Distant organ metastasis, often termed as organotropic metastasis or metastatic organotropism, is a fundamental feature of malignant tumours and accounts for most cancer-related mortalities. This process is orchestrated by many complex biological interactions and processes that are mediated by a combination of anatomical, genetic, pathophysiological and biochemical factors. Recently, extracellular vesicles (EVs) are increasingly being demonstrated as critical mediators of bi-directional tumour-host cell interactions, controlling organ-specific infiltration, adaptation and colonization at the secondary site. EVs govern organotropic metastasis by modulating the pre-metastatic microenvironment through upregulation of pro-inflammatory gene expression and immunosuppressive cytokine secretion, induction of phenotypespecific differentiation and recruitment of specific stromal cell types. This review discusses EV-mediated metastatic organotropism in visceral (brain, lung, liver, and lymph node) and skeletal (bone) metastasis, and discusses how the pre-metastatic education by EVs transforms the organ into a hospitable, tumour cell-friendly milieu that supports the growth of metastatic cells. Decoding the organ-specific traits of EVs and their functions in organotropic metastasis is essential in accelerating the clinical application of EVs in cancer management. K E Y WO R D SCancer, extracellular vesicles, intercellular communication, metastasis, organotropism  INTRODUCTIONMetastasis to distant organs is a fundamental feature of malignant neoplasms and is its most lethal attribute that accounts for > 90% of mortality from cancer. The conceptual framework of tumour progression towards metastasis has been welldescribed and simplified into a stepwise sequence of cell-biological events, which are collectively termed the invasion-metastasis cascade (Valastyan & Weinberg, 2011). Cumulative evidence has shown that each type of cancer exhibits striking disparities in the temporal course (relapse within a range of organs) of metastasis, kinetics (time to relapse/recur) of metastatic progression and the severity of metastasis in vital target organs (Nguyen et al., 2009). While genetics can determine the metastatic traits of each cancer type, these traits can be acquired by disseminated tumour cells (DTCs; tumour cells with a metastatic propensity residing in the permissive target tissues of distant organs) through organ-selective evolution or adaptation of metastatic cell populations (Nguyen et al., 2009). A large body of evidence has underscored the significance of host tissue characteristics such as theThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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The ever-growing perception of cancer stem cells (CSCs) as a plastic state rather than a hardwired defined entity has evolved our understanding of the functional and biological plasticity of these elusive components in malignancies. Pancreatic cancer (PC), based on its biological features and clinical evolution, is a prototypical example of a CSC-driven disease. Since the discovery of pancreatic CSCs (PCSCs) in 2007, evidence has unraveled their control over many facets of the natural history of PC, including primary tumor growth, metastatic progression, disease recurrence, and acquired drug resistance. Consequently, the current near-ubiquitous treatment regimens for PC using aggressive cytotoxic agents, aimed at ‘‘tumor debulking’’ rather than eradication of CSCs, have proven ineffective in providing clinically convincing improvements in patients with this dreadful disease. Herein, we review the key hallmarks as well as the intrinsic and extrinsic resistance mechanisms of CSCs that mediate treatment failure in PC and enlist the potential CSC-targeting ‘natural agents’ that are gaining popularity in recent years. A better understanding of the molecular and functional landscape of PCSC-intrinsic evasion of chemotherapeutic drugs offers a facile opportunity for treating PC, an intractable cancer with a grim prognosis and in dire need of effective therapeutic advances.

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