Mechanobiology of Autophagy: The Unexplored Side of Cancer

Abstract

Proper execution of cellular function, maintenance of cellular homeostasis and cell survival depend on functional integration of cellular processes and correct orchestration of cellular responses to stresses. Cancer transformation is a common negative consequence of mismanagement of coordinated response by the cell. In this scenario, by maintaining the balance among synthesis, degradation, and recycling of cytosolic components including proteins, lipids, and organelles the process of autophagy plays a central role. Several environmental stresses activate autophagy, among those hypoxia, DNA damage, inflammation, and metabolic challenges such as starvation. In addition to these chemical challenges, there is a requirement for cells to cope with mechanical stresses stemming from their microenvironment. Cells accomplish this task by activating an intrinsic mechanical response mediated by cytoskeleton active processes and through mechanosensitive protein complexes which interface the cells with their mechano-environment. Despite autophagy and cell mechanics being known to play crucial transforming roles during oncogenesis and malignant progression their interplay is largely overlooked. In this review, we highlight the role of physical forces in autophagy regulation and their potential implications in both physiological as well as pathological conditions. By taking a mechanical perspective, we wish to stimulate novel questions to further the investigation of the mechanical requirements of autophagy and appreciate the extent to which mechanical signals affect this process.

Keywords: autophagosome; biomembranes; cytoskeleton; mechanosensing; mechanotransduction.

Figure 1

Mechanics of the autophagic process. From a mechanical point of view, the autophagic process can be divided into seven main stages: initiation, nucleation, elongation, closure, autophagosome maturation, autolysosome formation, and finally, cargo degradation and recycling. Cytoskeletal active processes and membrane organization during the sequential steps of autophagy are highlighted. See the main text for details.

Figure 2

Schematic representation of signaling circuits for ULK1 complex activation in autophagy initiation. Initiation of autophagy via ULK1 signaling entails mTORC1 dissociation from ULK1, which becomes active and binds to ATG13 and FIP200 to form ULK1 complex. This dissociation and the following signaling cascade can be elicited by chemical stimuli, via e.g. enhancing the activity of AMPK and/or by mechanical stimuli. This second pathway is achieved via inhibition of mTORC1 by the mechanosensitive mTORC2, which responds to various mechanical stimuli. For instance, mTORC2 can be directly activated by the soluble form of focal adhesion kinase (FAK) that is releases from focal adhesion at low traction forces (e.g. detachment of the cells from the substrate).

Figure 3

Schematic representation of cell mechanics and its interplay with autophagy. Cells subjected to a great variety of mechanical forces (red arrows) from the environment that generate cell-autonomous forces mediated by the cytoskeleton. (A) There are two main different categories of forces sensed by the cells: short scale (blue boxes) and large scale (red boxes). Short and long-scale forces are perceived by the cells via various mechanosensors, including interfacial protein complexes (integrin- and cadherin-mediated adhesions), mechanosensitive ion channels (TRP, piezo), tension and curvature sensors at the plasma membrane and actin cortex (BAR proteins, filamin), and the primary cilium. (B) Mechanical inputs are transduced to biochemical signals (mechanotransducers), such as Ca²⁺, transcription factors (YAP/TAZ) and signaling proteins (phosphatases and kinases) that affect the cytoskeleton, gene regulation, and other cellular functions. Autophagy is directly (cellular signaling mediated) and indirectly (cooperative action with the cytoskeleton) activated by mechanical processes. While likely to exist, negative feedbacks (inhibitions and competition for cytoskeletal elements) are still underexplored in the literature. Autophagy regulates various mechanical processes via ensuring recycling of cellular components and providing energy during catabolism.

Figure 4

Autophagy and mechanics during cancer transformation. The role of autophagy in preserving cell homeostasis and protecting cells from mechanical environmental stress is represented and described in the left panel (dotted line separates the normal and cancer context). Cancer cells exploit autophagy to adapt to the tumor microenvironment and promote malignant progression. Right panel illustrate the mechanical components of the tumor microenvironment.