The CD44/COL17A1 pathway promotes the formation of multilayered, transformed epithelia

• DOI: 10.1016/j.cub.2021.04.078
• Publication Date: 2021-06-03T14:53:55Z
• Authors: Kei Kozawa; Miho Sekai; Kenji Ohba; Shoko Ito; Hiroaki Sako; Takeshi Maruyama; Mai Kakeno; Takanobu Shirai; Keisuke Kuromiya; Tomoko Kamasaki; Koki Kohashi; Shinya Tanaka; Susumu Ishikawa; Nanami Sato; Shota Asano; Hironori Suzuki; Nobuyuki Tanimura; Yohei Mukai; Noriko Gotoh; Mishie Tanino; Shinya Tanaka; Ken Natsuga; Tomoyoshi Soga; Tomonori Nakamura; Yukihiro Yabuta; Mitinori Saitou; Takahiro Ito; Kenkyo Matsuura; Makoto Tsunoda; Toyone Kikumori; Tadashi Iida; Yasuyuki Mizutani; Yuki Miyai; Kozo Kaibuchi; Atsushi Enomoto; Yasuyuki Fujita
• Keywords: Membrane Potential, Mitochondrial; 0301 basic medicine; Non-Fibrillar Collagens; Epithelium; Cell Line; Madin Darby Canine Kidney Cells; Mice; 03 medical and health sciences; Cell Transformation, Neoplastic; Dogs; Hyaluronan Receptors; Animals; Ferroptosis; Humans; Reactive Oxygen Species

At the early stage of cancer development, oncogenic mutations often cause multilayered epithelial structures. However, the underlying molecular mechanism still remains enigmatic. By performing a series of screenings targeting plasma membrane proteins, we have found that collagen XVII (COL17A1) and CD44 accumulate in RasV12-, Src-, or ErbB2-transformed epithelial cells. In addition, the expression of COL17A1 and CD44 is also regulated by cell density and upon apical cell extrusion. We further demonstrate that the expression of COL17A1 and CD44 is profoundly upregulated at the upper layers of multilayered, transformed epithelia in vitro and in vivo. The accumulated COL17A1 and CD44 suppress mitochondrial membrane potential and reactive oxygen species (ROS) production. The diminished intracellular ROS level then promotes resistance against ferroptosis-mediated cell death upon cell extrusion, thereby positively regulating the formation of multilayered structures. To further understand the functional role of COL17A1, we performed comprehensive metabolome analysis and compared intracellular metabolites between RasV12 and COL17A1-knockout RasV12 cells. The data imply that COL17A1 regulates the metabolic pathway from the GABA shunt to mitochondrial complex I through succinate, thereby suppressing the ROS production. Moreover, we demonstrate that CD44 regulates membrane accumulation of COL17A1 in multilayered structures. These results suggest that CD44 and COL17A1 are crucial regulators for the clonal expansion of transformed cells within multilayered epithelia, thus being potential targets for early diagnosis and preventive treatment for precancerous lesions.