Biology subjects

Egan, J. M.

Publications and source records attributed to Egan, J. M..

3 recordsLinked to original sources

bioRxiv2025

Tumor-myeloid crosstalk drives therapy resistance in localized bladder cancer

Neoadjuvant cisplatin-based chemotherapy results in pathologic complete response for only a minority of patients with muscle-invasive bladder cancer (MIBC), and mechanisms of resistance and the effects of chemotherapy on the MIBC microenvironment remain incompletely understood. Here, we defined the single-cell and spatial transcriptomes of cancer and immune cells from MIBC patients with resistance to cisplatin-based chemotherapy. Tumors with persistent MIBC after chemotherapy harbored cancer cells expressing epithelial-to-mesenchymal programs that were associated with worse overall survival in independent cisplatin-treated bladder cancer cohorts. These cisplatin-resistant tumor cells were infiltrated by macrophages that upregulated tumor permissive programs defined by increased PARP14 expression in spatially resolved multicellular niches. Macrophage reprogramming through PARP14 inhibition sensitized tumors to cisplatin via downregulation of tumor cell pathways implicated in resistance. Our results demonstrate that cancer cells and macrophages cooperate to promote cisplatin resistance and identify macrophage-directed PARP14 inhibition as a novel therapeutic strategy to sensitize MIBC to cisplatin.

cancer biology↗

bioRxiv2023

A hyper-quiescent chromatin state formed during aging is reversed by regeneration

Epigenetic alterations are a key hallmark of aging but have been limitedly explored in tissues. Here, using naturally aged murine liver as a model and extending to other quiescent tissues, we find that aging is driven by temporal chromatin alterations that promote a refractory cellular state and compromise cellular identity. Using an integrated multi-omics approach, and the first direct visualization of aged chromatin we find that globally, old cells show H3K27me3-driven broad heterochromatinization and transcription suppression. At the local level, site-specific loss of H3K27me3 over promoters of genes encoding developmental transcription factors leads to expression of otherwise non-hepatocyte markers. Interestingly, liver regeneration reverses H3K27me3 patterns and rejuvenates multiple molecular and physiological aspects of the aged liver.

genomics↗

bioRxiv2021

Human Taste Cells Express ACE2: A Portal for SARS-CoV-2 Infection

Loss and changes in taste and smell are well-reported symptoms of SARS-CoV-2 infection. The virus targets cells for entry by high affinity binding of its spike protein to cell-surface angiotensin-converting enzyme-2 (ACE2). It was not known whether ACE2 is expressed on taste receptor cells (TRCs) nor if TRCs are infected directly. Using an in-situ hybridization (ISH) probe and an antibody specific to ACE2, it seems evident that ACE2 is present on a subpopulation of specialized TRCs, namely, PLC{beta}2 positive, Type II cells in taste buds in taste papillae. Fungiform papillae (FP) of a SARS-CoV-2+ patient exhibiting symptoms of COVID-19, including taste changes, were biopsied. Based on ISH, replicating SARS-CoV-2 was present in Type II cells of this patient. Therefore, taste Type II cells provide a portal for viral entry that predicts vulnerabilities to SARS-CoV-2 in the oral cavity. The continuity and cell turnover of the FP taste stem cell layer of the patient were disrupted during infection and had not fully recovered 6 weeks post symptom onset. Another patient suffering post-COVID-19 taste disturbances also had disrupted stem cells. These results indicate that a COVID-19 patient who experienced taste changes had replicating virus in their taste buds and that SARS-CoV-2 infection results in deficient stem cell turnover needed for differentiation into TRCs.

pathology↗