Effect of microtubule-targeting drugs on cell–cell and cell–matrix junctions in tumor epithelial cells- Introduction

A Special Author Introduction
Anti-Cancer Drugs

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By Gianfranco Bazzoni

 In recent years, drug discovery aims at developing highly selective compounds. The rationale is that a target-selective drug should invariably inhibit a given function, thus increasing the effectiveness (while decreasing the side effects) of the novel drugs. However, even the best tactics have limitations. One of the shortcomings of the ‘one drug-one target-one response' strategy is the assumption that signaling events consist of linear chains of reactions, which link orderly an input with an output (e.g., growth factor stimulation and cell proliferation), via a series of intra-cellular mediators.

In practice, however, identifying such drug-target-response connections is a difficult task. First, our knowledge of the signaling pathways is limited. We still ignore the complete list of molecules involved and the exact mechanisms, whereby signals are translated from biochemical inputs into functional outputs. Second, as the ‘Network Biology' teaches us, even a single molecular perturbation often activates more (and highly inter-connected) pathways. Third, the same signal induces different responses in different contexts. Thus, the outcome of a pharmacological intervention (no matter how selectively targeted) is generally difficult to predict.

A relatively simple way of dealing with such biological complexity consists of studying drugs in a reasonably broader context. For instance, a multi-parametric in vitro approach should evaluate more functions in different contexts and dynamics. In our recent study, we investigated the effect of the microtubule-targeting drugs Vincristine and Docetaxel on the adhesive junctions of tumor epithelial cells. We focused on microtubules and junctions, because these structures regulate cell motility, which may contribute to the local invasiveness and metastatic spread of tumor cells.

Specifically, we measured different functional outcomes in different contexts (e.g., confluent versus sub-confluent cells) and dynamics (e.g., junction opening versus resealing). Even though we examined a limited number of drug-context-outcome combinations, the approach unveiled interesting combinations (e.g., sensitivity of the junctions to microtubule disassembly in sub-confluent cells) and an unanticipated robustness of cell adhesion even in the face of a strong pharmacological perturbation of the microtubules. We believe that these data and considerations draw attention to the need for system-level evaluations of cell contexts and dynamics, when studying drugs even in apparently simple in vitro assays.

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