Paula Blanco graduated in Biology in 2021 from the University of Santiago de Compostela (USC) and obtained her master's degree in Translational Biomedical Research at the Vall d'Hebron Research Institute (VHIR) and the Autonomous University of Barcelona in 2022.
During her academic training she has acquired specialized training in the fields of cellular senescence and cancer research. She carried out her Final Degree Project in the Cellular Senescence in Cancer and Ageing group led by Dr. Manuel Collado (Santiago), with the support of a Collaboration Grant from the Ministry of Education and Professional Training. In addition, during her master's degree she obtained an internship contract as Biomedical Research Support Staff at the Centro de Investigación Biomédica en Red (CIBER) to carry out her master's thesis in the group of Dr. Ibane Abasolo at VHIR (Barcelona) on the plasticity of tumour cells mediated by extracellular vesicles.
Since March 2023 she is part of Dr. Juan Carlos Acosta's group at IBBTEC, where she is developing her PhD with a FPU pre-doctoral grant from the Ministry of Universities. Her project involves the characterization of the inflammasome in RAS-induced senescence and its function in non-small-cell lung cancer.
Our research aims to study the molecular mechanisms controlling cellular senescence to reveal new targets for cancer and ageing treatments, and to address the outstanding fundamental question about the origin and function of the senescent cell state.
Cellular senescence is a terminal stress response that impairs the propagation of mutated and damaged cells. It is characterised by a robust cell cycle arrest and the induction of a complex pro-inflammatory response, the senescence-associated secretory phenotype (SASP). Activating cellular senescence in response to oncogenic activation (oncogene-induced senescence) functions as a potent tumour suppressor response impairing malignant transformation. However, the accumulation of senescent cells in tumours because of anti-cancer therapies, oncogenic activation, or ageing, can, in the long-term, facilitate cancer progression through the SASP. Thus, as the new therapeutic advances improve and extend the survival of cancer patients, novel strategies controlling the adverse effects of accumulating senescent cells in tumours are urgently needed. Besides, senescent cells accumulate during organismal ageing, behaving as "zombie-cells" that negatively affect the surrounding tissue through the pro-inflammatory SASP, promoting ageing and age-related diseases. Indeed, eliminating senescent cells in transgenic mouse models improves organismal ageing, indicating a fundamental role of senescent cells in such a process. Thus, we aim to identify molecular mechanisms controlling the SASP to design strategies to mitigate the side effects of accumulating senescent cells in cancer and during aging.
In recent years, therapies to target senescent cells (senotherapies) in cancer and ageing by, for example, using small chemical compounds exploiting senescent cell vulnerabilities that result in the specific killing of senescent cells (senolytics), have been shown effective in treating ageing and age-related diseases in preclinical models, and clinical trials are undergoing to assess their therapeutic potential in humans. Furthermore, two-punch anti-cancer therapeutic strategies inducing cellular senescence in cancer cells, followed by interventions to eliminate those senescent cancer cells (e.g. senolytics), have been proposed as a new rationale for anti-cancer therapies. However, most senolytic target pathways are mostly inactivated in human cancer (e.g. p53), so unique mechanistic insight is necessary to identify senolytic pathways to target senescent cancer cells in tumours. In our group, we discovered that receptors of the innate immune systems (known as pattern recognition receptors) are in the core machinery regulating cellular senescence and the SASP. Specifically, we have shown that innate immune signalling through inflammasomes (caspase-1 and -4) and toll-like receptors (TLR2) are critical for SASP activation. We propose manipulating those pathways to activate selective immune responses and inflict inflammatory cell death in targeted cancer cells using two-punch strategies as an exciting new prospect in the anti-cancer arsenal.
Our primary specific research aims are:
- To reveal new molecular mechanistic insight about the regulation of cellular senescence and the senescence-associated secretory phenotype (SASP)
- To characterise the innate-immune identity, origin, and function of the senescent cell state.
- To identify new senescent cell vulnerabilities to engineer innovative anti-cancer and anti-ageing therapies based on cellular senescence manipulation.
Our group has been vital in discovering the SASP and its dependency on innate immune signalling, and in unravelling transcriptional programs upon senescence-associated nuclear stress and chromatin organisation, resulting in highly cited publication in journals such as Cell, Nature Cell Biology, Genes & Development or Science Advances. We use high-throughput approaches (e.g. proteomics, transcriptomics, metabolomics) combined with focused phenotypic screens (e.g. loss of function genetic RNAi or CRISPR screens, and small chemical compounds) to identify critical functional candidate genes and pathways regulating cellular senescence and the SASP, state of the art molecular and cellular biology methods to characterise their mechanism of action, and preclinical animal models and analysis of human samples to investigate their relevance and functionality in vivo.
