Platelets in Tumor Biology: from Molecular Mechanisms to Clinical Applications

Editorial

13 February 2024

Editorial: Platelets in tumor biology: from molecular mechanisms to clinical applications

Mariana Aris

Anil K. Sood

and

Alexander Zaslavsky

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Editors

Mariana Aris

Centro de Investigaciones Oncológicas (CIO), FUCA

Anil Sood

University of Texas MD Anderson Cancer Center

Alexander Zaslavsky

Department of Urology, School of Medicine, Michigan Medicine, University of Michigan

Impact

Original Research

02 August 2023

In vitro cross-talk between metastasis-competent circulating tumor cells and platelets in colon cancer: a malicious association during the harsh journey in the blood

Zahra Eslami-S

, 10 more and

Catherine Alix-Panabières

Platelet transcriptomic changes upon indirect co-culture with three CTC lines. (A) Volcano plots showing the differential gene expression analysis of RNA-seq data. The log-transformed p-values are plotted on the y-axis and the log2 fold change values of platelets after indirect co-culture with CTC41, CTC41.4, and CTC41.5G cells vs. control (platelets alone) are plotted on the x-axis. The criteria were relative expression fold change ≤ −2.0 or ≥2.0 and p ≤ 0.05. Red dots and blue dots represent increased and decreased RNAs, respectively. (B) Venn diagram showing the number of shared differentially expressed mRNAs in platelets after indirect co-culture with CTC41, CTC41.4, and CTC41.5G cells vs. control. (C–F) Gene Set Enrichment Analysis (GSEA) was performed using the RNA-seq data to compare the transcriptome profiles of platelets after indirect co-culture with CTC41, CTC41.4, and CTC41.5G cells vs. control. (C,D) GSEA results showing significant enrichment of the EMT and Hypoxia signaling pathways among mRNAs increased in platelets after indirect co-culture with CTC41, CTC41.4, and CTC41.5G cells vs. control. (E,F) GSEA results showing that the Inflammatory response and Apoptosis pathways are significantly enriched in platelets after indirect co-culture with CTC41, CTC41.4, and CTC41.5G cells vs. control. Venn diagrams show the shared enriched transcripts in each experimental condition. The heatmaps (C–F) of the common transcripts among the three sample groups illustrate their expression level (red, high; blue, low) compared with control. Abbreviations: PLT = Platelets, NES = Normalized enrichment score, FDR = False discovery rate.

Background: Platelets are active players in hemostasis, coagulation and also tumorigenesis. The cross-talk between platelets and circulating tumor cells (CTCs) may have various pro-cancer effects, including promoting tumor growth, epithelial-mesenchymal transition (EMT), metastatic cell survival, adhesion, arrest and also pre-metastatic niche and metastasis formation. Interaction with CTCs might alter the platelet transcriptome. However, as CTCs are rare events, the cross-talk between CTCs and platelets is poorly understood. Here, we used our established colon CTC lines to investigate the colon CTC-platelet cross-talk in vitro and its impact on the behavior/phenotype of both cell types.

Methods: We exposed platelets isolated from healthy donors to thrombin (positive control) or to conditioned medium from three CTC lines from one patient with colon cancer and then we monitored the morphological and protein expression changes by microscopy and flow cytometry. We then analyzed the transcriptome by RNA-sequencing of platelets indirectly (presence of a Transwell insert) co-cultured with the three CTC lines. We also quantified by reverse transcription-quantitative PCR the expression of genes related to EMT and cancer development in CTCs after direct co-culture (no Transwell insert) with platelets.

Results: We observed morphological and transcriptomic changes in platelets upon exposure to CTC conditioned medium and indirect co-culture (secretome). Moreover, the expression levels of genes involved in EMT (p < 0.05) were decreased in CTCs co-cultured with platelets, but not of genes encoding mesenchymal markers (FN1 and SNAI2). The expression levels of genes involved in cancer invasiveness (MYC, VEGFB, IL33, PTGS2, and PTGER2) were increased.

Conclusion: For the first time, we studied the CTC-platelet cross-talk using our unique colon CTC lines. Incubation with CTC conditioned medium led to platelet aggregation and activation, supporting the hypothesis that their interaction may contribute to preserve CTC integrity during their journey in the bloodstream. Moreover, co-culture with platelets influenced the expression of several genes involved in invasiveness and EMT maintenance in CTCs.

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