Caveolin-1 mediates the utilization of extracellular proteins for survival in refractory gastric cancer

Sep 24, 2026

Uploaded by Mary Man

Gastric cancer shows extensive intertumoral heterogeneity and diverse lineages, producing inconsistent responses to anticancer therapy and leaving stem-like subtype patients with the worst chemoresistance and prognosis. This work defines a malignant SEM type integrating stem-like, genome stable, EMT, and mesenchymal features, and examines endocytosis-lysosome pathways. Caveolin-1 (CAV1) is specifically expressed in SEM-type tumors, drives endocytosis-dependent survival, and supports chloroquine (CQ) sensitivity. Results from patient-derived organoids and mouse models highlight CQ as a therapeutic alternative for refractory gastric cancer.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

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Introduction

Materials and methods

[www.nature.com/emm](www.nature.com/emm) ARTICLE OPEN Caveolin-1 mediates the utilization of extracellular proteins for survival in refractory gastric cancer Nahee Hwang1,2,3,8, Bo Kyung Yoon1,3,8, Kyu-Hye Chun1,2,3, Hyeonhui Kim2,4, Yoseob Lee1,2,3, Jae-Won Kim1,2,3, Hyeonuk Jeon1,2,3, Tae-Hyun Kim 1,3, Mi-Young Kim 1,3, Sungsoon Fang 2,3,4 ✉, Jae-Ho Cheong 2,3,5,6,7 ✉ and Jae-woo Kim1,3 ✉ © The Author(s) 2023 INTRODUCTION Gastric cancer (GC) exhibits high degrees of intertumoral heterogeneity and lineage diversity, resulting in inconsistent responses to anticancer treatments1. Therefore, classifying GC subtypes based on their molecular characteristics is necessary to enable individualized treatments. In a previous study, we classiﬁed GC into ﬁve subtypes (gastric, mixed, inﬂammatory, intestinal, and stem-like) based on transcriptomic proﬁles from a large pool of patients. Among these subtypes, the stem-like subtype exhibits the highest chemoresistance, leading to the worst prognosis1. Although chemoresistance is well known, there are no alternative treatment options available for stem-like subtype GC patients. Therefore, we focused on providing therapeutic alternatives for these patients. Additionally, we found that the stem-like subtype has genetic similarities to the most malignant types identiﬁed in other GC cohorts1: genome stable (GS) type of The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD), epithelial–mesenchymal transition (EMT) type of Asian Cancer Research Group (ACRG), and mesenchymal type classiﬁed by Lei et al. 2. In this study, we integrated these malignant GC types with similar characteristics by designating them as the SEM (stem-like, GS, EMT, and mesenchymal) type. Endocytosis is the process of internalization of the plasma membrane and its components into cells3. Once inside the cell, these components undergo degradation via the lysosomedependent pathway. Lysosomes contain various hydrolytic enzymes that break down biological compounds, such as proteins, lipids, and nucleic acids, to produce energy and support anabolic processes3–5. Because tumor cells are exposed to a metabolically stressful environment in vivo, targeting the endocytosis-lysosomemediated pathway is considered a new therapeutic approach6–10. Additionally, endocytosis can be broadly classiﬁed into four categories: phagocytosis, macropinocytosis, clathrin-mediated endocytosis, and caveolae-mediated endocytosis, based on their distinct shape, size, and constituent proteins. Among these categories, caveolae-mediated endocytosis is associated with the internalization of albumin and is mainly regulated by the protein caveolin-1 (CAV1)3, 11, 12. The role of CAV1 in cancer cells is still controversial13–19. Although CAV1 has been known to be upregulated in cancer cells20,21, there are reports that CAV1 is downregulated in lung, breast, colon, and ovarian cancer22,23. In breast cancer, CAV1 has been shown to inhibit the growth and metastasis of cancer cells and suppress the self-renewal capacity of cancer stem cells19,24. However, in colon cancer, the re-expression of CAV1 blocked tumor formation. This highlights the need to clarify the function of CAV1 in chemorefractory GC. In this study, we revealed that CAV1 is speciﬁcally expressed in the most malignant SEM-type GC, and CAV1-driven endocytosis is a critical survival mechanism of malignant GC. Considering endocytosis as a potential “Achilles’ heel” of GC cells, we applied chloroquine (CQ), an antimalarial drug with the 1Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea. 2Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea. 3Chronic Intractable Disease for Systems Medicine Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea. 4Severance Biomedical Science Institute, Gangnam Severance Hospital, Yonsei Uni

FAQs

Why are tailored treatments needed for gastric cancer subtypes?

Gastric cancer exhibits high intertumoral heterogeneity and lineage diversity, causing inconsistent responses to anticancer treatments. Molecular subtype classification enables more individualized therapy.

What is the SEM type and why was it defined?

The study integrates malignant gastric cancer types with similar properties—stem-like, genome stable, EMT, and mesenchymal—designating them as SEM type to represent the most malignant group.

How does caveolin-1 contribute to survival in refractory gastric cancer?

Caveolin-1 is specifically expressed in SEM-type gastric cancer and CAV1-driven endocytosis is identified as a critical survival mechanism in chemorefractory disease.

Sep 24, 2026

Uploaded by Mary Man