Cancer and Metastasis Reviews (2020) 39:505–517 https://doi.org/10.1007/s10555-020-09899-2 Membrane tension buffering by caveolae: a role in cancer? Vibha Singh1 & Christophe Lamaze1 Published online: 30 May 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract Caveolae are bulb-like invaginations made up of two essential structural proteins, caveolin-1 and cavins, which are abundantly present at the plasma membrane of vertebrate cells. Since their discovery more than 60 years ago, the function of caveolae has been mired in controversy. The last decade has seen the characterization of new caveolae components and regulators together with the discovery of additional cellular functions that have shed new light on these enigmatic structures. Early on, caveolae and/ or caveolin-1 have been involved in the regulation of several parameters associated with cancer progression such as cell migration, metastasis, angiogenesis, or cell growth. These studies have revealed that caveolin-1 and more recently cavin-1 have a dual role with either a negative or a positive effect on most of these parameters. The recent discovery that caveolae can act as mechanosensors has sparked an array of new studies that have addressed the mechanobiology of caveolae in various cellular functions. This review summarizes the current knowledge on caveolae and their role in cancer development through their activity in membrane tension buffering. We propose that the role of caveolae in cancer has to be revisited through their response to the mechanical forces encountered by cancer cells during tumor mass development. Keywords Caveolae . Cancer . Mechanosensing . Mechanotransdcution . Membrane tension . EHD2 1 Introduction allowed a stream of cell biology and biochemistry experi- ments, which led to the discovery of several cellular functions The cell membrane of eukaryotic cells is compartmentalized regulated by caveolae, the role of caveolae has been constantly into microdomains with distinct functions. One such kind of mired with controversy. The last decade has seen a new un- specialized microdomains is called caveolae, and is present in derstanding of this fascinating organelle through a combina- many mammalian cell types. Structurally and biochemically tion of new techniques, tools, and in vitro reconstitutions. In caveolae differ from the other invaginations of the plasma this chapter, we will more particularly address the recently membrane (PM), as they have a characteristic bulb-like shape discovered function of caveolae in cell mechanics and how (size around ~ 70 nm) and are enriched in sphingolipids and this new aspect could be related to the long known but still cholesterol. Caveolae were first described in 1953 as non- enigmaticroleofcaveolaeincancer. clathrin-coated “plasmalemmal vesicles” [1], and subsequent- ly in 1955 as “caveola intracellularis” as they displayed a “cave-like shape” [2]. Caveolae have been reported in many different cell types, with the exception of neuronal and lym- 2 Caveolae components phoid cells, and are prominently abundant in adipocytes, en- dothelial, and muscle cells. Caveolin-1 (Cav1), the main struc- The two core families of proteins that represent the structural tural protein of caveolae, was initially characterized as a sub- components of caveolae are caveolins and cavins. Caveolin strate of the v-Src tyrosine kinase, almost 40 years after the has three isoforms. Caveolin-1 (Cav1) is a 24-kDa protein discovery of caveolae [3]. If the characterization of Cav1 identified almost 30 years ago [3, 4], expressed in most cell types, except muscle cells, and mainly localized at the plasma membrane and the trans-Golgi network [4, 5]. Caveolin-2 * Christophe Lamaze (Cav-2) is a 20-kDa protein with similarity to Cav-1 in many [email protected] aspects, but differs in its functional interaction with signaling 1 UMR3666, INSERM U1143, Membrane Mechanics and Dynamics molecules [6]. The third isoform caveolin-3 (Cav3) is restrict- of Intracellular Signaling Laboratory, Institut Curie – Centre de ed to vascular smooth muscle, skeletal muscles, and cardiac Recherche, PSL Research University, CNRS, 75005 Paris, France cells [7, 8]. All caveolin isoforms have an N-terminal caveolin 506 Cancer Metastasis Rev (2020) 39:505–517 scaffolding domain (CSD), a transmembrane domain, and a the plasma membrane where it has affinity for PS clusters [11, C-terminal domain [5]. Cav1 and Cav3, but not Cav2, are 12]. Accessory proteins such as Pacsin2 [13]andEHD2[20, indispensable for caveolae formation. 27] are recruited to the caveolin-1 complex where they con- The role and importance of the second core family of protein, tribute to caveolae morphogenesis. It was therefore unexpect- cavins, were discovered much later since the first member, cavin- ed that the expression of Cav1 alone in bacteria was sufficient 1, was identified initially as PTRF (polymerase I and transcript to drive the formation of caveolae-like structures without the release factor) in 2004 [9]. The cavin family encompasses four aid of accessory proteins [28]. members, cavin-1 (PTRF), cavin-2 or SDPR (serum deprivation The very existence of caveolae was unveiled in the fifties response protein), cavin-3 or SBRC (serum deprivation response by their typical shape in electron microscopy. Although the factor-related gene product that binds to C-kinase), and muscle- general morphology of caveolae has been known for decades, specific cavin-4 or MURC (muscle-restricted coiled coil) [10, the field has awaited the high-resolution architecture of the 11]. While each cavin isoform has a specific role in caveolae caveolae protein subunits for more than five decades, a delay function, only cavin-1 is indispensable for caveolae formation attributed to the unusual topology of Cav1 and the peculiarity [12]. In addition to caveolins and cavins, several accessory pro- of its interaction with the other caveolae constituents. The teins have been reported to modulate various aspects of caveolae study of the ultrastructure of caveolae by high-resolution scan- biogenesis, stability, and function, by mechanisms that are often ning and frozen deep-etch transmission electron microscopy, not fully characterized. Pacsin2/Syndapin2 belongs to the F- first revealed the presence of organized striations or spike-like BAR domain containing protein family which is instrumental structures on the inner surface of the caveolar bulb [29, 30]. to membrane curvature. Pacsin2 appears to control caveolae mor- Caveolae were defined as uncoated invaginations to distin- phogenesis and mobility in concert with the membrane scission guish them from the well-studied and better described GTPase dynamin 2 [13, 14]. EHD2 is a dynamin-like ATPase clathrin-coated pits [31]. Recent ultrastructural studies on that oligomerizes in a ring-like structure at the neck of caveolae cavin-1 have however refuted this long believed postulate. [15]. EHD2 stabilizes caveolae at the plasma membrane and Thus, the crystal structure of cavin-1 revealed that cavin-1 regulates their dynamics [16] through association with the actin oligomers are assembled as trimeric coiled coil structures that cytoskeleton [16–20]. Whereas the three other members of the organize a striated coat made up of cavin polymers [11, 32]. family do not normally localize to caveolae, in the absence of Recently, a model using cryoEM and 3D electron tomography EHD1, EHD2 and EHD4 can be recruited to the neck of caveo- was proposed, where cavin1 HR1 domain results in trimeric lae under repeated mechanical stress, revealing a certain redun- coiled coil structures, which eventually forms cavin oligo- dancy within the family [16]. It is noteworthy that accessory mers. This has become highly appreciated model in recent proteins only partly colocalize with caveolae suggesting a tran- time, where cavin-1 trimers decorate the membrane surface, sient association or the existence of caveolae subpopulations. and cavin-caveolin-lipid interaction stimulates invagination to Lipids represent another class of important players involved in provide the peculiar caveola shape [27]. As crystallization different aspects of caveolae biology. Early on, it has been re- methods are continually improving, crystal structure of ported that membrane lipids such as phosphatidylserine [21], caveolin-1 (alone or in complex with associated lipids and/or glycosphingolipids [21], and cholesterol [22] are required for proteins) will definitely enhance our understanding of caveola caveolae formation, dynamics, and integrity. Caveolin-1 local- formation and function to a much greater depth. izes in the inner leaflet of plasma membrane where it interacts with cholesterol through its CSD, and this interaction brings about the unique shape of caveolae [23]. Caveolae are also a 3 Caveolae functions hub for important signaling lipids such as ceramide, phosphatidic acid, and glycosphingolipids [21, 24, 25]. Over the years, many functions have been attributed to cave- If caveolin-1 and cavin-1 are established as the minimal olae and/or caveolin-1 ranging from plasma membrane orga- structural proteins required for the formation of the caveolar nizers [33], lipid trafficking [34], endocytosis [35], signaling invagination, the coordination of their likely complex step- [36], and more recently mechanosensors [37, 38]. Some of wise assembly is far from being fully understood. Caveolin- these functions have been recently revisited and the consensus 1 is synthesized in the endoplasmic reticulum