Tawil Nadim, Mohammadnia Abdulshakour, Rak Janusz
Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
Neuroimmunology Unit, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Rue University, Montreal, QC, Canada.
Front Med (Lausanne). 2023 Dec 20;10:1252417. doi: 10.3389/fmed.2023.1252417. eCollection 2023.
Single cell analysis of cancer cell transcriptome may shed a completely new light on cancer-associated thrombosis (CAT). CAT causes morbid, and sometimes lethal complications in certain human cancers known to be associated with high risk of venous thromboembolism (VTE), pulmonary embolism (PE) or arterial thromboembolism (ATE), all of which worsen patients' prognosis. How active cancers drive these processes has long evaded scrutiny. While "unspecific" microenvironmental effects and consequences of patient care (e.g., chemotherapy) have been implicated in pathogenesis of CAT, it has also been suggested that oncogenic pathways driven by either genetic (mutations), or epigenetic (methylation) events may influence the coagulant phenotype of cancer cells and stroma, and thereby modulate the VTE/PE risk. Consequently, the spectrum of driver events and their downstream effector mechanisms may, to some extent, explain the heterogeneity of CAT manifestations between cancer types, molecular subtypes, and individual cases, with thrombosis-promoting, or -protective mutations. Understanding this molecular causation is important if rationally designed countermeasures were to be deployed to mitigate the clinical impact of CAT in individual cancer patients. In this regard, multi-omic analysis of human cancers, especially at a single cell level, has brought a new meaning to concepts of cellular heterogeneity, plasticity, and multicellular complexity of the tumour microenvironment, with profound and still relatively unexplored implications for the pathogenesis of CAT. Indeed, cancers may contain molecularly distinct cellular subpopulations, or dynamic epigenetic states associated with different profiles of coagulant activity. In this article we discuss some of the relevant lessons from the single cell "omics" and how they could unlock new potential mechanisms through which cancer driving oncogenic lesions may modulate CAT, with possible consequences for patient stratification, care, and outcomes.
癌细胞转录组的单细胞分析可能会为癌症相关血栓形成（CAT）带来全新的认识。CAT在某些已知与静脉血栓栓塞（VTE）、肺栓塞（PE）或动脉血栓栓塞（ATE）高风险相关的人类癌症中会导致病态，有时甚至是致命的并发症，所有这些都会恶化患者的预后。活跃的癌症如何驱动这些过程长期以来一直未受到仔细研究。虽然“非特异性”微环境效应和患者护理（如化疗）的后果已被认为与CAT的发病机制有关，但也有人提出，由遗传（突变）或表观遗传（甲基化）事件驱动的致癌途径可能会影响癌细胞和基质的凝血表型，从而调节VTE/PE风险。因此，驱动事件及其下游效应机制的范围在一定程度上可以解释不同癌症类型、分子亚型和个体病例之间CAT表现的异质性，以及促血栓形成或抗血栓形成的突变。如果要部署合理设计的对策来减轻CAT对个体癌症患者的临床影响，了解这种分子因果关系很重要。在这方面，对人类癌症的多组学分析，尤其是在单细胞水平上的分析，为肿瘤微环境的细胞异质性、可塑性和多细胞复杂性概念赋予了新的意义，对CAT的发病机制具有深远且仍相对未被探索的影响。事实上，癌症可能包含分子上不同的细胞亚群，或与不同凝血活性谱相关的动态表观遗传状态。在本文中，我们讨论了单细胞“组学”的一些相关经验教训，以及它们如何揭示癌症驱动的致癌病变可能调节CAT的新潜在机制，这可能对患者分层、护理和预后产生影响。
