumors, without the necessity of obtaining primary tumor tissue, to obtain partial information regarding the tumor, presents a feasible approach. Furthermore, valuable and unique data that is distinct from the primary tumor can be gathered through the analysis of CTCs. On one hand, as it can be detected at the early stage in many cancers [9,10,11,12], CTCs have the potential to enhance the early screening of cancer through the analysis of CTCs. For instance, cancer can be initially diagnosed through the recognition of CTC-specific antigens [13]. On the other hand, it can also contribute to a more profound understanding of the mechanisms underlying metastasis by studying CTCs. In this context, we elucidate the present status of multi-omics investigations on CTCs conducted in recent years. It is important to emphasize that the biological phenotype of tumor cells is the result of a complex interplay between genetics and the environment, including morphological and phenotypic states, and the specific environment in which CTCs exist determines their unique biological phenotype [14, 15]. Therefore, this review will present the latest research findings concerning the survival status of CTCs in the bloodstream in recent years. This includes the EMT phenotype, as well as the interactions of CTCs with other constituents of the blood and the molecular characteristics of CTC-clusters.

Multi-omics studies of CTCs

Genomic research of CTCs

Genomic research has played a crucial role in identifying genes that are specific or of particular significance in various types of cancer. And it has led to significant advancements in uncovering genetic mutations associated with cancer initiation and progression, encompassing mechanisms of pathogenesis, immune evasion, metastasis, proliferation, and resistance to apoptosis [16]. The genome of cancer is markedly unstable, which may be a major driver of cancer development [17, 18]. Certain gene mutations have been clinically validated to predict cancer prognosis, establish associations with chemotherapy or immunotherapy responsiveness, and facilitate the development of tailored treatment plans for individual variations [19,20,21,22,23,24,25,26]. However, unveiling the "veil" of the cancer metastasis mechanism cannot be achieved solely through the exploration of the genome of solid cancer [27]. Profiling the genome of CTCs reveals unique implications distinct from those of the primary tumor. Distant metastasis from primary tumors involves a genetic mutation process, with most distant metastases acquiring driving mutations that are absent in primary tumors [28]. The process of hematogenous metastasis entails genetic changes in tumor cells. In the research of metastatic breast cancer, certain mutations with targeted potential, such as BRCA2 p.Q1931X and PTCH1 p.E1242X mutations, were present in CTCs and remain undetected in the corresponding tumor tissue [29]. Similarly, in pancreatic ductal adenocarcinoma, the KRAS mutations present in CTCs are inconsistent with those observed in the primary tumors, indicating genetic differences in their characteristics [30]. In expanded genomic profiling of CTCs in metastatic breast cancer patients, differences in the mutation statuses of ESR1 and ERBB2 between CTCs and their matched primary tumors were observed [31]. CTCs genome also holds potential significance for personalized therapy. On the one hand, the presence of genetic mutations in CTCs exhibits pronounced inter-patient heterogeneity. In genomic analysis of CTCs in colorectal cancer, there were notable disparities in the mutation statuses of KRAS, BRAF, and PIK3CA, as well as variations in the amplification status of epidermal growth factor receptor-1 (EGFR), among CTCs from different patients. Consequently, CTCs exhibit considerable heterogeneity from one patient to another, underscoring their potential as a foundation for personalized cancer treatment [32]. The genomic research findings on CTCs in non-small cell lung cancer similarly support this conclusion [33]. One the other hand, gene mutations in CTCs have a certain impact on treatment. In a study of metastatic breast cancer, disparities were identified in the CTC mutation status before and after treatment. Remarkably, a small quantity of CTCs carrying specific mutations could remain survival after treatment. These findings indicate that CTCs with certain gene mutations may develop resistance to drugs [34]. Gene mutations in CTCs can be used to study resistance mechanisms or to develop targeted therapeutics [35]. The utilization of targeted medications against drug-resistant mutations in cancer has demonstrated some effectiveness [36]. Consequently, genomic studies of circulating tumor cells (CTCs) offer substantial potential not only in understanding their heterogeneity but also in refining treatment strategies to tackle the challenging of cancer drug resistance.

Transcriptomic research of CTCs

Transcriptomic research serves as a vital bridge connecting the genome to the proteome. The analysis of the transcriptome is indispensable for understanding the intricacies of the genome, unveiling the molecular composition of tumor cells, and addressing the progression of diseases. Together, the genome and transcriptome provide a comprehensive perspective on individual cancer patients, significantly influencing clinical decisions [37]. Notably, the gene expression of CTCs does not align perfectly with that of the primary tumor. In certain breast cancer patients, markers such as EGFR, epidermal growth factor receptor-2 (HER-2), and estrogen receptor (ER) may exhibit a negative status in the primary tumor, but CTCs can still manifest positive expression [38,39,40]. It has been proven to have certain prognostic significance in breast cancer and bladder cancer [41, 42]. In CTCs with specific phenotypes, there are specific pathway activation that can induce CTC proliferation [38]. The gene expression profiles discussed above carry significant implications for therapeutic strategies, such as targeted therapies. Within CTCs, there exist numerous promising targets awaiting exploration. The incorporation of this data is anticipated to enhance the precision and efficacy of cancer treatment [43]. Through transcriptome sequencing, a wealth of metastasis-related information can be obtained from CTCs, enriching genes associated with enhanced tumor cell proliferation and increased invasive capacity. These are essential components in exploring the mechanism of tumor metastasis [44,45,46]. Among them, there are numerous potential therapeutic targets, various pro-cancer pathways or more invasive CTC subpopulations [47,56], laser capture microdissection [57], NanoVelcro-LMD technology [58] and manual cell picking through micromanipulators [59]. Single-cell technology now allows comprehensive analysis of CTCs to reveal aspects of metastasis and resistance mechanisms in cancer therapy [52]. Moreover, existing sequencing technologies such as Hydro-Seq [60], Smart-seq [61], and Smart-seq2 [62] gave a strong basis to the feasibility of individual CTCs for RNA-seq analysis, allowing contamination-free high-throughput and sensitive analysis of the transcriptome of CTCs. Substantial progress has been achieved in revealing the heterogeneity of CTCs using single-cell transcriptomics. By comparing the single-cell RNA-sequencing results of CTCs from different vascular sites, including the hepatic vein, peripheral artery, peripheral vein and portal vein, in patients with hepatocellular carcinoma, Sun YF et al. found there was significant heterogeneity in CTCs between different vascular sites and different patients, involving differences in gene expression related to immunity, oxidative phosphorylation/metabolism, G protein-coupled receptor signaling, cell cycle, EMT, tumor cell-platelet microaggregates, and immune-suppressive chemokines [63, 64]. In the study of CTCs in breast cancer, CTCs in the blood from patients at different time stages (including active and dormant phases) as well as from mouse models show differential expression of cytokinesis and mitotic genes such as Ki67 [65]. Therefore, transcriptome sequencing for CTCs needs to be more systematic, taking into account time and space. Single-cell RNA sequencing (scRNA-seq) for CTCs is also an important source of information for metastatic targets and drug resistance mechanisms. The results of scRNA-seq on individual CTCs isolated from patients with pancreatic cancer, breast cancer, and prostate cancer have revealed that extracellular matrix (ECM) protein genes are highly expressed in human CTCs [66]. Considering the role of ECM lectins in cancer metastasis [67, 68], and the high expression of ECM gene family members in CTCs from several cancer types,  their upregulation may play a crucial role in the generation of CTCs from primary tumors. ScRNA-seq analysis of prostate cancer CTCs by David T. Miyamoto has shown that CTCs exhibit various alterations in androgen receptors (AR), including AR splice variants and point mutations, which are associated with clinical resistance to anti-androgen therapy [46]. In pancreatic ductal adenocarcinoma, scRNA-seq analysis has revealed that the expression of apoptosis inhibitor protein family member BIRC5 (survivin) is higher in CTCs compared to the primary tumor. This may be closely related to the survival mechanisms of CTCs in the bloodstream. Therefore, BIRC5 may be a significant target for reducing metastasis [69].

Proteomic research of CTCs

At present, research on CTCs primarily focuses on genomics and transcriptomics. However, various modifications of proteins are necessary during the translation process, and transcriptomic data cannot fully reflect the qualitative and quantitative changes in protein expression during tumor development [70, 71]. Moreover, transcriptome and protein expression are not completely correlated [72,73,74]. Typically, single-cell proteomics analysis methods offer higher precision compared to current scRNA-seq methods. Proteomics technology enables high-throughput and rapid analysis of various proteins expressed in tumors, making it possible to identify numerous protein markers with diagnostic value [75, 76]. These proteins may provide new targets for tumor treatment and effective tumor biomarkers for early diagnosis. However, the limited number of CTCs in peripheral blood, the complexity of protein types within single cells, low protein content, and non-amplifiability pose challenges to CTC proteomics research. Mass spectrometry-based single-cell proteomics research on CTCs has not been reported yet. Nevertheless, some studies have identified some of the proteins present on CTCs by specific means, such as targeting assays. Single-cell resolution western blotting have identified glyceraldehyde-3-phosphate dehydrogenase, β-microtubulin, pankeratin, extracellular regulated protein kinases, epithelial cell adhesion molecule (EpCAM), ER, eIF6E and other proteins expressed in CTCs derived from breast cancer patients [77]. Reza KK et al. successfully detected the heterogeneity of melanoma CTCs and changes in biomarkers after treatment by a surface-enhanced Raman spectroscopy-based simple microfluidic device [78]. The studies described above were based on targeted detection of known proteins and could not detect the possible presence of unknown proteins in CTCs, which may have implications for metastatic drivers, tumor markers, and therapeutic targets. Single-cell proteomics based on mass spectrometry is rapidly advancing, allowing for the identification of biomarkers and the uncovering of heterogeneity within CTCs [79,80,81,82,83]. Therefore, proteomic studies of CTCs are very promising.

Metabolomic research of CTCs

Metabolomics is the analytical research of small molecule metabolites, similar to other "histological" techniques, which can provide critical information about the status of cancers [84]. The metabolic status of cancers is available to differentiate cancer cell subtypes [85], identify cancer biomarkers and drivers of tumorigenesis and can also provide advice for targeted therapies [86, 87]. Tumor cells can adapt to the complex microenvironment and promote immune escape by altering metabolic patterns or reprogramming multiple metabolic pathways [88]. Thus, CTCs in the circulation should have a unique and suitable metabolic pattern. Due to the trace presence of CTCs in the blood, the identification of CTC metabolites poses a formidable challenge. Studies on the metabolomics of CTCs are currently limited to the validation of the presence of known metabolic pathways in CTCs, such as through gene expression assays or performing in vitro cultures of CTC lineage cells to gain insight into the metabolism of CTCs [89,90,91]. The in-depth exploration of CTCs metabolomics remains a significant gap in current research. The limited presence of CTCs in the bloodstream poses a formidable challenge for the non-targeted identification of their metabolites. On one front, it is focused on the intracellular metabolites of CTCs. Currently, single-cell metabolomics based on mass spectrometry is rapidly advancing. Takayuki Kawai integrated capillary electrophoresis with mass spectrometry and identified 40 metabolites from single HeLa cell [92]. Shuting Xu and colleagues developed a multidimensional organic mass cytometry platform based on chip-nanoelectrospray ionization mass cytometry system, capable of providing 100 metabolic parameters at single-cell resolution [93]. The use of magnetic bead separation combined with downstream laser desorption/ionization mass spectrometry has been developed and holds potential for identifying metabolic products in CTCs [94]. However, the metabolic products secreted by CTCs and the influence of the blood microenvironment on CTCs are factors that cannot be ignored in the study of CTC metabolism. This includes factors such as blood flow shear stress, oxygen levels, nutrients, and the impact of immune cells on CTCs. Simulating the microenvironment in which CTCs exist in the blood is essential. Currently, relevant research on simulating the blood environment has made some progress, including the simulation and real-time monitoring of hemodynamics, which involves shear stress, blood oxygen transport, and content [123]. Taken together, formation of CTC clusters is regulated by various factors, including genetic mutations, the action of various adhesion factors, and the activation of signaling pathways. (Fig. 2). However, the current research on the molecular characteristics of CTC clusters is largely concentrated in breast cancer. The complexity of the formation mechanism of CTC clusters implies that current studies are relatively limited. The presence of CTC clusters has been confirmed in various cancers, highlighting the importance of focusing on the diversity and heterogeneity across different cancer types.

CTC clusters grasp the advantage

CTC cluster size will not hinder their capacity to reach metastatic sites via capillaries. [124]. In breast cancer, compared to single CTCs, binding sites for stemness- and proliferation-associated transcription factors, including OCT4, NANOG, SOX2, and SIN3A, are specifically hypomethylated in the methylation region of CTC cluster DNA [125], which may confer enhanced metastatic and proliferative potential to CTC clusters. Furthermore, combination and collaboration among CTCs within the clusters could provide CTC clusters with an advantage through blood flow stresses, such as loss of nest apoptosis, shear force and immune attack, and colonization of distant organs [126]. In the mouse breast cancer model, there is an increase in the intercellular adhesion and epithelial gene expression of CTC clusters. This leads to a decrease in the expression of the activation ligands for NK cells, conferring low sensitivity of CTC clusters to NK-mediated suppression [127].

Potential therapeutic value in CTC clusters

Clinical follow-up studies on colorectal cancer and hepatocellular carcinoma suggest that chemotherapy cannot completely eliminate CTC clusters [128, 129], which leads to potential risks of recurrence and metastasis. The persistence of CTC clusters significantly increases the probability of metastasis. Therefore, treatment targeting CTC clusters is of crucial importance in reducing the occurrence of metastasis and improving prognosis. This can be approached from two perspectives: firstly, disassembling CTC clusters. As mentioned above, the formation of CTC clusters is regulated by various factors in some cancers, and targeting the facilitators of CTC cluster formation may help reduce their occurrence or facilitate their disassembly. One study showed that urokinase-type fibrinogen activators had an inhibitory effect on CTC clusters and had the potential to improve survival in a mouse model of lung metastasis [130]. Na/K-ATPase inhibitors, such as ouabain and digitoxin (DT), could dissociate CTC clusters by increasing the intracellular calcium concentration, resulting in the inhibition of cell–cell junctions, and have the ability to inhibit the spontaneous shedding of CTC clusters from cancerous lesions and reduce the ability of cancer metastatic seeding [125]. What is more, the anti-EGFR monoclonal antibody (clone LA1) blocking EGFR has been shown to effectively inhibit in vitro the CD44-mediated aggregation of triple-negative breast cancer cells, reducing metastasis [131]. The use of celecoxib can reduce the formation of CTC clusters by inhibiting COX-2 and downregulating E-cadherin protein expression within xenograft tumors [132]. On the other hand, during tumor cell aggregation, it induced a hypoxic environment, including mitochondrial autophagy mediated by hypoxia-inducible factor 1-alpha (Hif1α) and restriction of reactive oxygen species (ROS). This ultimately reduces dependence on glycolysis for ATP production. Disrupting these metabolic adaptations may have the potential to decrease the survival and metastatic capability of tumor cells [133]. This is limited to cell line, and further expansion is needed to delve into research involving CTC clusters sourced directly from patients. However, treatment targeting CTC clusters also requires the development of efficient and convenient clinical detection methods [134]. Additionally, translating research into clinical applications necessitates a deeper understanding of the molecular characteristics of CTC clusters in different cancers. Clusters of CTCs in different types of cancer may harbor specific cancer-associated molecular characteristics. For instance, this could potentially offer more comprehensive guidance for the treatment of CTC clusters [135]. Treating solely targeting the CTC clusters may not achieve a significant enough effect, while combining with other treatment methods such as chemotherapy may lead to more pronounced outcomes [136]. The therapeutic potential and clinical applicability of identified targets also require further assessment.

CTCs and EMT

In cancers, EMT plays a role in tumorigenesis, invasion and metastasis [137, 138]. Although the necessity of EMT in cancer metastasis remains controversial [139,140,141], its role in metastasis cannot be ignored. EMT studies of CTCs would more visually reflect the impact of EMT on metastasis and its therapeutic significance for CTCs. EMT is a complex process where tumor cells gradually shed their epithelial characteristics, leading to reduced intercellular adhesion. They then partially or completely acquire migratory and invasive properties, often resulting in the presentation of epithelial (E), mesenchymal (M), or epithelial/mesenchymal (E/M) hybrid phenotypes (Fig. 1). This transformation is accompanied by a decrease in the expression of epithelial markers such as EpCAM and E-calmodulin, while there is an increase in mesenchymal markers like vimentin, twist, and others. In the clinic, phenotypic detection of CTCs has shown potential in monitoring treatment resistance and prognosis prediction in cancer patients [142]. It has been found that human breast cancer cells and lung cancer cells with E/M hybrid phenotypes have stronger proliferative and invasive abilities [143, 144]. The value of E/M-CTCs in predicting adverse outcomes in patients and the occurrence of metastases has been confirmed in cohort studies of colorectal carcinoma [145], non-small cell lung carcinoma [

Data availability

Not applicable.

Code availability

Not applicable.

Abbreviations

AR:

Androgen receptor

CTC-WBCs:

CTC-associated WBCs

CTCs:

Circulating tumor cells

DT:

Digitoxin

E:

Epithelial

E/M:

Epithelial/mesenchymal

ECM:

Extracellular matrix

EGFR:

Epidermal growth factor receptor

EMT:

Epithelial-mesenchymal transition

ER:

Estrogen receptor

GPC3:

Glypican-3

HER-2:

Epidermal growth factor receptor-2

HLA-E:

Human leukocyte antigen

ICAM:

Intercellular cell adhesion molecule-1

M:

Mesenchymal

MDSC:

Myeloid-derived suppressor cells

NK cells:

Natural killer cells

NETs:

Neutrophil extracellular traps

PMN-MDSC:

Polymorphonuclear-myeloid-derived suppressor cells

RNA-seq:

RNA sequencing

ROS:

Reactive oxygen species

scRNA-seq:

Single-cell RNA sequencing

SF:

Sorafenib

WBC:

White blood cells

WNT:

Wingless/integrated

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Acknowledgements

Thanks for the help of Zhang group members.

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 82073008), Key Research and Development Project of Hunan Province (Nos.2020SK2071), and Natural Science Foundation of Hunan Province (Nos.2020JJ4924).

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Authors and Affiliations

  1. NHC Key Laboratory of Cancer Proteomics, Department of Oncology, **angya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China

    Qingming **e, Shilei Liu, Sai Zhang & Pengfei Zhang

  2. National Clinical Research Center for Geriatric Disorders, **angya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China

    Qingming **e, Shilei Liu, Sai Zhang & Pengfei Zhang

  3. Department of Breast Surgery, Hunan Clinical Meditech Research Center for Breast Cancer, **angya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China

    Liqiu Liao, Zhi **ao & Shouman Wang

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  1. Qingming **e
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Contributions

PZ, SW and QX conceived the manuscript, QX drafted the manuscript, and QX drew the figures. PZ, SW and QX discussed the concepts of the manuscript. PZ and SW critically reviewed the manuscript. SL, SZ, SW, LL and ZX provided valuable suggestion. All authors read and approved the final manuscript.

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Correspondence to Shouman Wang or Pengfei Zhang.

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**e, Q., Liu, S., Zhang, S. et al. Research progress on the multi-omics and survival status of circulating tumor cells. Clin Exp Med 24, 49 (2024). https://doi.org/10.1007/s10238-024-01309-z

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