Aberrant activation of fatty acid synthesis suppresses primary cilium formation and distorts tissue development.
Aberrant activation of fatty acid synthesis is a key feature of many advanced human cancers. Unlike in classical lipogenic tissues, this process has been implicated in membrane production required for rapid cell proliferation. Here, to gain further insight into the consequences of tumor-associated fatty acid synthesis, we have mimicked the lipogenic phenotype of cancer cells in Xenopus embryos by microinjection of RNA encoding the lipogenic transcription factor sterol regulatory element binding protein 1c (SREBP1c). Dramatic morphologic changes were observed that could be linked to alterations in Wnt and Hedgehog signaling, and ultimately to a distortion of the primary cilium. This is a sophisticated microtubular sensory organelle that is expressed on the surface of nearly every cell type and that is lost in many cancers. SREBP1c-induced loss of the primary cilium could be confirmed in mammalian Madin-Darby canine kidney (MDCK) cells and was mediated by changes in the supply of fatty acids. Conversely, inhibition of fatty acid synthesis in highly lipogenic human prostate cancer cells restored the formation of the primary cilium. Lipid-induced ciliary loss was associated with mislocalization of apical proteins, distortion of cell polarization, and aberrant epithelial tissue development as revealed in three-dimensional cultures of MDCK cells and in the developing mouse prostate. These data imply that tumor-associated lipogenesis, in addition to rendering cells more autonomous in terms of lipid supply, disturbs cilium formation and contributes to impaired environmental sensing, aberrant signaling, and distortion of polarized tissue architecture, which are all hallmarks of cancer.
Willemarck
Nicolas
N
Laboratory for Experimental Medicine and Endocrinology, Department of Experimental Medicine, Molecular Small Animal Imaging Centre, K.U. Leuven, Leuven, Belgium.
Rysman
Evelien
E
Brusselmans
Koen
K
Van Imschoot
Griet
G
Vanderhoydonc
Frank
F
Moerloose
Katrien
K
Lerut
Evelyne
E
Verhoeven
Guido
G
van Roy
Frans
F
Vleminckx
Kris
K
Swinnen
Johannes V
JV
D000818:Animals; D018929:Cell Culture Techniques; D002460:Cell Line; D045744:Cell Line, Tumor; D002923:Cilia / Q000235:genetics / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000378:metabolism*; D005227:Fatty Acids / Q000096:biosynthesis*; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050155:Lipogenesis / Q000235:genetics; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008845:Microinjections; D018613:Microscopy, Confocal; D008855:Microscopy, Electron, Scanning; D011467:Prostate / Q000254:growth & development / Q000378:metabolism; D012313:RNA / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D014981:Xenopus; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism
D005227:Fatty Acids; D053823:Hedgehog Proteins; D051780:Sterol Regulatory Element Binding Protein 1; D051153:Wnt Proteins; D029867:Xenopus Proteins; D012313:RNA