Biology subjects

Caffrey, T. C.

Publications and source records attributed to Caffrey, T. C..

3 recordsLinked to original sources

bioRxiv2026

An Integrated Preclinical Platform for Lethal Neuroendocrine Prostate Cancer from Rapid Autopsy Bone and Liver Metastases.

Treatment-emergent neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant disease arising in up to 20% of castration resistant prostate cancers, yet robust biologically relevant preclinical models remain scarce. Here, we describe a technical blueprint for establishing an integrated platform of patient-derived models from visceral and bone metastases collected through a prostate cancer rapid autopsy program (PC RAP). We report the establishment and characterization of patient-derived xenograft (PDX) models from liver metastasis tissue, liver and bone metastasis-derived organoid lines (PDOs), and corresponding patient-derived organoid xenograft (PDOX) models. In addition, we established, to our knowledge, the first mesenchymal stem cell (MSC) cultures derived from neuroendocrine prostate cancer (NEPC) bone metastases. The PDOs preserved intratumoral heterogeneity, displaying both CRPC-NE and CRPC-adenocarcinoma features. These organoids retained neuroendocrine identity across multiple passages, with transcriptomic profiles concordant with the original patient tissue and matched PDX models generated at our institution and at the National Cancer Institute (NCI Patient-Derived Models Repository). To model the bone metastatic microenvironment, we generated novel organoid-based New Approach Methodologies (NAMs) by co-culturing PDOs with iPSC-derived bone marrow organoids, establishing a physiologically relevant vascularized organotypic model of PC bone metastasis. To extend our studies in vivo, we established preclinical models using the liver and bone metastasis-derived organoid models. The PDOX models were tumorigenic and developed spontaneous lymph node metastases, providing clinically relevant models for investigating lethal NEPC biology. Together, these complementary patient-derived models provide a robust and versatile platform for investigating NEPC biology, metastatic progression, and evaluating new therapeutic strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/740121v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@1c641f1org.highwire.dtl.DTLVardef@113696aorg.highwire.dtl.DTLVardef@16dcc72org.highwire.dtl.DTLVardef@1898d9f_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LINovel preclinical models of visceral and bone metastases established from a prostate cancer rapid autopsy program. C_LIO_LIThis study is the first to establish mesenchymal stem cell cultures from NEPC bone metastases. C_LIO_LIPDOs preserve heterogeneity, showing both CRPC-NE and CRPC-Adeno features, with transcriptomic profiles concordant with originator tissue and PDX models. C_LIO_LIPC RAP-derived organoids are tumorigenic in vivo and generate spontaneous lymph node metastases. C_LI

cancer biology↗

bioRxiv2025

An Iron-regulated Signalling Pathway Controls Adipose Browning and Cancer Cachexia

The browning and atrophy of white adipose tissue (WAT) are early events in cachexia, a lethal metabolic disorder affecting nearly half of cancer patients, including those with pancreatic ductal adenocarcinoma (PDA). Using patient-derived specimens and PDA mouse models, we identified perturbations in iron metabolism and proteinaceous methionine oxidation as key initiating events of adipose browning. In particular, the iron influxes that accompany WAT browning induce the activity of methionine sulfoxide reductase A (MSRA), an enzyme that reverses the oxidation of proteinaceous methionine residues. Mechanistically, iron coordination by the conserved iron-binding motifs (E203-xx-H206) of two MSRA polypeptides serves to multimerize, stabilize, and enzymatically activate MSRA. This in turns facilitates adipose browning by maintaining the reduced state of two methionines near the ATP-binding site of Protein Kinase A (PKA). Remarkably, in mouse models of PDA, MsrA deletion impairs WAT browning, significantly mitigates cachexia, and improves the overall survival of tumor-bearing animals. By establishing the iron-MSRA-PKA axis as a key nexus of cancer-associated cachexia, our study offers new perspectives for the treatment of this condition.

cancer biology↗

bioRxiv2025

AI-powered Deep Visual Proteomics reveals critical molecular transitions in pancreatic cancer precursors

Pancreatic ductal adenocarcinoma (PDAC) evolves through non-invasive precursor lesions, yet its earliest molecular events remain unclear. We established the first spatially resolved proteomic atlas of these lesions using Deep Visual Proteomics (DVP). AI-driven computational pathology classified normal ducts, acinar-ductal metaplasia (ADM), and pancreatic intraepithelial neoplasia (PanIN) from cancer-free organ donors (incidental, "iPanINs") and PDAC patients (cancer-associated, "cPanINs"). Laser microdissection of 96 discrete regions containing as few as 100 phenotypically matched cells and ultrasensitive mass spectrometry quantified a total of 8,512 proteins from formalin-fixed tissues. Distinct molecular signatures stratifying cPanINs from iPanINs, and remarkably, many cancer-associated proteins already marked histologically normal epithelium. Four core programs - stress adaptation, immune engagement, metabolic reprogramming, mitochondrial dysfunction - emerged early and intensified during progression. By integrating DVP with AI-guided tissue annotation, we demonstrate that molecular reprogramming precedes histological transformation, creating opportunities for earlier detection and interception of a near-uniformly lethal cancer. SignificanceOur spatially-resolved proteomics atlas uncovers distinct molecular signatures in pancreatic cancer adjacent precursor lesions, clearly diverging from those in incidental, cancer-free pancreatic lesions. Our deep proteomics dataset offers a valuable resource for identifying novel biomarkers and therapeutic targets, informed by the earliest cancer-associated molecular events in archival pancreatic tissues.

cancer biology↗