TMPRSS4 Dynamics in Cancer Progression

TMPRSS4 is a type II transmembrane serine protease widely upregulated across multiple cancers. Through its proteolytic activity, it modulates the tumour microenvironment and activates intracellular signalling cascades that drive cancer cell invasion, proliferation, survival and angiogenesis. Enhanced TMPRSS4 expression correlates with poor prognosis in carcinomas of the lung, pancreas, breast, gastric tract, thyroid and others. Mechanistically, TMPRSS4 induces epithelial–mesenchymal transition (EMT) by up-regulating transcription factors such as Slug and Snail and engages pathways including Raf/MEK/ERK and NF-κB. Moreover, TMPRSS4 contributes to chemoresistance by promoting survival signals and inhibiting anoikis, supporting metastatic dissemination. Strategies targeting TMPRSS4, including small-molecule inhibitors and synthetic lethal approaches, have shown promise in preclinical models, highlighting the protease as a multifunctional therapeutic target with potential to improve outcomes across diverse tumour types.

Research from Nature Portfolio

• Novel serine protease inhibitors based on 2-hydroxydiarylamide derivatives have been shown to suppress TMPRSS4-mediated invasion, migration and proliferation in prostate, colon and lung cancer cell lines. Lead compounds reduced Sp1/3, AP-1 and NF-κB activity, enhanced anoikis sensitivity and diminished bcl-2 and survivin expression, while in vivo administration significantly impaired prostate and colon tumour growth in xenograft studies. • A synthetic lethal interaction between TMPRSS4 and DDR1 has been identified in non-small cell lung cancer models. Dual depletion of TMPRSS4 and DDR1 induced G₀/G₁ arrest, loss of E2F1 and cyclins A/B, increased p21 and apoptotic rates, and sensitised cells to cisplatin, culminating in tumour regression in mouse xenografts. • Foundational studies in hepatocellular carcinoma unveiled that TMPRSS4 drives EMT via Snail and Slug induction downstream of Raf/MEK/ERK1/2 signalling, suppresses the angiogenesis inhibitor RECK, and fosters tumour vascularisation, confirming its role in metastatic progression and its potential as a prognostic marker.

TMPRSS4 Dynamics in Cancer Progression publication trend

The graph below shows the total number of articles in tmprss4 dynamics in cancer progression across all publications each year (not limited to Nature Index journals).

Technical terms

Transmembrane serine protease 4 (TMPRSS4): A membrane-bound serine protease implicated in cancer cell invasion, metastasis and survival through its proteolytic and signalling activities.

Epithelial–mesenchymal transition (EMT): A cellular programme whereby epithelial cells acquire mesenchymal traits, enhancing migratory capacity and invasiveness in cancer progression.

Synthetic lethality: A genetic interaction where simultaneous impairment of two genes leads to cell death, offering a strategy to target cancer-specific vulnerabilities.

Anoikis: A form of programmed cell death triggered when anchorage-dependent cells detach from the extracellular matrix; its inhibition facilitates metastatic spread.

References

1. TMPRSS4, a type II transmembrane serine protease, as a potential therapeutic target in cancer. Experimental & Molecular Medicine (2023).
2. Anti-cancer activity of the novel 2-hydroxydiarylamide derivatives IMD-0354 and KRT1853 through suppression of cancer cell invasion, proliferation, and survival mediated by TMPRSS4. Scientific Reports (2019).
3. Identification of a novel synthetic lethal vulnerability in non-small cell lung cancer by co-targeting TMPRSS4 and DDR1. Scientific Reports (2019).
4. TMPRSS4 facilitates epithelial-mesenchymal transition of hepatocellular carcinoma and is a predictive marker for poor prognosis of patients after curative resection. Scientific Reports (2015).
5. TMPRSS4 Promotes Cell Proliferation and Inhibits Apoptosis in Pancreatic Ductal Adenocarcinoma by Activating ERK1/2 Signaling Pathway. Frontiers in Oncology (2021).
6. TMPRSS4 is a novel biomarker and correlated with immune infiltration in thyroid carcinoma. BMC Endocrine Disorders (2022).