A Novel Invadopodia-Specific Marker for Invasive and Pro-Metastatic Cancer Stem Cells

Shenq-Shyang Huang; Wen-Ying Liao; Chung-Chi Hsu; Tze-Sian Chan; Tai-Yan Liao; Pei-Ming Yang; Li-Tzong Chen; Shian-Ying Sung; Kelvin K Tsai

doi:10.3389/fonc.2021.638311

A Novel Invadopodia-Specific Marker for Invasive and Pro-Metastatic Cancer Stem Cells

Front Oncol. 2021 May 31:11:638311. doi: 10.3389/fonc.2021.638311. eCollection 2021.

Authors

Shenq-Shyang Huang^{1

2}, Wen-Ying Liao², Chung-Chi Hsu³, Tze-Sian Chan^{2

4

5}, Tai-Yan Liao², Pei-Ming Yang⁶, Li-Tzong Chen^{7

8}, Shian-Ying Sung⁹, Kelvin K Tsai^{2

4

5

7

10

11}

Affiliations

¹ Graduate Program of Biotechnology in Medicine, Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.
² Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan.
³ School of Medicine, College of Medicine, I-Shou University, Kaohsiung City, Taiwan.
⁴ Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan.
⁵ Integrated Therapy Center for Gastroenterological Cancers, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan.
⁶ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
⁷ National Institute of Cancer Research, National Health Research Institutes, Tainan City, Taiwan.
⁸ Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan.
⁹ The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei City, Taiwan.
¹⁰ Clinical Research Center, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan.
¹¹ Taipei Medical University (TMU) and Affiliated Hospitals Pancreatic Cancer Groups, Taipei Medical University, Taipei City, Taiwan.

Abstract

Introduction: Stem-like cancer cells or cancer stem cells (CSCs) may comprise a phenotypically and functionally heterogeneous subset of cells, whereas the molecular markers reflecting this CSC hierarchy remain elusive. The glycolytic enzyme alpha-enolase (ENO1) present on the surface of malignant tumor cells has been identified as a metastasis-promoting factor through its function of activating plasminogen. The expression pattern of surface ENO1 (sENO1) concerning cell-to-cell or CSC heterogeneity and its functional roles await further investigation.

Methods: The cell-to-cell expression heterogeneity of sENO1 was profiled in malignant cells from different types of cancers using flow cytometry. The subcellular localization of sENO1 and its functional roles in the invadopodia formation and cancer cell invasiveness were investigated using a series of imaging, molecular, and in vitro and in vivo functional studies.

Results: We showed here that ENO1 is specifically localized to the invadopodial surface of a significant subset (11.1%-63.9%) of CSCs in human gastric and prostate adenocarcinomas. sENO1⁺ CSCs have stronger mesenchymal properties than their sENO1^- counterparts. The subsequent functional studies confirmed the remarkable pro-invasive and pro-metastatic capacities of sENO1⁺ CSCs. Mechanistically, inhibiting the surface localization of ENO1 by downregulating caveolin-1 expression compromised invadopodia biogenesis, proteolysis, and CSC invasiveness.

Conclusions: Our study identified the specific expression of ENO1 on the invadopodial surface of a subset of highly invasive and pro-metastatic CSCs. sENO1 may provide a diagnostically and/or therapeutically exploitable target to improve the outcome of patients with aggressive and metastatic cancers.

Keywords: ENO1; cancer stem cells; gastric cancer; invadopodia; metastasis; prostate cancer.