Biology subjects

Matkowskyj, K. A.

Publications and source records attributed to Matkowskyj, K. A..

9 recordsLinked to original sources

bioRxiv2026

Spatial multi-omics and single-cell transcriptomics uncover senescence-associated cellular programs during colon adenoma to cancer progression

Colorectal cancer develops through a normal-adenoma-carcinoma sequence, yet only 5-10% of adenomas progress to malignancy, and the cellular programs governing that sequence remain poorly defined. Here we generate a spatial multi-omics atlas of human colon adenomas, combining Visium CytAssist and protein co-detection across 24 nonadvanced and advanced tubular adenomas with single-cell resolution Xenium Prime 5K profiling of 101 patient-matched normal, adenoma, and carcinoma cores from 16 patients. Integrating whole-transcriptome and 31-plex protein data identifies nine spatial clusters and two dysplastic epithelial populations that co-express stemness, proliferation, and senescence programs. These programs occupy a shared, spatially confined epithelial niche that expands from adenoma to carcinoma. Spatial analysis revealed GDF15, a senescence-associated secretory factor, mediated the coupling between senescence and stemness in advanced adenomas, and that GDF15-high epithelium locally excludes CD8+ T cells in adenoma and, more broadly, in carcinoma. These findings position senescence as a spatially instructive rather than merely tumor-suppressive program during colorectal carcinogenesis and suggest GDF15 might be a potential candidate target for cancer prevention and interception in the colon.

cancer biology↗

bioRxiv2026

The DNAJB1-PRKACA Oncogenic Fusion Drives Stepwise Biliary and Pancreatic Carcinogenesis from Intraductal Precursor Lesions

Intraductal oncocytic papillary neoplasms (IOPNs) are rare tumors that develop from biliary and pancreatic ductal epithelium and progress to lethal cancers. Human IOPNs and IOPN-associated carcinomas are known to harbor the DNAJB1-PRKACA gene fusion, however the role of the oncogenic fusion in carcinogenesis is poorly understood. We developed a Cre-inducible mouse model of human DNAJB1-PRKACA expression and substantiated that the DNAJB1-PRKACA fusion gene is a bona fide driver of IOPN-associated biliary and pancreatic carcinoma. By analyzing the unique histopathologic and transcriptional changes that occur at each stage of tumor development, we found that these murine tumors closely mimic human DNAJB1-PRKACA driven tumors. Furthermore, we identified that many of the salient features of invasive carcinoma are established at the pre-invasive stage, including evidence of tumor cell metabolic dysregulation, immunosuppressive tumor stroma and expression of genes strongly associated with invasive DNAJB1-PRKACA driven cancer in humans. Finally, we found that Slc16a14, a characteristic DNAJB1-PRKACA regulated super-enhancer associated gene, serves as a robust biomarker of malignant transformation from IOPN to invasive carcinoma.

cancer biology↗

bioRxiv2026

Translating Histopathology Foundation Model Embeddings into Cellular and Molecular Features for Clinical Studies

AI-powered pathology foundation models provide general-purpose representations of histopathological images by encoding image tiles into numerical embeddings. However, these embeddings are not directly interpretable in biological or clinical terms and must be translated into biologically meaningful features, such as cell-type composition or gene expression, to enable downstream clinical applications. To bridge this gap, we developed STpath, a framework that integrates histopathology image embeddings derived from existing pathology foundation models with matched, spatially resolved transcriptomics data. STpath consists of cancer-specific XGBoost models trained to infer cell-type compositions and gene expression from histopathology image tiles. We evaluated STpath in colorectal and breast cancer datasets and showed that it provides accurate estimates of the composition of major cell types and the expression of a subset of genes, with further performance gains achieved by combining embeddings from multiple foundation models. Finally, we demonstrated that STpath inferred features that can be used in downstream studies to evaluate their associations with clinical outcomes.

bioinformatics↗

bioRxiv2024

Invasive cancer and spontaneous regression two weeks after papillomavirus infection

Development of invasive cancer in mammals is thought to require months or years after initial events such as mutation or viral infection. Rarely, invasive cancers regress spontaneously. We show that cancers can develop and regress on a timescale of weeks, not months or years. Invasive squamous cell carcinomas developed in normal adult, immune-competent mice as soon as 2 weeks after infection with mouse papillomavirus MmuPV1. Tumor development, regression or persistence was tissue- and strain-dependent. Cancers in infected mice developed rapidly at sites also prone to papillomavirus-induced tumors and cancers in humans - the throat, anus, and skin - and their frequency was increased in mice constitutively expressing the papillomavirus E5 oncogene, which MmuPV1 lacks. Cancers and dysplasia in the throat and anus regressed completely within 4-8 weeks of infection; however, skin lesions in the ear persisted. T-cell depletion in the mouse showed that regression of throat and anal tumors requires T cells. We conclude that papillomavirus infection suffices for rapid onset of invasive cancer, and persistence of lesions depends on factors including tissue type and host immunity. The speed of these events should promote rapid progress in the study of viral cancer development, persistence, and regression. Summary Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/611275v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1da9642org.highwire.dtl.DTLVardef@1bef109org.highwire.dtl.DTLVardef@c2ba0eorg.highwire.dtl.DTLVardef@451baf_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice

Low protein (LP) diets promote health and longevity in diverse species. Although the precise components of an LP diet that mediate its beneficial effects have not been defined, reducing dietary levels of the three branched-chain amino acids (BCAAs) leucine, isoleucine and valine promotes metabolic health in both sexes, and increases lifespan while reducing frailty in male, but not female, C57BL/6J mice. Each BCAA has unique metabolic effects, and we recently showed that restriction of isoleucine is both sufficient to promote metabolic health and required for the metabolic benefits of an LP diet in male C57BL/6J mice. Here, we tested the hypothesis that specifically restricting isoleucine could promote healthy aging in genetically heterogenous UM-HET3 mice. We find that a reduced isoleucine diet improves the metabolic health of both young and old HET3 mice, promoting leanness and glycemic control. Restriction of isoleucine starting in adult, 6 month old HET3 mice reprograms hepatic metabolism in a way distinct from an LP diet. Finally, we find that a reduced isoleucine diet reduces frailty and extends the lifespan of both male and female HET3 mice, but to a much greater degree in males. Our results demonstrate that restricting dietary isoleucine can increase health span and longevity in a genetically diverse population of mice, and suggests that reducing dietary levels of isoleucine may have great potential as a geroprotective intervention.

physiology↗

bioRxiv2022

Chronic Jetlag Accelerates Pancreatic Neoplasia in Conditional Kras-Mutant Mice

Misalignment of the circadian clock compared to environmental cues causes circadian desynchrony, which is pervasive in humans. Clock misalignment can lead to various pathologies including obesity and diabetes, both of which are associated with pancreatic ductal adenocarcinoma - a devastating cancer with an 80% five-year mortality rate. Although circadian desynchrony is associated with an increased risk of several solid-organ cancers, the correlation between clock misalignment and pancreas cancer is unclear. Using a chronic jetlag model, we investigated the impact of clock misalignment on pancreas cancer initiation in mice harboring a pancreas-specific activated Kras mutation. We found that chronic jetlag accelerated the development of pancreatic cancer precursor lesions, with a concomitant increase in precursor lesion grade. Cell-autonomous knock-out of the clock in pancreatic epithelial cells of Kras-mutant mice demonstrated no acceleration of precursor lesion formation, indicating non-cell-autonomous clock dysfunction was responsible for the expedited tumor development. Therefore, we applied single-cell RNA sequencing over time and identified fibroblasts as the cell population manifesting the greatest clock-dependent changes, with enrichment of specific cancer-associated fibroblast pathways due to circadian misalignment. Collectively, these results suggest fibroblasts as the putative target of chronic jetlag-induced accelerated pancreas cancer initiation.

cancer biology↗

bioRxiv2022

Pdx1 expression in hematopoietic cells activates Kras-mutation to drive leukemia in KC (Pdx1-Cre ; LSL-KrasG12D/+) mice

BackgroundPdx1 expression in pancreatic lineage cells underlies the utility of the KC mouse model (Pdx1-Cre; LSL-KrasG12D/+) for understanding how KrasG12D-mutation drives formation of pancreas cancer precursor lesions and carcinoma. The highly utilized KC model has a reported mortality rate of about 30%, which has been attributed to pancreas cancer, despite lack of substantive evidence. This study describes a novel cause of the early deaths, in which KC mice develop Kras-driven T-cell acute lymphoblastic leukemia (T-ALL). MethodsKC mice and control mice underwent histopathologic examination including thymus, liver, spleen, bone marrow and pancreas, and immunohistochemistry (IHC) was used to confirm leukemia development. A reporter strain (Ai14) was used to identify location of Pdx1-Cre expression and concomitant mutant-Kras activation, which was confirmed using flow cytometry, IHC, immunofluorescence, mRNA analysis, and bone marrow transplant studies. ResultsPdx1 expression in the hematopoietic compartment of KC mice resulted in Cre-recombinase mediated excision of lox-stop and activation of mutant-Kras gene (KrasG12D/+) in the multipotent progenitor cells (MPP), and subsequent development of Kras-mutant T-ALL creating thymic tumors in a subset of mice. Overall, 20% (5/25) of KC mice developed a large thymic tumor due to T-ALL by 9 months of age. Moreover, through isolation and transplantation of pooled bone marrow from KC mice into CD45 congenic mice, 100% of recipient mice were found to develop T-ALL. These results further confirm mutant-Kras expression in the hematologic compartment is driving the development of T-ALL in the KC mouse model. ConclusionsThese results are an essential consideration for investigators while utilizing this model in pancreas cancer studies, particularly when evaluating factors that may coincidentally enhance the formation of KrasG12D-driven T-ALL (e.g. transcription factors impacting hematopoietic cells). Finally, the lower penetrance of T-ALL development in KC mice (compared to existing leukemia models) suggest that the KC mouse could be considered as an alternative research model to evaluate onset and factors that exacerbate development of T-ALL.

cancer biology↗

bioRxiv2021

Integrating Subclonal Response Heterogeneity to Define Cancer Organoid Therapeutic Sensitivity

Tumor heterogeneity is predicted to confer inferior clinical outcomes, however modeling heterogeneity in a manner that still represents the tumor of origin remains a formidable challenge. Sequencing technologies are limited in their ability to identify rare subclonal populations and predict response to the multitude of available treatments for patients. Patient-derived organotypic cultures have significantly improved the modeling of cancer biology by faithfully representing the molecular features of primary malignant tissues. Patient-derived cancer organoid (PCO) cultures contain numerous individual organoids with the potential to recapitulate heterogeneity, though PCOs are most commonly studied in bulk ignoring any diversity in the molecular profile or treatment response. Here we demonstrate the advantage of evaluating individual PCOs in conjunction with cellular level optical metabolic imaging to characterize the largely ignored heterogeneity within these cultures to predict clinical therapeutic response, identify subclonal populations, and determine patient specific mechanisms of resistance.

cancer biology↗

bioRxiv2019

Optical Metabolic Imaging of Heterogeneous Drug Response in Pancreatic Cancer Patient Organoids

New tools are needed to match pancreatic cancer patients with effective treatments. Patient-derived organoids offer a high-throughput platform to personalize treatments and discover novel therapies. Currently, methods to evaluate drug response in organoids are limited because they cannot be completed in a clinically relevant time frame, only evaluate response at one time point, and most importantly, overlook cellular heterogeneity. In this study, non-invasive optical metabolic imaging (OMI) of cellular heterogeneity in organoids was evaluated as a predictor of clinical treatment response. Organoids were generated from fresh patient tissue samples acquired during surgery and treated with the same drugs as the patient's prescribed adjuvant treatment. OMI measurements of heterogeneity in response to this treatment were compared to later patient response, specifically to the time to recurrence following surgery. OMI was sensitive to patient-specific treatment response in as little as 24 hours. OMI distinguished subpopulations of cells with divergent and dynamic responses to treatment in living organoids without the use of labels or dyes. OMI of organoids agreed with long-term therapeutic response in patients. With these capabilities, OMI could serve as a sensitive high-throughput tool to identify optimal therapies for individual pancreatic cancer patients, and to develop new effective therapies that address cellular heterogeneity in pancreatic cancer.

bioengineering↗