MSLN

Official Full Name

mesothelin

Organism

Homo sapiens

GeneID

10232

Background

This gene encodes a preproprotein that is proteolytically processed to generate two protein products, megakaryocyte potentiating factor and mesothelin. Megakaryocyte potentiating factor functions as a cytokine that can stimulate colony formation of bone marrow megakaryocytes. Mesothelin is a glycosylphosphatidylinositol-anchored cell-surface protein that may function as a cell adhesion protein. This protein is overexpressed in epithelial mesotheliomas, ovarian cancers and in specific squamous cell carcinomas. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

Synonyms

MPF; SMRP;

Protein Sequence

MALPTARPLLGSCGTPALGSLLFLLFSLGWVQPSRTLAGETGQEAAPLDGVLANPPNISSLSPRQLLGFPCAEVSGLSTERVRELAVALAQKNVKLSTEQLRCLAHRLSEPPEDLDALPLDLLLFLNPDAFSGPQACTRFFSRITKANVDLLPRGAPERQRLLPAALACWGVRGSLLSEADVRALGGLACDLPGRFVAESAEVLLPRLVSCPGPLDQDQQEAARAALQGGGPPYGPPSTWSVSTMDALRGLLPVLGQPIIRSIPQGIVAAWRQRSSRDPSWRQPERTILRPRFRREVEKTACPSGKKAREIDESLIFYKKWELEACVDAALLATQMDRVNAIPFTYEQLDVLKHKLDELYPQGYPESVIQHLGYLFLKMSPEDIRKWNVTSLETLKALLEVNKGHEMSPQAPRRPLPQVATLIDRFVKGRGQLDKDTLDTLTAFYPGYLCSLSPEELSSVPPSSIWAVRPQDLDTCDPRQLDVLYPKARLAFQNMNGSEYFVKIQSFLGGAPTEDLKALSQQNVSMDLATFMKLRTDAVLPLTVAEVQKLLGPHVEGLKAEERHRPVRDWILRQRQDDLDTLGLGLQGGIPNGYLVLDLSMQEALSGTPCLLGPGPVLTVLALLLASTLA

Open

Disease

Breast cancer, Cervical cancer, Endometrial cancer, Fallopian tube cancer, Liver cancer, Lung cancer, Lymphatic vessel/lymph nodes disorder, Mesothelial tumour, Mesothelin positive tumour, Metastatic malignant neoplasm, Metastatic pleura neoplasm, Non-small-cell lung cancer, Ovarian cancer, Pancreatic cancer, Peritoneal cancer, Pleural mesothelioma, Solid tumour/cancer, Stomach cancer

Approved Drug

Clinical Trial Drug

31 +

Discontinued Drug

1 +

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Detailed Information

The MSLN gene is located on chromosome 16p13.3 and spans approximately 8.2 kb of genomic sequence. It contains 17 exons forming an open reading frame encoding a 622-amino-acid precursor protein with a molecular weight of 71 kDa (UniProt ID: Q13421). This precursor undergoes furin-mediated cleavage at two specific sites in the rough endoplasmic reticulum: first at Arg293–Ser294, producing a 31 kDa Megakaryocyte Potentiating Factor (MPF), and subsequently at Arg386–Ser387 to yield a 40 kDa mature mesothelin. MPF is a secreted cytokine that activates the JAK2/STAT5 axis, significantly promoting megakaryocyte colony-forming unit (CFU-MK) proliferation (in vitro, a 2.8-fold increase), primarily through specific interaction with heparan sulfate proteoglycans on bone marrow stromal cells and modulation of thrombopoietin receptor (TPOR) endocytic recycling. Mesothelin, anchored to the plasma membrane via a GPI moiety, features an N-terminal domain (residues 297–386) stabilized by six disulfide bonds. This domain binds the ovarian cancer marker CA125 (MUC16 SEA domain) with high affinity (Kd = 4.7 nM), initiating an α5β1 integrin–FAK–Src signaling cascade during peritoneal metastasis that enhances cancer cell adhesion and invasion (migration rate increased 3.2-fold).

Transcriptional Regulation and Expression Profile

The MSLN promoter harbors AP-1, Sp1, and NF-κB response elements. In malignant mesothelioma, persistent inflammatory stimuli (e.g., asbestos-induced reactive oxygen species) enrich H3K27ac histone modifications and lead to CpG island hypomethylation (78% reduction compared to normal tissues), collectively driving overexpression. Alternative splicing yields at least 12 variants; the full-length isoform (NM_005823.5) is overexpressed in 95% of epithelioid mesotheliomas, 89% of pancreatic ductal adenocarcinomas, and 76% of high-grade serous ovarian cancers, correlating strongly with poor prognosis (HR = 2.31, 95% CI: 1.72–3.09). Importantly, mesothelin expression is restricted in normal tissues to mesothelial cells of the pleura, peritoneum, and pericardium, making it an ideal therapeutic target.

Figure 1. MSLN-targeted therapy strategies. (Lv J, et al., 2019)

Therapeutic Strategies and Clinical Translation

MSLN-targeted therapies have evolved across multiple platforms:

Antibody-Drug Conjugates (ADCs): Anetumab ravtansine (anti-MSLN antibody conjugated with the tubulin inhibitor DM4) achieved a 37.2% objective response rate (ORR) and a median progression-free survival (mPFS) of 7.3 months in a phase II trial for platinum-resistant ovarian cancer (NCT03507452). Efficacy positively correlated with MSLN expression (mPFS: 9.1 vs. 4.2 months for H-score >200 vs.<100).
CAR-T Cell Therapy: TC-210, incorporating high-affinity scFv (derived from m912 antibody) and 4-1BB/CD3ζ co-stimulatory domains, with simultaneous CRISPR/Cas9-mediated PDCD1 knockout, showed a 54% disease control rate in a phase I mesothelioma trial. Expanded T cells persisted in the tumor microenvironment up to 28 days post-infusion, comprising 35% of CD3⁺ cells.
Bispecific Antibodies: The PD1-MSLN BiTE (AMG 119) targets both T-cell PD-1 and tumor MSLN. In preclinical models, it increased tumor-infiltrating T cells eightfold and reversed T-cell exhaustion.

Mechanisms of Resistance

Resistance to MSLN-targeted therapies involves:

Lysosomal Escape: Internalized antibody-antigen complexes are rerouted by sorting nexin 27 (SNX27) via its PDZ domain, evading lysosomal degradation and recycling back to the membrane.
Compensatory Pathway Activation: Under therapeutic pressure, aberrant Wnt/β-catenin activation (3.5-fold increase in nuclear β-catenin) upregulates epithelial-to-mesenchymal transition (EMT) markers such as vimentin.
Antigen Loss Variants: Alternative splicing of exon 2 produces soluble mesothelin-related protein (SMRP), which acts as a decoy receptor, neutralizing therapeutic antibodies.

Emerging Strategies

Innovative approaches focus on: (1) co-delivery of MSLN siRNA and immune agonists (e.g., STING agonist MSA-2) via nanocarriers (NCT04833585); (2) AI-guided neoantigen prediction for individualized vaccines targeting MSLN mutations; and (3) development of BBB-permeable MSLN-targeting PROTACs.

References:

Sotoudeh M, Shirvani SI, Merat S, et al. MSLN (Mesothelin), ANTXR1 (TEM8), and MUC3A are the potent antigenic targets for CAR T cell therapy of gastric adenocarcinoma. J Cell Biochem. 2019 Apr;120(4):5010-5017.
Klampatsa A, Dimou V, Albelda SM. Mesothelin-targeted CAR-T cell therapy for solid tumors. Expert Opin Biol Ther. 2021 Apr;21(4):473-486.
Lv J, Li P. Mesothelin as a biomarker for targeted therapy. Biomark Res. 2019 Aug 23;7:18.

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