Brain metastasis is the most common type of brain cancer and metastasis accounts for 90% of cancer deaths. Lung cancer is the most common primary tumor to generate metastasis in the brain. Cancer stem cells have been characterized as a key target for metastasis therapy, being able to acquire invading properties, migrate to other tissues and proliferate. Our laboratory developed an antitumoral peptide based on Cx43 sequence, TAT-Cx43266-283
, which inhibits the oncoprotein Src activity, reducing proliferation, migration and invasion properties and improving survival in glioblastoma models. Given the relevance of Src for lung cancer brain metastasis, we analyzed the potential of TAT-Cx43266-283
as a treatment for this disease.
In vitro models showed how TAT-Cx43266-283
impaired migration and invasion, and reduced cell viability of human and mouse lung cancer cell lines. Using a murine in vivo model of lung cancer brain metastasis based on the intracranial implantation of mouse lung cancer cells, we showed that TAT-Cx43266-283
improved mouse survival. To identify the molecular mechanism of TATCx43266-283
effect in these models, we relied on phosphoproteomics. With this approach, we unveiled ERK as a key mediator of TAT-Cx43266-283
effect in lung cancer brain metastasis, which included changes in cytoskeleton and vascularization. We also studied the effect of TATCx43266-283
in combination with inhibitors of MEK1/2, PKC, GSK-3ß and CaMKII showing promising results.
Overall, the results presented in this work support further research to advance in the proposal of TAT-Cx43266-283
as a candidate for brain metastasis treatment, alone or in combination with other therapies.
Publicaciones Relacionadas:
-Gangoso E, Thirant C, Chneiweiss H, Medina JM, Tabernero A. A cellpenetrating peptide based on the interaction between c-Src andconnexin43 reverses glioma stem cell phenotype. Cell Death Dis. 2014; 5(1):e1023.
-Jaraíz-Rodríguez M, Tabernero MD, González-Tablas M, et al. A Short Region of Connexin43 Reduces Human Glioma Stem Cell Migration, Invasion, and Survival through Src, PTEN, and FAK. Stem Cell Reports. 2017; 9(2):451-463.
-Pelaz SG, Jaraíz-Rodríguez M, Álvarez-Vázquez A, et al. Targeting metabolic plasticity in glioma stem cells in vitro and in vivo through specific inhibition of c-Src by TATCx43. EBioMedicine. 2020; 62:103134.
-Pelaz SG, Ollauri-Ibáñez C, Lillo C, Tabernero A. Impairment of Autophagic Flux Participates in the Antitumor Effects of TAT-Cx43. Cancers (Basel). 2021; 13(17).
-García-Vicente L. The anti-tumor peptide Tat-Cx43266-283 Modulates the interplay between glioblastoma cells and tumorassociatedastrocytes, University of Salamanca; 2022.
-Jaraíz-Rodríguez M, Talaverón R, García-Vicente L, et al. Connexin43 peptide, TAT-Cx43266-283, selectively targets glioma cells, impairs malignant growth, andenhances survival in mouse models in vivo. Neuro Oncol. 2020; 22(4):493-504.
-Álvarez-Vázquez A, San-Segundo L, Cerveró-García P, et al. EGFR amplification and EGFRvIII predict and participate in TAT-Cx43266-283 antitumor response in preclinical glioblastoma models. Neuro Oncol. 2024. 20:noae060.
