Volume 4,Issue 3
Research Progress of TMEM2 in Extracellular Matrix Remodeling and Tumor Microenvironment Regulation
Remodeling of the extracellular matrix (ECM) and regulation of the tumor microenvironment (TME) are essential processes in tumorigenesis and tumor progression. Transmembrane protein 2 (TMEM2), a recently identified cell surface hyaluronidase, participates in various physiological and pathological processes by degrading hyaluronan (HA) in the ECM. This review summarizes the molecular structure and enzymatic properties of TMEM2, the current evidence and controversy regarding its intrinsic catalytic activity, and the mechanisms by which TMEM2 mediates ECM remodeling. Emphasis is placed on recent advances in TMEM2 research in a variety of solid tumors, including its roles in tumor cell proliferation and migration, epithelial-mesenchymal transition, chemoresistance, and regulation of the tumor microenvironment through HA metabolism. Current evidence is mainly derived from bioinformatics analyses, cell-based experiments, and limited animal studies, and further prospective validation is still needed. The potential of TMEM2 as a prognostic biomarker and therapeutic target is also discussed, together with current limitations and future directions, with the goal of providing a reference for basic research and clinical translation in this field.
[1] Toole BP, 2004, Hyaluronan: From Extracellular Glue to Pericellular Cue. Nature Reviews Cancer, 4(7): 528–539.
[2] Whatcott CJ, Han H, Posner RG, et al., 2011, Targeting the Tumor Microenvironment in Cancer: Why Hyaluronidase Deserves a Second Look. Cancer Discovery, 1(4): 291–296.
[3] Tammi RH, Kultti A, Kosma VM, et al., 2008, Hyaluronan in Human Tumors: Pathobiological and Prognostic Messages from Cell-Associated and Stromal Hyaluronan. Seminars in Cancer Biology, 18(4): 288–295.
[4] Chanmee T, Ontong P, Itano N, 2016, Hyaluronan: A Modulator of the Tumor Microenvironment. Cancer Letters, 375(1): 20–30.
[5] Provenzano PP, Cuevas C, Chang AE, et al., 2012, Enzymatic Targeting of the Stroma Ablates Physical Barriers to Treatment of Pancreatic Ductal Adenocarcinoma. Cancer Cell, 21(3): 418–429.
[6] Provenzano PP, Hingorani SR, 2013, Hyaluronan, Fluid Pressure, and Stromal Resistance in Pancreas Cancer. British Journal of Cancer, 108(1): 1–8.
[7] Stern R, 2008, Hyaluronidases in Cancer Biology. Seminars in Cancer Biology, 18(4): 275–280.
[8] Yamamoto H, Tobisawa Y, Inubushi T, et al., 2017, A Mammalian Homolog of the Zebrafish Transmembrane Protein 2 (TMEM2) Is the Long-Sought-After Cell-Surface Hyaluronidase. Journal of Biological Chemistry, 292(18): 7304–7313.
[9] Yamaguchi Y, 2025, TMEM2: A New Dimension in Hyaluronan Biology. Proteoglycan Research, 3(2): e70019.
[10] Yoshida H, Inoue S, Okada Y, 2025, New Molecules Indispensable for Hyaluronan Degradation, HYBID (CEMIP/KIAA1199) and TMEM2 (CEMIP2): Differential Roles in Physiological and Pathological Non-Neoplastic Conditions. Proceedings of the Japan Academy, Series B, 101(6): 317–338.
[11] Lee H, Goodarzi H, Tavazoie SF, et al., 2016, TMEM2 Is a SOX4-Regulated Gene That Mediates Metastatic Migration and Invasion in Breast Cancer. Cancer Research, 76(17): 4994–5005.
[12] Kudo Y, Sato N, Adachi Y, et al., 2020, Overexpression of Transmembrane Protein 2 (TMEM2), a Novel Hyaluronidase, Predicts Poor Prognosis in Pancreatic Ductal Adenocarcinoma. Pancreatology, 20(7): 1479–1485.
[13] Gao L, Tong S, Liu J, et al., 2023, TMEM2 Induces Epithelial-Mesenchymal Transition and Promotes Resistance to Temozolomide in GBM Cells. Heliyon, 9(6): e16559.
[14] Gan L, Yang H, Xiong Z, et al., 2020, miR-518a-3p Suppresses Triple-Negative Breast Cancer Invasion and Migration Through Regulation of TMEM2. Technology in Cancer Research & Treatment, 19: 1533033820977523.
[15] Yamaguchi Y, Yamamoto H, Tobisawa Y, et al., 2019, TMEM2: A Missing Link in Hyaluronan Catabolism Identified? Matrix Biology, 78–79: 139–146.
[16] Sato S, Miyazaki M, Fukuda S, et al., 2023, Human TMEM2 Is Not a Catalytic Hyaluronidase, but a Regulator of Hyaluronan Metabolism via HYBID (KIAA1199/CEMIP) and HAS2 Expression. Journal of Biological Chemistry, 299(6): 104826.
[17] Narita T, Tobisawa Y, Bobkov A, et al., 2023, TMEM2 Is a Bona Fide Hyaluronidase Possessing Intrinsic Catalytic Activity. Journal of Biological Chemistry, 299(9): 105120.
[18] Sato S, Mizutani Y, Abe M, et al., 2024, Naked Mole-Rat TMEM2 Lacks Physiological Hyaluronan-Degrading Activity and Resembles Human TMEM2 More Closely Than Active Mouse TMEM2. Archives of Biochemistry and Biophysics, 758: 110098.
[19] Tobisawa Y, Fujita N, Yamamoto H, et al., 2021, The Cell Surface Hyaluronidase TMEM2 Is Essential for Systemic Hyaluronan Catabolism and Turnover. Journal of Biological Chemistry, 297(5): 101281.
[20] Bourguignon V, Flamion B, 2016, Respective Roles of Hyaluronidases 1 and 2 in Endogenous Hyaluronan Turnover. The FASEB Journal, 30(6): 2108–2114.
[21] Chowdhury B, Hemming R, Hombach-Klonisch S, et al., 2013, Murine Hyaluronidase 2 Deficiency Results in Extracellular Hyaluronan Accumulation and Severe Cardiopulmonary Dysfunction. Journal of Biological Chemistry, 288(1): 520–528.
[22] Schinzel RT, Higuchi-Sanabria R, Shalem O, et al., 2019, The Hyaluronidase, TMEM2, Promotes ER Homeostasis and Longevity Independent of the UPR(ER). Cell, 179(6): 1306–1318.e18.
[23] Zhang H, Tsui CK, Garcia G, et al., 2024, The Extracellular Matrix Integrates Mitochondrial Homeostasis. Cell, 187(16): 4289–4304.e26.
[24] Irie F, Tobisawa Y, Murao A, et al., 2021, The Cell Surface Hyaluronidase TMEM2 Regulates Cell Adhesion and Migration via Degradation of Hyaluronan at Focal Adhesion Sites. Journal of Biological Chemistry, 296: 100481.
[25] Evanko SP, Tammi MI, Tammi RH, et al., 2007, Hyaluronan-Dependent Pericellular Matrix. Advanced Drug Delivery Reviews, 59(13): 1351–1365.
[26] Yao N, Fu Y, Wang T, et al., 2025, CEMIP2 Sensitizes PDAC to Chemotherapy Through Extracellular Matrix Remodeling by Hyaluronan Degradation. Cancer Letters, 630: 217898.
[27] Nieto MA, Huang RY, Jackson RA, et al., 2016, EMT: 2016. Cell, 166(1): 21–45.
[28] Hanahan D, Weinberg RA, 2011, Hallmarks of Cancer: The Next Generation. Cell, 144(5): 646–674.
[29] Misra S, Hascall VC, Markwald RR, et al., 2015, Interactions Between Hyaluronan and Its Receptors (CD44, RHAMM) Regulate the Activities of Inflammation and Cancer. Frontiers in Immunology, 6: 201.
[30] Srivastava P, Yadav VK, Chang TH, et al., 2024, In-Silico Analysis of TMEM2 as a Pancreatic Adenocarcinoma and Cancer-Associated Fibroblast Biomarker, and Functional Characterization of NSC777201, for Targeted Drug Development. American Journal of Cancer Research, 14(6): 3010–3035.
[31] Jacobetz MA, Chan DS, Neesse A, et al., 2013, Hyaluronan Impairs Vascular Function and Drug Delivery in a Mouse Model of Pancreatic Cancer. Gut, 62(1): 112–120.
[32] Kudo Y, Sato N, Oba T, et al., 2022, Concurrent Overexpression of Two Hyaluronidases, KIAA1199 and TMEM2, Strongly Predicts Shorter Survival After Resection in Pancreatic Ductal Adenocarcinoma. Pancreas, 51(7): 800–807.
[33] Jiang Q, Wang X, Yang Q, et al., 2021, TMEM2 Combined with IDH and 1p19q in Refining Molecular Subtypes for Predicting Survival of Patients with Glioma. DNA and Cell Biology, 40(11): 1381–1395.
[34] Xiang Y, Li C, Liao Y, et al., 2019, An Integrated mRNA-lncRNA Signature for Relapse Prediction in Laryngeal Cancer. Journal of Cellular Biochemistry, 120(9): 15883–15890.
[35] Inubushi T, Nakanishi Y, Abe M, et al., 2022, The Cell Surface Hyaluronidase TMEM2 Plays an Essential Role in Mouse Neural Crest Cell Development and Survival. PLoS Genetics, 18(7): e1009765.
[36] Niu M, McGrath M, Sammon D, et al., 2023, Structure of the Transmembrane Protein 2 (TMEM2) Ectodomain and Its Apparent Lack of Hyaluronidase Activity. Wellcome Open Research, 8: 76.
