A5019544820- Immune cells in cancer
- Pancreatic and Hepatic Oncology Research
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Cancer Cells and Metastasis
- Cancer Genomics and Diagnostics
- Phagocytosis and Immune Regulation
- Nanoplatforms for cancer theranostics
- 3D Printing in Biomedical Research
- Single-cell and spatial transcriptomics
- Cell Adhesion Molecules Research
- interferon and immune responses
- Cellular Mechanics and Interactions
- Cancer, Stress, Anesthesia, and Immune Response
- Peptidase Inhibition and Analysis
- Immune Response and Inflammation
- Digital Imaging in Medicine
- Glioma Diagnosis and Treatment
- Colorectal Cancer Treatments and Studies
- Protein Structure and Dynamics
- Medicine and Dermatology Studies History
- Biochemical and Molecular Research
- Bioinformatics and Genomic Networks
- Caveolin-1 and cellular processes
- Radiomics and Machine Learning in Medical Imaging
- Machine Learning in Bioinformatics
Broad Institute
2022-2024
Massachusetts General Hospital
2022-2024
Harvard University
2022-2024
Brigham and Women's Hospital
2024
Center for Cancer Research
2022-2024
Center for Systems Biology
2022-2024
Cornell University
2020-2023
Massachusetts Institute of Technology
2022
Harvard University Press
2022
Abstract We have shown that KRAS–TP53 genomic coalteration is associated with immune-excluded microenvironments, chemoresistance, and poor survival in pancreatic ductal adenocarcinoma (PDAC) patients. By treating cooperativity as a model for high-risk biology, we now identify cell-autonomous Cxcl1 key mediator of spatial T-cell restriction via interactions CXCR2+ neutrophilic myeloid-derived suppressor cells human PDAC using imaging mass cytometry. Silencing cell-intrinsic...
Abstract Tumor invasion within the interstitial space is critically regulated by force balance between cell-extracellular matrix (ECM) and cell-cell interactions. Interstitial flows (IFs) are present in both healthy diseased tissues. However, roles of IFs modulating cell subsequently tumor understudied. In this article, we develop a microfluidic model which spheroids embedded 3D collagen matrices with well-defined IFs. Using co-cultured (1:1 mixture metastatic non-tumorigenic epithelial...
Pancreatic ductal adenocarcinoma (PDAC) is one of the most treatment refractory and lethal malignancies. The diversity endothelial cell (EC) lineages in tumor microenvironment (TME) impacts efficacy antineoplastic therapies, which turn remodel EC states distributions. Here, we present a single-cell resolution framework diverse PDAC TME context neoadjuvant chemotherapy, radiotherapy, losartan. We analyzed custom single-nucleus RNA-seq dataset derived from 37 primary specimens (18 untreated,...
Tumor invasion, the process by which tumor cells break away from their primary and gain access to vascular systems, is an important step in cancer metastasis. Most current 3D invasion assays consisted of single embedded within extracellular matrix (ECM). These taught us much what we know today on how key biophysical (e.g. ECM stiffness) biochemical cytokine gradients) parameters microenvironment guided regulated invasion. One limitation cell assay was that it did not account for cell-cell...
In combination with cell intrinsic properties, interactions in the tumor microenvironment modulate therapeutic response. We leveraged high-plex single-cell spatial transcriptomics to dissect remodeling of multicellular neighborhoods and cell-cell human pancreatic cancer associated specific malignant subtypes neoadjuvant chemotherapy/radiotherapy. developed Spatially Constrained Optimal Transport Interaction Analysis (SCOTIA), an optimal transport model a cost function that includes both...
Abstract Pancreatic cancer is a challenging disease which lacks robust precision oncology framework. Prior work has demonstrated that transcriptional subtypes in pancreatic can stratify patients by response to chemotherapy and overall survival. These include classical basal-like as the predominant untreated disease, well transdifferentiated neural-like malignant subtype enriched after standard-of-care chemotherapy. Nonetheless, our understanding of remains critically limited genetic...
Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with a five-year overall survival only 11%. Treatment failure ubiquitous, driven by genetic and phenotypic heterogeneity combined highly desmoplastic immunosuppressive microenvironment. Identifying novel therapeutic targets in tumor microenvironment (TME) critical to improving patient outcomes can be advanced through understanding cell intrinsic states cell-cell interactions driving clinically-relevant...
Abstract Precision medicine approaches using molecular tumor profiling have resulted in striking clinical benefits certain patient populations. However, targeted therapy pancreatic cancer has been unable to displace multi-agent chemotherapy, part due lack of actionable biomarkers anchor stratification. To address this need, we conducted a biomarker focused analysis dependencies and cell surface targets understand specific vulnerabilities present subgroups. We started by interrogating genome...
Abstract The most well-described mechanism of immune evasion in PDAC is exclusion cells by a desmoplastic stroma, but such not uniform. Through single-nucleus RNA-seq and whole-transcriptome digital spatial profiling patient tumors, we previously reported marked heterogeneity the composition PDAC. Here, developed novel multi-omics workflow integrating single cell proteomics (96-plex, Akoya Phenocycler®-Fusion) transcriptomics (990-plex, Nanostring CosMx) primary tumors to systematically...
Abstract The aggressive nature of pancreatic ductal adenocarcinoma (PDAC) is driven by cell-intrinsic features and cell-extrinsic interactions between tumor cells the desmoplastic stroma, which infiltrated with heterogeneous populations cancer-associated-fibroblasts (CAFs) immune cells. These are able to drive emergent properties such as chemoresistance through diverse not yet fully elucidated mechanisms. Through single-nucleus RNA-seq whole-transcriptome digital spatial profiling PDAC...
Abstract Pancreatic ductal adenocarcinoma (PDAC) is notorious for poor survival rates, underscoring the urgency of understanding factors that drive tumor progression. A key player in this process epithelial-mesenchymal transition (EMT), known its role enhancing cancer cell adaptability, resistance to treatment, and metastasis. Our study focuses on EMT within PDAC, using single-cell spatial transcriptomics explore how microenvironment influences changes cellular states. We introduce a novel...
<p>Supplementary Methods Supplementary Figures with legends Tables S2, S4, S5-7</p>
<p>Supplementary Methods Supplementary Figures with legends Tables S2, S4, S5-7</p>