Role of p38α in lung tumor progression

[eng] Tumors evolve by sequentially acquiring genetic abnormalities, like K-Ras activation and Tp53 loss of function, which enable transformed cells to survive, proliferate, invade, and reprogram their microenvironment. Simultaneously, transformed cells need to cope with a stressful scenario, including an accelerated metabolism, genome instability, or immune surveillance. Therefore, cancer cells must rely on some non-oncogenic signaling pathways to tolerate homeostatic control deficiencies, adapt to the new demands, and monitor continuous changes in the microenvironment to respond accordingly. The p38 MAPK signaling pathway is a stress-related pathway that cells use to transduce extracellular cues and orchestrate appropriate responses. p38α, the most widely expressed p38 MAPK family member, has been classically attributed tumor suppressor functions due to its ability to arrest the cell cycle, induce cell differentiation, and trigger apoptosis. Nevertheless, in several human tumor types, p38 MAPK activity levels have been found increased and sometimes correlated to poor survival, suggesting a pro-tumorigenic role. In this study, we observed a negative correlation between p38α mRNA expression levels and the overall survival of lung adenocarcinoma patients. Using a K-RasG12V driven mouse model of lung cancer, we show that indeed p38α signaling plays a dual role during lung tumorigenesis. On one hand, p38α avoids malignant transformation in lung epithelial cells by promoting their differentiation. However, in the transformed lung epithelial cells, p38α enhances proliferation as well as the secretion of inflammatory cytokines to form a favorable niche for cancer progression. p38α also plays a pro-tumorigenic role by promoting tumor vascularization and immunotolerance of tumor-infiltrated myeloid cells. Altogether, our data suggest that targeting this pathway might be therapeutically useful for lung adenocarcinoma. [spa] Los tumores evolucionan al adquirir anormalidades genéticas de manera secuencial, como la activación de K-Ras y la pérdida de funcionalidad de Tp53, que permiten a las células transformadas sobrevivir, proliferar, e invadir, así como acondicionar su microambiente. Simultáneamente, las células transformadas también han de lidiar con situaciones de estrés, incluyendo un metabolismo acelerado, un genoma altamente inestable, o el sistema de vigilancia de las células inmunes. Por lo tanto, las células cancerosas han de apoyarse en vías de señalizació