Functional analysis of circulating tumour cells: the KEY to understand the biology of the metastatic cascade

Eslami-S, Zahra; Cortés‐Hernández, Luis Enrique; Thomas, Fréderic; Pantel, Klaus; Alix‐Panabières, Catherine

doi:10.1038/s41416-022-01819-1

Cited by 50 publications

(39 citation statements)

References 91 publications

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“…Further, it would also be interesting to investigate whether circulating tumor cells of ctDNA-positive stage II CRCs correlates with a TFunctionalProg high-risk subgroup, and this may help the understanding of the functionality and the origin of heterogenous circulating tumor cells. [31] TFunctionalProg utilize standard FFPE slides that can be stored at room temperature and provides an alternative to ctDNA-based prognostic biomarkers.…”

Section: Discussionmentioning

confidence: 99%

Dissected subgroups predict the risk of recurrence of stage II colorectal cancer and select rational treatment

Wang

Zhou

et al. 2022

Preprint

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BackgroundStage II colorectal cancer(CRC) patients after surgery alone have a five-year survival rate of ∼60-80%; the incremental benefit of adjuvant chemotherapy is <5%. Predicting risk of recurrence and selecting effective personalized adjuvant drugs for stage II CRC using formalin-fixed, paraffin-embedded(FFPE) samples is a major challenge.Methods1319 stage II CRC patients who enrolled in 2011-2019 at Sun Yat-sen University Cancer Center were screened. RNAseq data of FFPE tumor samples of 222 stage II MSS CRC patients(n.recurrence=47, n.norecurrence=175, median follow-up=41 months) were used to develop a method TFunctionalProg for dissecting heterogeneous subgroups of recurrence, predicting risk of recurrence and proposing adjuvant drugs.ResultsTFunctionalProg showed significant predictive values in 222 stage II MSS CRCs. The TFunctionalProg low-risk group had significantly better RFS (validation set (HR=4.78, p-value=1e-4, low-risk group three-year RFS=92.6%, high-risk group three-year RFS=59.7%). TFunctionalProg dissected two subgroups of transition states of stage II MSS CRCs at a high risk of recurrence; each state displays distinct levels of hybrid epithelial-mesenchymal traits, cytotoxic cell inhibition and FOLFOX resistance. Based on mechanisms in two subgroups, TFunctionalProg proposed personalized rational adjuvant drug combinations of immunotherapy, chemotherapy and repurposed CNS drugs. The complementary utility of TFunctionalProg and ctDNA-based prognostic biomarkers were presented.ConclusionTFunctionalProg was validated using FFPE samples to predict the risk of recurrence and propose rational adjuvant drug combinations for stage II CRCs.

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Section: Discussionmentioning

confidence: 99%

Dissected subgroups predict the risk of recurrence of stage II colorectal cancer and select rational treatment

Wang

Zhou

et al. 2022

Preprint

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“…Besides their value as diagnostic markers, the analyses of CTCs in patients with cancer (and experimental models) can contribute to understand the complexity of metastatic spread which may eventually lead to a favorable outcome of patients with solid malignancies. 10 In this context, mathematical modeling might help to encompass the complex process of the metastatic cascade. Dujon et al used simulations (adaptation of the Drake equation) based on published breast cancer data and demonstrated that the survival of CTCs in the bloodstream is a key step in the complex process of the metastatic cascade.…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, these models provide insights into CTC biology and in particular might help to identify pathways specific for metastasis-competent CTCs, discover new CTC markers and unravel mechanisms of drug resistance of these CTCs. 10…”

Section: Introductionmentioning

confidence: 99%

Crucial roles of circulating tumor cells in the metastatic cascade and tumor immune escape: biology and clinical translation

Pantel

Alix‐Panabières

2022

J Immunother Cancer

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Cancer-related deaths are mainly caused by metastatic spread of tumor cells from the primary lesion to distant sites via the blood circulation. Understanding the mechanisms of blood-borne tumor cell dissemination by the detection and molecular characterization of circulating tumor cells (CTCs) in the blood of patients with cancer has opened a new avenue in cancer research. Recent technical advances have enabled a comprehensive analysis of the CTCs at the genome, transcriptome and protein level as well as first functional studies using patient-derived CTC cell lines. In this review, we describe and discuss how research on CTCs has yielded important insights into the biology of cancer metastasis and the response of patients with cancer to therapies directed against metastatic cells. Future investigations will show whether CTCs leaving their primary site are more vulnerable to attacks by immune effector cells and whether cancer cell dissemination might be the ‘Achilles heel’ of metastatic progression. Here, we focus on the lessons learned from CTC research on the biology of cancer metastasis in patients with particular emphasis on the interactions of CTCs with the immune system. Moreover, we describe and discuss briefly the potential and challenges for implementing CTCs into clinical decision-making including detection of minimal residual disease, monitoring efficacies of systemic therapies and identification of therapeutic targets and resistance mechanisms.

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“…Besides factors such as shear stress and anoikis, several studies suggest that CTCs survival might be hindered by mechanisms of immune-mediated clearance (8,16). Research interest in understanding the interplay between CTCs and circulating immune cells is growing as it holds great promise to understand the process of metastasis, predict patients' outcome and pave the way for new treatment strategies (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Clinical relevance of the combined analysis of circulating tumor cells and anti-tumor T-cell immunity in metastatic breast cancer patients

et al. 2022

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BackgroundMetastatic breast cancer (mBC) is a heterogeneous disease with varying responses to treatments and clinical outcomes, still requiring the identification of reliable predictive biomarkers. In this context, liquid biopsy has emerged as a powerful tool to assess in real-time the evolving landscape of cancer, which is both orchestrated by the metastatic process and immune-surveillance mechanisms. Thus, we investigated circulating tumor cells (CTCs) coupled with peripheral T-cell immunity to uncover their potential clinical relevance in mBC.MethodsA cohort of 20 mBC patients was evaluated, before and one month after starting therapy, through the following liquid biopsy approaches: CTCs enumerated by a metabolism-based assay, T-cell responses against tumor-associated antigens (TAA) characterized by interferon-γ enzyme-linked immunosorbent spot (ELISpot), and the T-cell receptor (TCR) repertoire investigated by a targeted next-generation sequencing technique. TCR repertoire features were characterized by the Morisita’s overlap and the Productive Simpson Clonality indexes, and the TCR richness. Differences between groups were calculated by Fisher’s, Mann-Whitney or Kruskal-Wallis test, as appropriate. Prognostic data analysis was estimated by Kaplan-Meier method.ResultsStratifying patients for their prognostic level of 6 CTCs before therapy, TAA specific T-cell responses were detected only in patients with a low CTC level. By analyzing the TCR repertoire, the highest TCR clonality was observed in the case of CTCs under the cut-off and a positive ELISpot response (p=0.03). Whereas, at follow-up, patients showing a good clinical response coupled with a low number of CTCs were characterized by the most elevated TCR clonality (p<0.05). The detection of CTCs≥6 in at least one time-point was associated with a lower TCR clonality (p=0.02). Intriguingly, by combining overall survival analysis with TCR repertoire, we highlighted a potential prognostic role of the TCR clonality measured at follow-up (p=0.03).ConclusionThese data, whether validated in a larger cohort of patients, suggest that the combined analysis of CTCs and circulating anti-tumor T-cell immunity could represent a valuable immune-oncological biomarker for the liquid biopsy field. The clinical application of this promising tool could improve the management of mBC patients, especially in the setting of immunotherapy, a rising approach for BC treatment requiring reliable predictive biomarkers.

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Functional analysis of circulating tumour cells: the KEY to understand the biology of the metastatic cascade

Cited by 50 publications

References 91 publications

Dissected subgroups predict the risk of recurrence of stage II colorectal cancer and select rational treatment

Dissected subgroups predict the risk of recurrence of stage II colorectal cancer and select rational treatment

Crucial roles of circulating tumor cells in the metastatic cascade and tumor immune escape: biology and clinical translation

Clinical relevance of the combined analysis of circulating tumor cells and anti-tumor T-cell immunity in metastatic breast cancer patients

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