Biology subjects

Curtis, M. B.

Publications and source records attributed to Curtis, M. B..

3 recordsLinked to original sources

bioRxiv2025

Targeting Neutrophil Extracellular Traps to inhibit Colon Cancer Tumor Necrosis and Metastasis

Necrosis, conventionally thought of as a passive consequence of aggressive tumor growth, is associated with poor prognosis in colorectal cancer (CRC). We recently discovered that necrosis can be caused by neutrophils and neutrophil extracellular traps (NETs) aggregates driving vascular occlusion within the tumor vasculature in models of breast cancer. Here, we evaluated the role of NETs in inducing necrosis and metastasis in CRC. We found that the numbers of neutrophils primed to form NETs were elevated in the circulation of patients with CRC as compared to controls. CD177Low neutrophils were also elevated, and they showed reduced extravasation capacity with intact ability to form NETs. The extent of necrosis correlated with metastasis (stage IV disease), independent of tumor size, in our human cohort. In both human and murine CRC tumors, necrotic regions were characterized by neutrophil infiltration and NET accumulation, and NET aggregates were observed in the vasculature next to the necrotic regions. Single cell RNA sequencing and spatial transcriptomic analysis of human CRC and liver metastases revealed that necrotic tumors activate pathways associated with increased metastatic potential, including epithelial-to-mesenchymal-transition. Using a mouse model of DNA mismatch repair proficient CRC, we found neutrophil infiltration and NETs increased with tumor progression. Genetic or pharmacological inhibition of NET formation decreased necrosis and metastasis, and importantly enhanced chemotherapy efficacy. Altogether, our findings show that NET formation in human CRC is a key feature of tumor necrosis, that it is associated with metastasis, and further suggest that preventing NET formation may offer clinical benefits to CRC patients.

cancer biology↗

bioRxiv2022

Automated protein-protein structure prediction of the T cell receptor-peptide major histocompatibility complex

T Cell Receptor (TCR) recognition of a peptide-major histocompatibility complex (pMHC) is a crucial component of the adaptive immune response. The identification of therapeutically relevant TCR-pMHC pairs is a significant bottleneck in the implementation of TCR-based immunotherapies but may be augmented by computational methodologies. The ability to computationally design TCRs to target a specific pMHC will require an automated integration of next-generation sequencing, protein-protein structure prediction, molecular dynamics (MD), and TCR ranking. We present a generic pipeline to evaluate patient-specific, sequence-based TCRs to a target pMHC. Using the three most frequently expressed TCRs from 16 colorectal cancer patients, we predicted the protein-protein structure of the TCRs to the target CEA peptide-MHC using Modeller and ColabFold. Then, these TCR-pMHC structures were compared by performing an automated molecular dynamics equilibration. ColabFold generates starting configurations that require, on average, a ~2.5X reduction in simulation time to equilibrate TCR-pMHC structures compared to Modeller. In addition, the structural differences between Modeller and ColabFold are demonstrated by an increase in root mean square deviation (~0.20 nm) between clusters of equilibrated configurations, which can impact the number of hydrogen bonds and Lennard-Jones contacts between the TCR and pMHC. Finally, we identify a TCR ranking criteria that may be used to prioritize TCRs for evaluation of in vitro immunogenicity.

biophysics↗

bioRxiv2020

Organ-on-a-chip model of vascularized human bone marrow niches

Animal models of bone marrow have limited spatial and temporal resolution to observe biological events (intravasation and cellular egress) and are inadequate to dissect dynamic events at the niche level (100 microns). Utilizing microfluidic and stem cell technology, we present a 3D in vitro model of human bone marrow that contains perivascular and endosteal niches complete with dynamic, perfusable vascular networks. We demonstrate that our model can perform in vivo functions including maintenance and differentiation of CD34+ hematopoietic stem/progenitor cells (HSPC) for up to fourteen days, egress of myeloid progenitors, and expression of markers consistent with in vivo human bone marrow. The platform design enables the addition of tissue niches at a later timepoint to probe mechanisms such as tumor cell migration. Overall, we present a novel organ-on-a-chip platform that is capable of recapitulating the human bone marrow microenvironment to observe hematopoietic phenomena at high spatial and temporal resolution.

bioengineering↗