Biology subjects

Martinez, C. G.

Publications and source records attributed to Martinez, C. G..

3 recordsLinked to original sources

bioRxiv2024

Morpho-molecular features of Epithelial Mesenchymal Transition associate with clinical outcome in patients with rectal cancer

In rectal cancer, where part of the patients undergoes chemoradiotherapy, there is a need for improved pretreatment biomarkers applicable to biopsies. Tumor budding (TB) is a biomarker used in colon cancer, and due to its link to epithelial-mesenchymal transition (EMT), is hypothesized to be a potential marker for therapy resistance. Assessment of the utility of tumor buds in rectal biopsies is challenging due to their rarity. As EMT-related processes are also seen in other morphological features beyond tumor buds, we investigated EMT in tumor tissue including morphological features such as tumor cluster size and fibril-like structures. To do so, we leveraged a cohort of colon cancer whole-slide images and another cohort consisting of rectal cancer biopsies, visualized using hyperplex immunofluorescence to identify tumor and EMT-associated proteins. We built a custom image analysis pipeline to detect and segment tumor buds and other morphological features and correlated them with molecular expression intensities. We found strong correlations of EMT up-regulation and morphological transition states, both at the invasive margin and the tumor center. We furthermore observed a link between morpho-molecular transitions and histological growth patterns, which in turn can inform novel biomarkers. Finally, quantification of these morpho-molecular transition states in rectal biopsies showed their impact on survival after neoadjuvant chemoradiotherapy.

cancer biology↗

bioRxiv2024

Caspase-11 drives macrophage hyperinflammation in models of Polg-related mitochondrial disease

Mitochondrial diseases (MtD) represent a significant public health challenge due to their heterogenous clinical presentation, often severe and progressive symptoms, and lack of effective therapies. Environmental exposures, such bacterial and viral infection, can further compromise mitochondrial function and exacerbate the progression of MtD. Infections in MtD patients more frequently progress to sepsis, pneumonia, and other detrimental inflammatory endpoints. However, the underlying immune alterations that enhance immunopathology in MtD remain unclear, constituting a key gap in knowledge that complicates treatment and increases mortality in this vulnerable population. Here we employ in vitro and in vivo approaches to clarify the molecular and cellular basis for innate immune hyperactivity in models of polymerase gamma (Polg)-related MtD. We reveal that type I interferon (IFN-I)-mediated upregulation of caspase-11 and guanylate-binding proteins (GBPs) increase macrophage sensing of the opportunistic microbe Pseudomonas aeruginosa (PA) in Polg mutant mice. Furthermore, we show that excessive cytokine secretion and activation of pyroptotic cell death pathways contribute to lung inflammation and morbidity after infection with PA. Our work sheds new light on innate immune dysregulation in MtD and reveals potential targets for limiting infection- and inflammation-related complications in Polg-related MtD.

immunology↗

bioRxiv2020

Type I interferon potentiates metabolic dysfunction, inflammation, and accelerated aging in mtDNA mutator mice

Mitochondrial dysfunction is a key driver of inflammatory responses in human disease. However, it remains unclear whether alterations in mitochondria-innate immune crosstalk contribute to the pathobiology of mitochondrial disorders and aging. Using the polymerase gamma (POLG) mutator model of mitochondrial DNA (mtDNA) instability, we report that aberrant activation of the type I interferon (IFN-I) innate immune axis potentiates immunometabolic dysfunction, reduces healthspan, and accelerates aging in mutator mice. Mechanistically, elevated IFN-I signaling suppresses activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which increases oxidative stress, enhances pro-inflammatory cytokine responses, and accelerates metabolic dysfunction. Ablation of IFN-I signaling attenuates hyper-inflammatory phenotypes by restoring Nrf2 activity and reducing aerobic glycolysis, which combine to lessen cardiovascular and myeloid dysfunction in aged mutator mice. These findings further advance our knowledge of how mitochondrial dysfunction shapes innate immune responses and provide a framework for understanding mitochondria-driven immunopathology in POLG-related diseases and aging.

immunology↗