Determinants of early-onset cachexia in transgenic mouse model of pancreatic cancer
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PROVIDER: PRJNA885622 | ENA |
REPOSITORIES: ENA
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Project description:Since the lack of understanding of signaling mechanisms in cancer cachexia progress, the exact time point of cachexia onset remains unpredictable. To determine the molecular phenotypes of single cells at the utmost approximated timepoint of cachexia onset, we hypothesized that the tumor microenvironment and circulating blood cells could serve as biomarkers of cachexia-onset to map out the determinants of muscle wasting in a mouse model of cancer cachexia. Depending on individual tumors, subcutaneous syngeneic implantation of xenografts derived from the transgenic KrasG12D/+;Trp53flox/flox;Pdx1-Cre mouse model of pancreatic cancer-induced early-onset cachexia (EOCX) and Pre-cachexia (PreCX) in individual recipient mice. To characterize the dominants of cachexia-onset, immediate fresh collection of samples and processing for single-cell RNA sequencing, allowed the analysis of gene expression in the subcutaneous xenografted tumors and the peripheral blood mononuclear cells (PBMC) at the single-cell level. Our dataset classified high-quality cells-- 29,885 PBMCs and 24,925 subcutaneous tumor cells into subtypes. By dissecting the differentially expressed markers genes of EOCX versus the PreCX, these markers may represent the determinants of cachexia in multiple cell types in circulating PBMCs and in tumors at the single-cell resolution.
2025-08-13 | GSE214497 | GEO
Project description:Cachexia frequently develops in patients with pancreatic ductal adenocarcinoma (PDAC) and contributes to cancer deaths.Sex differences have been observed in cancer cachexia; however, the underlying molecular mechanisms are far less addressed. We assessed sex difference in PDAC cachexia phenotypes in the KPC (Kras-G12D;Trp-R172H;Pdx1::Cre) genetically engineered mouse model of PDAC and profiled gene expression in the quadriceps skeletal muscles. Males with PDAC experienced earlier cachexia-onset than the female counterpart and activin blockade by ACVR2B/Fc reduced cachexia sympotomes in males but not females. PDAC induced earlier global transcritome alterations in males than females.
2022-05-10 | GSE157251 | GEO
Project description:Pancreatic cancer is characterized by a high frequency of cachexia, pain and neural invasion (N-inv). Neural damage is occurred by N-inv and modulates pain and muscle atrophy via the activation of astrocyte in the connected spine. The activated astrocyte by N-inv, thus, may affect cachexia in pancreatic cancer. Clinical studies in patients and autopsy cases with pancreatic cancer have revealed that N-inv is related to cachexia and astrocytic activation. We established a novel murine model of cancer cachexia using N-inv of human pancreatic cancer cells. Mice with N-inv showed a loss of body weight, skeletal muscle, and fat mass without appetite loss, which are compatible with an animal model of cancer cachexia. Activation of astrocytes in the spinal cord connected with N-inv was observed in our model. Experimental cachexia was suppressed by disrupting neural routes or inhibiting the activation of astrocytes. These data provide the first evidence that N-inv induces cachexia via astrocytic activation of neural route in pancreatic cancer. We produced neural invasion (N-inv) model using intraneural injection of Capan-1 cells to left sciatic nerve of male SCID mouse. For controls, subcutaneous model (SC) and PBS model were produced. Microarray analysis was performed using the first lumbar cord (L1) from PBS, SC, and N-inv mice at 6 w (n = 2 each).
2011-12-07 | E-GEOD-34189 | biostudies-arrayexpress
Project description:More than 85% of patients with pancreatic ductal adenocarcinoma (PDAC) suffer from cachexia, a debilitating syndrome characterized by loss of muscle and fat. To model PDAC cachexia in mice, 12-week-old C57BL/6J male mice were implanted with the cachexia inducing pancreatic cell line, KPC32908, into the pancreas. Controls underwent a sham surgery. Mice were euthanized under isoflurane anesthesia when the tumor-bearing mice exhibited cachexia, including ~18% loss of quadriceps mass versus sham controls. Quadriceps muscle was flash frozen at euthanasia. 1mg quadriceps protein lysate per sample was used for kinome profiling.
2025-04-21 | PXD047411 | Pride
Project description:Pancreatic cancer is characterized by a high frequency of cachexia, pain and neural invasion (N-inv). Neural damage is occurred by N-inv and modulates pain and muscle atrophy via the activation of astrocyte in the connected spine. The activated astrocyte by N-inv, thus, may affect cachexia in pancreatic cancer. Clinical studies in patients and autopsy cases with pancreatic cancer have revealed that N-inv is related to cachexia and astrocytic activation. We established a novel murine model of cancer cachexia using N-inv of human pancreatic cancer cells. Mice with N-inv showed a loss of body weight, skeletal muscle, and fat mass without appetite loss, which are compatible with an animal model of cancer cachexia. Activation of astrocytes in the spinal cord connected with N-inv was observed in our model. Experimental cachexia was suppressed by disrupting neural routes or inhibiting the activation of astrocytes. These data provide the first evidence that N-inv induces cachexia via astrocytic activation of neural route in pancreatic cancer.
2011-12-07 | GSE34189 | GEO
Project description:Cancer cachexia syndrome is observed in 80% of patients with advanced-stage cancer, and it is one of the most frequent causes of death. Severe wasting accounts for more than 80% in patients with advanced pancreatic cancer. Here we wanted to define, by using an microarray approach and the Pdx1-cre;LSL-KrasG12D;INK4a/arffl/fl, the pathways involved in muscle, liver and white adipose tissue wasting. The aim of our work was to characterize as extensively as possible the pathways activated by the pancreatic cancer-induced cachectic tissues. For this purpose, we generated and compared genome-wide expression profiles of white adipose tissue, skeletal muscle and liver, from Pdx1-cre;LSL-KrasG12D;INK4a/arffl/fl and LSL-KrasG12D;INK4a/arffl/fl mice at 10 weeks-old. Tissue samples by triplicate was obtained from liver, muscle and adipose tissues in both groups, controls and cachectic mice. Total RNA samples was processed and profiled on Affymetrix Mouse Gene 1.0 ST arrays as previously described (Cano et al, 2012)
2014-01-10 | E-GEOD-51931 | biostudies-arrayexpress
Project description:Cancer cachexia syndrome is observed in 80% of patients with advanced-stage cancer, and it is one of the most frequent causes of death. Severe wasting accounts for more than 80% in patients with advanced pancreatic cancer. Here we wanted to define, by using an microarray approach and the Pdx1-cre;LSL-KrasG12D;INK4a/arffl/fl, the pathways involved in muscle, liver and white adipose tissue wasting.
2014-01-10 | GSE51931 | GEO
Project description:The aim of the study is to test if Gemcitabine in combination with nab-paclitaxel can prevent muscle wasting and cardiac dysfunction in a mouse model of pancreatic cancer cachexia.
2025-04-04 | GSE234545 | GEO
Project description:Background. Pancreatic Ductal AdenoCarcinoma (PDAC), the most frequent pancreatic cancer, is a deadly cancer since often diagnosed late and resistant to current therapies. A high proportion of PDAC patients are affected by cachexia induced by the tumor. This cachexia, characterized by loss of muscle mass and strength, contributes to patient frailty and poor therapeutic response. We showed that mitochondrial metabolism is reprogrammed in PDAC tumor cell and constitutes a vulnerability, opening novel therapeutic avenues. The objective of the present work was to investigate the molecular mechanisms underlying mitochondrial remodeling in PDAC cachectic skeletal muscle. Methods. Our study focused on the gastrocnemius muscle of genetically-engineered mice developing spontaneously a PDAC associated with cachexia (KIC GEMM). We compared KIC mice developing a pancreatic tumor in 9-10 weeks to control littermates. We did an integrative study combining in vivo functional analyses by non-invasive Magnetic Resonance, and ex-vivo histology, Seahorse, RNA-sequencing, and proteomic mass spectrometry and western blotting analyses. Results. The cachectic KIC PDAC mice show a severe sarcopenia with loss of muscle mass and strength associated with a diminution in muscle fiber’s size and induction of protein degradation processes. Mitochondria in PDAC atrophic muscles show decreased respiratory capacities and structural alterations (“hyperfused” mitochondria), associated with deregulation of oxidative phosphorylation and mitochondrial dynamics pathways at the molecular level. Increased expression of multiple reactive oxygen species (ROS) defense genes suggests oxidative stress prone to affect mitochondrial macromolecules and homeostasis. Interestingly, multiple genes and proteins involved in DNA metabolism pathways, such as DNA damage, degradation of DNA, nucleotide synthesis, and folate pathway were found altered in sarcopenic mitochondria. While the number of mitochondria was not changed, the mitochondrial mass was decreased by a factor of 2 and the mitochondrial DNA by a factor of 3, suggesting a defect in mitochondrial genome homeostasis. Conclusions. We unveiled that mitochondrial alterations in skeletal muscle play a central role in PDAC-induced cachexia. Muscle atrophy is associated with strong mitochondrial metabolic defects that are not limited to carbohydrates and protein, but concern also lipids, ROS and nucleic acids. Our data provide a frame to guide towards the most relevant molecular markers that would be affected at the start of tumor development and could be targets in the clinic to limit PDAC-induced cachexia at early stages of the pathology.
2024-04-09 | PXD036752 | Pride
Project description:Pancreatic Ductal AdenoCarcinoma (PDAC), the most common pancreatic cancer, is a deadly cancer since it is often diagnosed late and resistant to current therapies. A large proportion of PDAC patients are affected by tumor-induced cachexia. This cachexia, characterized by a loss of muscle mass and strength (sarcopenia), contributes to patient frailty and poor therapeutic response. We have shown that mitochondrial metabolism is reprogrammed in PDAC tumors and constitutes a vulnerability, opening new therapeutic avenues. The objective of this work was to study the molecular mechanisms underlying mitochondrial remodeling in PDAC cachectic skeletal muscle. Our study focused on the gastrocnemius muscle of genetically-engineered mice spontaneously developing an autochthonous pancreatic tumor and cachexia (KIC GEMM). We compared KIC mice developing a pancreatic tumor in 9-11 weeks to control littermates. We performed an integrative study combining in vivo functional analyses by non-invasive Magnetic Resonance, and ex-vivo histology, Seahorse, RNA-sequencing, and proteomic mass spectrometry and Western blotting analyses. KIC cachectic PDAC mice exhibit severe sarcopenia with loss of muscle mass and strength associated with reduced muscle fiber’s size and induction of protein degradation processes. Mitochondrial alterations in skeletal muscle play a central role in PDAC-induced cachexia. Muscle atrophy is associated with strong mitochondrial metabolic defects that are not limited to carbohydrates and protein metabolism, but concern also lipids, ROS and nucleic acids. Our data provide a framework to guide towards the most relevant molecular markers that would be affected early in tumor development and could be targeted in the clinic to limit PDAC-induced cachexia at early stages of the pathology.
2024-03-11 | GSE226898 | GEO