Recently, the research group of Dr. Hua Gao and Dr. Filippo G. Giancotti discovered a new TM4SF1-involving signaling pathway of breast cancer metastasis. TM4SF1 couples with collagen receptor DDR1 (tyrosine-protein kinase activity), and then recruits Syntenin 2 and PKC, which activates downstream JAK2-STAT3 signal pathway, promoting the expression of the downstream transcription factors Sox2, Oct4, and Nanog, thus promoting the metastasis of breast cancer to lung, bone, brain and other target organs [1].
Based on this, TM4SF1 becomes a new target for studying tumor metastasis. Destroying the interaction between DDR1 and TM4SF1 with antibody drugs, or discovering JAK2 kinase inhibitors with higher safety might be the potential therapeutic pathways [1].
TM4SF1 (transmembrane-4-L-six-family member 1), also called the tumor-associated antigen L6 (TAAL6), was first found in spleen tissue of lung cancer by Hellstrom in 1986 [2] and first cloned and identified by Marken in 1992 [3]. It is a protein with four transmembrane domains belonging to the tetraspanin superfamily.
Structurally, TM4SF1 consists of four transmembrane domains (TM1-4), N-terminal and C-terminal intracellular domains, two extracellular domains: a small domain EC1 located between TM1 and TM2, and a large domain EC2 lying between TM3 and TM4 and containing a three-α-loop (A,B, and E) and a changing domain (Figure 1). In the C-terminal cytoplasmic portion of TM4SF1, there is an unconventional PDZ-domain-binding motif (X-Tyr-X-Cys) that can react with syntenin-2 and further activates syntenin-1 to participate in cancer cell proliferation and migration [4].
Figure 1. TM4SF1 structure
This picture is cited from: https://www.frontiersin.org/articles/10.3389/fmolb.2020.00202/full
TM4SF1 is located on the cell surface and can transmit extracellular signals into the cytoplasm.
TM4SF1 was found in a variety of normal human and mouse tissues, including the endothelium, skin, lung, and germ cells, at low to moderate concentrations.
TM4SF1 functions to regulate intracellular calcium levels, tyrosine phosphorylation, and protein kinase C-dependent function.
Additionally, TM4SF1 interacts with tetraspanins, integrins, receptor tyrosine kinases, PDZ-domain-containing proteins, and other proteins to form tetraspanin-rich microdomains (TEMs), which induce multiple cellular activities, including promoting cell proliferation, cell migration, cell adhesion, cell invasion, and forming vascular endothelial pseudopodia or nanopodia.
TM4SF1 promotes the migration and invasion of cancer cells by inducing epithelial-mesenchymal transformation (EMT), self-renewal ability, tumor angiogenesis, invagination, and regulating related signaling pathways (Figure 2). TM4SF1 modulates the growth, invasion, and metastasis of tumor cells and is linked to poor prognosis.
Figure 2. The proposed mechanism underlying the roles of TM4SF1 toward cancer phenotypes and progression
The is picture is cited from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9867095/
Ample studies have shown that TM4SF1 is overexpressed in many epithelial-derived malignancies, including glioma, prostate cancer, breast cancer, pancreatic cancer, bladder cancer, colon cancer, lung cancer, and stomach cancer. In addition to being highly expressed in tumor cells, TM4SF1 is also significantly highly expressed in tumor vascular endothelial cells but not in normal tissues.
The study of Sun Y. et al. showed that overexpression of TM4SF1 decreased human breast cancer cell line MDA-MB-231 cell apoptosis [5][6]. siRNA-inducing TM4SF1 silencing improved cell apoptosis and lowered the expression of phosphorylated AKT, m-TOR, and p70, indicating that TM4SF1 could regulate breast cancer invasion and migration through the PI3K/AKT/mTOR pathway.
Jia Cao et al. demonstrated that TM4SF1 silencing enhanced the sensitivity of gemcitabine in pancreatic cancer AsPC-1, MIA PaCa-2, and PANC-1 cell lines and downregulated the mRNA expression of multidurg resistance (MDR) genes in pancreatic cancer cells in vitro [7].
In lung cancer, TM4SF1 is related to cancer progression and plays an important role in tumor cell growth, maintenance of chemoresistance, and metastasis [8]. TM4SF1 regulated DDR1 expression and the Akt/ERK/mTOR pathway, thus changing cell sensitivity to chemo-reagents and contributing to invasion and metastasis. TM4SF1 silencing downregulated DDR1/AKT pathway after mTOR inhibitor treatment.
Guang Chen et al. demonstrated that TM4SF1 was a cell membrane marker of cancer stem cells (CSCs), and monoclonal antibodies targeting the functional extracellular domain of TM4SF1 suppressed CSCs [9].
Besides, TM4SF1 is internalized to the nucleus via microtubules. This abnormal expression pattern and unique internalization pathway enable TM4SF1 to be used as an antibody-drug conjugate (ADC) targets with dual mechanisms of action.
TM4SF1's ability to regulate the invasion and metastasis of malignant tumor cells and indicate poor prognosis and selective expression in cancer cells make TM4SF1 a potential target for tumor radioimmunotherapy and antibody targeting therapy.
Furthermore, Zixian Zhao et al. found that in severe COVID-19 patients, there is a remarkable expansion of TM4SF1+ lung progenitor cells [10]. The TM4SF1+ progenitor cells could play crucial roles in alveolar cell regeneration and epithelial barrier re-establishment.
CUSABIO, as a good partner of life science research, manufactures and provides TM4SF1-related products to facilitate your research in this area, including recombinant proteins and polyclonal antibodies.
References
[1] Hua Gao, Goutam Chakraborty, et al. Multi-organ Site Metastatic Reactivation Mediated by Non-canonical Discoidin Domain Receptor 1 Signaling [J]. Cell. 2016 Jun 30; 166(1): 47–62.
[2] Hellstrom I, Horn D, Linsley P, et al Monoclonal mouse antibodies raised against human lung carcinoma [J]. Cancer research. 1986, 46(8): 3917-3923.
[3] Marken, J.S., Schieven, G., et al Cloning and expression of the tumor-associated antigen L6 [J]. Proc. Natl. Acad. Sci. USA 1992, 89, 3503–3507.
[4] Borrell-Pages M, Fernandez-Larrea J, et al. The carboxy-terminal cysteine of the tetraspanin L6 antigen is required for its interaction with SITAC, a novel PDZ protein [J]. Mol Biol Cell. 2000;11:4217–25.
[5] Sun Y., Xu Y., et al. Role of TM4SF1 in regulating breast cancer cell migration and apoptosis through PI3K/AKT/mTOR pathway [J]. Int. J. Clin. Exp. Pathol. 2015;8:9081–9088.
[6] Nur Syafiqah Rahim, Yuan Seng Wu, et al. Three Members of Transmembrane-4-Superfamily, TM4SF1, TM4SF4, and TM4SF5, as Emerging Anticancer Molecular Targets against Cancer Phenotypes and Chemoresistance [J]. Pharmaceuticals (Basel). 2023 Jan; 16(1): 110.
[7] Cao J., Yang J., et al. TM4SF1 Promotes Gemcitabine Resistance of Pancreatic Cancer In Vitro and In Vivo [J]. PLoS ONE. 2015;10:e0144969.
[8] Ye L., Pu C., et al. Transmembrane-4 L-six family member-1 (TM4SF1) promotes non-small cell lung cancer proliferation, invasion and chemo-resistance through regulating the DDR1/Akt/ERK-mTOR axis [J]. Respir Res. 2019;20:106.
[9] Chen, G., She, X., Yin, Y. et al. Targeting TM4SF1 exhibits therapeutic potential via inhibition of cancer stem cells [J]. Sig Transduct Target Ther 7, 350 (2022).
[10] Zixian Zhao, Yu Zhao, et al. Single-cell analysis reveals the function of lung progenitor cells in COVID-19 patients [J]. Cell Prolif. 2020 Dec; 53(12): e12931.
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