Biology subjects

Zimmers, T. A.

Publications and source records attributed to Zimmers, T. A..

4 recordsLinked to original sources

bioRxiv2025

Pancreatic Cancer Induces Population-Specific Switching of Myosin Isoforms and Discrete Activation of Cachexia Genes in Skeletal Muscle Myocytes

Skeletal muscle loss in pancreatic cancer is a significant cause of morbidity and mortality for patients. In order to understand myocytes changes we examined myonuclei- and myofiber-specific dynamics during pancreatic cancer cachexia progression. Single-nucleus RNA-seq was used to interrogate myonuclear gene expression, and RNAscope and immunofluorescence characterized myofiber-specific changes. Bulk RNA-seq of skeletal muscle provided a whole-muscle transcriptomic profile. Cachexia induces a progressive loss of muscle differentiation factor Maf and its target Myh4, accompanied by increased expression of Myh1 and Myh2. This myofiber dedifferentiation occurs without evidence for fiber type shifting, regeneration, or proliferation. Single-nuclei analysis reveals global shifts in myofiber gene expression identity including the identification of a cachexia only myonuclear subpopulation. Cachexia gene expression was not restricted solely to this PDAC-specific myonuclear subpopulation and did not overlap with Myh1 and Myh2 expressing myonuclei early in cachexia. Altogether, PDAC cachexia elicits distinct transcriptional responses across different myonuclear populations. These results reveal population-specific heterogeneity in cachexia gene activation, rather than a uniform upregulation of cachexia mediators across muscle tissue. Our data suggest that myonuclei fate occurs prior to overt muscle wasting when cachexia gene expression only modestly overlaps with differentiation factors, with a strong association after irreversible muscle wasting. These findings explain the challenge of effectively targeting skeletal muscle wasting in cancer cachexia requires addressing the changing cell population induced through non overlapping mechanisms.

cancer biology↗

bioRxiv2025

MicroCT enables simultaneous longitudinal tracking of murine pancreatic cancer progression and cachexia

Preclinical models of pancreatic ductal adenocarcinoma (PDAC) can greatly benefit from non-invasive imaging for evaluating disease progression and therapeutic response. Imaging approaches that can accurately and simultaneously track primary tumor growth, metastatic dissemination, and host cachexia over time are lacking. Here, we report an optimized dual-contrast micro-computed tomography (microCT) protocol for longitudinal imaging in orthotopic murine models of PDAC. This method enables high-resolution, volumetric quantification of orthotopic primary tumors, liver and lung metastases, and paraspinal skeletal muscle, providing a dynamic view of both tumor and host physiology. MicroCT primary tumor measurements strongly correlated with endpoint tumor weights and outperformed 2D ultrasound in early detection and volumetric accuracy, particularly for small or irregularly shaped tumors. This platform revealed heterogeneous metastatic kinetics across PDAC models and uncovered early, heterogeneous onset of skeletal muscle wasting, a hallmark of cancer cachexia. Notably, this protocol mimics clinical CT surveillance by enabling opportunistic cachexia assessment from tumor imaging datasets and offers substantial advantages over destructive endpoint analyses. Further, microCT radiation had no effect on our model endpoints. By capturing the temporal dynamics of tumor progression and host response, dual contrast microCT serves as a powerful translational platform for preclinical PDAC research and therapeutic testing. SignificanceDual-contrast microCT provides high-resolution, whole-body, non-invasive imaging in orthotopic murine PDAC models, enabling simultaneous tracking of tumor growth, metastasis, and skeletal muscle wasting-offering a clinically relevant, translational imaging platform.

cancer biology↗

bioRxiv2018

Identification of circulating protein biomarkers for pancreatic cancer cachexia

BackgroundOver 80% of patients with pancreatic ductal adenocarcinoma (PDAC) suffer from cachexia, characterized by severe muscle and fat loss. Although various model systems have improved our understanding of cachexia, translating the findings to human cachexia has remained a challenge. In this study, our objectives were to i) identify circulating protein biomarkers using serum for human PDAC cachexia, (ii) identify the ontological functions of the identified biomarkers and (iii) identify new pathways associated with human PDAC cachexia by performing protein co-expression analysis.\n\nMethodsSerum from 30 patients with PDAC was collected. Body composition measurements of skeletal muscle index (SMI), skeletal muscle density (SMD), total adipose index (TAI) were obtained from computed tomography scans (CT). Cancer associated weight loss (CAWL), an ordinal classification of history of weight loss and body mass index (BMI) was obtained from medical record. Serum protein profiles and concentrations were generated using SOMAscan, a quantitative aptamer-based assay. Ontological analysis of the proteins correlated with clinical variables (r[≥] 0.5 and p<0.05) was performed using DAVID Bioinformatics. Protein co-expression analysis was determined using pairwise Spearmans correlation.\n\nResultsOverall, 111 proteins of 1298 correlated with these clinical measures, 48 proteins for CAWL, 19 for SMI, 14 for SMD, and 30 for TAI. LYVE1, a homolog of CD44 implicated in tumor metastasis, was the top CAWL-associated protein (r= 0.67, p=0.0001). Other proteins such as INHBA, MSTN/GDF11, and PIK3R1 strongly correlated with CAWL. Proteins correlated with cachexia included those associated with proteolysis, acute inflammatory response, as well as B cell and T cell activation. Protein co-expression analysis identified networks such as activation of immune related pathways such as B-cell signaling, Th1 and Th2 pathways, natural killer cell signaling, IL6 signaling, and mitochondrial dysfunction.\n\nConclusionTaken together, these data both identify immune system molecules and additional secreted factors and pathways not previously associated with PDAC and confirm the activation of previously identified pathways. Identifying altered secreted factors in serum of PDAC patients may assist in developing minimally invasive laboratory tests for clinical cachexia as well as identifying new mediators.

cancer biology↗

bioRxiv2018

The systemic activin response to pancreatic cancer: Implications for effective cancer cachexia therapy

Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy with high rates of cachexia. Serum activin correlates with PDAC cachexia and mortality, while activin administration causes cachexia in mice. We studied activin in human tumors and in mice with orthotopic or genetic PDAC. Cachexia severity correlated with activin expression in tumor lines. Activins were expressed in both cancer and tumor stromal cells, but also in organs in murine PDAC cachexia. Tumor cells expressed activin-{beta}A, or Inhba, while organs expressed both activin-{beta}A and activin-{beta}B, or Inhbb. PDAC elicits activin expression; PDAC conditioned medium induced activin and atrophy of myotubes. Treatment with the activin trap, ACVR2B/Fc, reduced cachexia and prolonged survival in mice with activin-low tumors, and reduced cachexia in activin-high tumors, without affecting activin expression in organs. Mice expressing dominant negative ACVR2B in muscle were protected for weight loss but not survival. Overall our results indicate that PDAC induces a systemic activin response, leading to cachexia, and that activin targets might include organs beyond muscle. Targeting of both tumor-derived and host-derived activins could improve cachexia therapy.

cancer biology↗