Clinical Implications of Serum Matrix Metalloproteinase-12 and Tumor Cadherin-13 for Molecular Subtyping and Personalized Therapy in Lung Cancer

Summary

This study evaluates serum matrix metalloproteinase-12 (MMP-12) and tumor cadherin-13 (CDH13) as complementary biomarkers in lung cancer. These markers correlate with molecular subtypes, treatment response, and survival, supporting their potential use in subtyping, treatment stratification, and prognostic assessment.

Abstract

Lung cancer remains a leading cause of cancer-related mortality worldwide, largely due to its biological heterogeneity, frequent late-stage diagnosis, and limitations in comprehensive molecular testing. Single biomarkers are often insufficient for guiding clinical decision-making, highlighting the need for complementary and clinically feasible indicators that integrate systemic and tumor-specific biology. In this single-center cohort study, 262 patients with lung cancer were enrolled. Serum matrix metalloproteinase-12 (MMP-12) levels were measured using enzyme-linked immunosorbent assay (ELISA), and tumor cadherin-13 (CDH13) expression was assessed by immunohistochemistry (IHC) using a validated immunoreactive score (IRS). Molecular subtyping was obtained from routine clinical testing, and associations with treatment response and survival outcomes were evaluated using multivariable logistic and Cox regression models. MMP-12 and CDH13 showed inverse distributions across molecular subtypes (P < 0.001), such that epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)-altered tumors exhibited lower MMP-12 and higher CDH13, whereas Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant and wild-type tumors demonstrated the opposite pattern. Higher programmed death-ligand 1 (PD-L1) expression was consistently associated with increased MMP-12 and reduced CDH13 (all P < 0.05). Elevated MMP-12 was independently associated with reduced objective response rate (ORR) (adjusted odds ratio [OR] = 0.662, P < 0.001) and poorer survival (progression-free survival [PFS] hazard ratio [HR] = 1.382; overall survival [OS] HR = 1.421; both P < 0.001), while higher CDH13 predicted improved response (adjusted OR = 1.201, P < 0.001) and survival (PFS HR = 0.884; OS HR = 0.862; both P < 0.001). The combined high MMP-12/low CDH13 signature identified a subgroup with significantly worse outcomes (PFS HR = 2.281; OS HR = 2.506; P < 0.001). These findings suggest that serum MMP-12 and tumor CDH13 may serve as complementary biomarkers for molecular subtyping, therapeutic stratification, and prognostic assessment in lung cancer.

Introduction

Lung cancer remains a dominant global health burden, accounting for nearly 2.5 million new cases and about 1.8 million deaths worldwide in 2022¹. Despite substantial progress in screening, imaging, and systemic therapy, survival remains limited for many patients because lung cancer is biologically heterogeneous and often diagnosed at an advanced stage^2,3,4,5. Precision oncology has therefore become central to contemporary lung cancer care, particularly for non-small cell lung cancer (NSCLC), where actionable driver al....

Protocol

All procedures complied with institutional and national regulations and were approved by the Ethics Committee of Xingtai People’s Hospital (No. 2024-124). The requirement for written informed consent was waived because routinely collected clinical data and residual specimens were used. All data were anonymized prior to analysis.

Study design, setting, and overall schematic
This study was conducted as a single-center observational cohort designed to evaluate the clinical implications of serum MMP-12 and tumor CDH13, individually and in combination, for lung cancer molecular subtyping and personalized therapy. The....

Results

Cohort assembly and molecular subtype distribution
The overall study workflow is summarized in Figure 1. In total, 262 consecutive patients with lung cancer were included and stratified into four clinically relevant molecular subtypes: EGFR (n = 92), ALK (n = 48), KRAS (n = 54), and wild-type (n = 68). Baseline clinicopathologic features differed across subtypes (Table 1). Patients with EGFR and ALK alterations were younger on average than those in the K.......

Discussion

This study evaluates the complementary roles of serum MMP-12 and tumor CDH13 as an integrated biomarker approach to support the clinical interpretation of molecular subtypes and therapy stratification in lung cancer. The core hypothesis stems from the complementary biological roles of these two biomarkers: MMP-12, a circulating protease reflecting immune-stromal remodeling and tumor aggressiveness, and CDH13, a tissue-based tumor suppressor linked to epigenetic regulation and epithelial plasticity²⁶

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Antibody, anti-CDH13 (T-cadherin)	Abcam, Cambridge, UK	ab15126	Primary antibody for immunohistochemistry; validated for FFPE tissue
Centrifuge (high-speed refrigerated)	Eppendorf, Hamburg, Germany	5424 R	Used for serum separation and sample clarification
DAB Substrate Kit	ZSGB-Bio, Beijing, China	ZLI-9017	For chromogenic detection in immunohistochemistry
ELISA Microplate Reader	BioTek Instruments, Winooski, USA	ELx800	Used for absorbance reading at 450 nm with reference correction
Formalin (10% neutral buffered)	Sinopharm Chemical Reagent Co., Shanghai, China	10009218	For fixation of biopsy and surgical tissue specimens
Hematoxylin and Eosin Staining Kit	Solarbio, Beijing, China	G1120	For counterstaining and quality control of IHC slides
Human MMP-12 ELISA Kit	Abcam, Cambridge, UK	ab246533	Quantitative measurement of serum matrix metalloproteinase-12
Microscope (Bright-field)	Nikon, Tokyo, Japan	Eclipse E200	Used for evaluation of CDH13 immunostaining and scoring
Microtome	Leica Biosystems, Wetzlar, Germany	RM2235	For sectioning paraffin-embedded tissue at 3–4 µm thickness
Mounting Medium	Solarbio, Beijing, China	S2100	For permanent slide mounting after IHC staining
Paraffin Embedding Station	Leica Biosystems, Wetzlar, Germany	EG1150	For FFPE tissue block preparation
Phosphate Buffered Saline (PBS)	Gibco, Thermo Fisher Scientific, USA	10010023	Used for washing during IHC staining
Polymer Detection System	MXB Biotechnologies, Fuzhou, China	DAB-0031	Secondary detection kit for IHC
R Statistical Software	R Foundation for Statistical Computing, Vienna, Austria	Version 4.3.0	Used for statistical analysis and modeling
Serum Separator Tubes	BD Vacutainer, Franklin Lakes, USA	367988	For collection of peripheral venous blood
SPSS Statistics Software	IBM Corp., Armonk, USA	Version 26.0	Used for statistical analysis of continuous and categorical data
Storage Cryovials	Corning Inc., Corning, USA	430488	Low-binding cryovials for aliquoting serum samples
Water Bath (for antigen retrieval)	Grant Instruments, Cambridge, UK	JBN26	Maintains constant temperature during antigen retrieval