What we are interested in
We are interested in identifiying new pathways that regulate the transmission of mechanical signals to cell organelles, and in understanding how these pathways regulate processes such as cell proliferation, aging, differentiation and other physiological processes. We are also interested in how these pathways regulate cancer progression and other human diseases.
It is known that mechanical signals are sensed by some cell organelles, yet how they do so is unclear. If you want to understand these processes, feel free to visit our lab at Centro de Investigaciones Biológicas Margarita Salas.
The nuclear envelope: a mechanosensitive hub
The nuclear envelope contains important mechanosensitive macromolecular structures, such as the lamina, the LINC complex and the nuclear pore complex (NPC). These systems sense, transduce and/or respond to mechanical signals, leading to nuclear and cellular mechanoadaptation. Mechanotransduction pathways of the nuclear envelope are important in multiple cellular processes, such as cell migration, proliferation and differentiation, cell contraction, inflammatory and innate immune responses, and the regulation of aging. However, the identity of all mechanotransduction pathways operating in the nuclear envelope and how the different mechanoresponsive systems communictae remanins unknwon (Echarri A. Biomolecules 2022).
We have recently shown that at least one nuclear import factor, named Imp7, is highly mechanoresponsive, and is essential for the crossing of the nuclear envelope of different mechanoresponsive transcriptional regulators (García-García et al., Nature Communications, 2022). Using bioinformatic and quantitative proteomic approaches we have identified additional proteins that respond to mechanical signals, some of which are localized to the nuclear envelope and are barely studied (shown in the left image). This research line aims to characterize these proteins and understand their function in cell and nuclear mechanoadaptation. To do this, we will use a combination of molecular biology and biochemistry techniques, functional genetics and approaches based on different omics, so that we can provide a deep understanding of their cellular function.
Regulation of tumor associated mechanosensors
Cancer is a disease that dramatically changes the functional and mechanical properties of the original tissue. In the case of solid tumors, they tend to be much more rigid than the original tissue, and palpation of tissues has been used as a diagnostic approach to identify malignant growths. Therefore, signaling pathways that are regulated by mechanical parameters are frequently altered in cancer cells, contributing to the progression and spread of tumors (metastasis).
Some of the most potent oncogenes, including c-Abl tyrosine kinase and YAP/TAZ transcriptional regulators are regulated by mechanical forces (Echarri et al., Nature Communications, 2019) and understanding this phenomenon is useful to design strategies oriented to prevent their activation. We have identified a mechanoresponsive pathway, led by the nuclear import factor Imp7, that is responsible for YAP/TAZ nuclear translocation (García-García et al., Nature Communications, 2022), which provides a new opportunity to block YAP/TAZ function. Inhibition of YAP/TAZ is pursued by several pharmaceutical companies, due to the involvement of these factors in the progression of multiple tumors. In this research line, we aim to design new strategies to prevent the harmful effects of mechanoresponsive oncogenes, such as YAP/TAZ. In addition, we are developing new approaches to identify new mechanotransduction pathways important for tumor progression and metastasis.