Genomic resemblance of mouse models to human hepatocellular carcinoma matogenous metastasis of ovarian cancer: Re-thinking mode of spread
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PROVIDER: PRJNA434135 | ENA |
REPOSITORIES: ENA
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Project description:Ovarian cancer has a clear predilection for metastasis to the omentum, but the underlying mechanisms involved in ovarian cancer spread are not well understood. Here, we used a parabiosis model that demonstrates preferential hematogenous metastasis of ovarian cancer to the omentum. Our studies revealed that the ErbB3-neuregulin1 (NRG1) axis is a dominant pathway responsible for hematogenous omental metastasis. Elevated levels of ErbB3 in ovarian cancer cells and NRG1 in the omentum allowed for tumor cell localization and growth in the omentum. Depletion of ErbB3 in ovarian cancer substantially impaired omental metastasis. Our results highlight hematogenous metastasis as a previously under-recognized mode of ovarian cancer metastasis. These findings have implications for designing new strategies aimed at preventing and treating ovarian cancer metastasis.
2014-07-14 | GSE52999 | GEO
Project description:Two groupsHepatocellular carcinoma (HCC) is a heterogeneous malignant disease with molecularly and clinically distinct subtypes discovered in genomic studies. Mouse models are commonly used as preclinical model to study hepatocarcinogenesis, but how well these models recapitulate molecular subtypes of human HCC is unclear. Thus, we aimed to correlate nine mouse HCC models with clinical subtypes of human HCC by systematically comparing their genomic data. By integrating nine molecularly and clinically defined genomic signatures for human HCC with genomic data from nine mouse HCC models, we identified the mouse models that best resembled subtypes of human HCC and determined the clinical relevance of each model. Mst1/2 KO, Sav1 KO, and SV40 T antigen mouse model best recapitulated poor prognostic subtypes of human HCC, whereas the Myc transgenic model best resembled human HCCs with more favorable prognoses. The Myc model was also significantly associated with activation of β-catenin. E2f1, E2f1/Myc, E2f1/Tgfa, and diethylnitrosamine (DENA)-induced models were heterogeneous and were unequally split to poor and favorable prognoses. Most interestingly, Mst1/2 KO and Sav1 KO models best resembles human HCC with hepatic stem cell characteristics. When we applied a genomic predictor for immunotherapy, the six-gene interferon-γ (IFNG6) score, Mst1/2 KO, Sav1 KO, SV40, and DEN models were predicted to be the least responsive to immunotherapy. Further analysis of immune checkpoint genes showed that high expression of immune inhibitory genes (Cd276 and Pvrl2) in Mst1/2 KO, Sav1 KO, SV40 and low expression of immune stimulatory genes (Cd86) in DENA model might be accountable for lack of predictive response to immunotherapy. Conclusion: Most of the mouse models effectively recapitulated molecular characteristics of human subtypes, including response to immunotherapy. of samples are included: 1.SKOV3-ip1 2.SKOV3-OM3. Gene expression profiles of SKOV3-OM3 cells were compared to that of parental SKOV3 ip1 cells.
2019-01-01 | GSE110627 | GEO
Project description:Ovarian cancer has a clear predilection for metastasis to the omentum, but the underlying mechanisms involved in ovarian cancer spread are not well understood. Here, we used a parabiosis model that demonstrates preferential hematogenous metastasis of ovarian cancer to the omentum. Our studies revealed that the ErbB3-neuregulin 1 (NRG1) axis is a dominant pathway responsible for hematogenous omental metastasis. Elevated levels of ErbB3 in ovarian cancer cells and NRG1 in the omentum allowed for tumor cell localization and growth in the omentum. Depletion of ErbB3 in ovarian cancer impaired omental metastasis. Our results highlight hematogenous metastasis as an important mode of ovarian cancer metastasis. These findings have implications for designing alternative strategies aimed at preventing and treating ovarian cancer metastasis.
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Project description:Epithelial ovarian cancer (EOC) is a high-risk cancer presenting with heterogeneous tumors. The high incidence of EOC metastasis from primary tumors to nearby tissues and organs is a major driver of EOC lethality. We used cellular models of spheroid formation and re-adherence to investigate cellular signaling dynamics in each step toward EOC metastasis. In our system, adherent cells model primary tumors, spheroids formation represents the initiation of metastatic spread, while re-adherent spheroid cells represent secondary tumors. Proteomic and phosphoproteomic analyses show that spheroid cells are hypoxic and show markers for cell cycle arrest. Aurora kinase B (AURKB) abundance and downstream substrate phosphorylation are significantly reduced in spheroids and re-adherent cells, explaining their cell cycle arrest phenotype. The proteome of re-adherent cells is most similar to spheroids, yet greater changes in the phosphoproteome show that spheroid cells stimulate Rho-associated kinase 1 (ROCK1) mediated signaling, which controls cytoskeletal organization. In spheroids, we found significant phosphorylation of ROCK1 substrates that were reduced in both adherent and re-adherent cells. Application of the ROCK1-specific inhibitor Y-27632 to spheroids increased the rate of re-adherence and spheroid density. The data suggest ROCK1 inhibition increases EOC metastatic potential. We identified novel pathways controlled by AURKB and ROCK1 as major drivers of metastatic behavior in EOC cells. Our data show that phosphoproteomic reprogramming precedes proteomic changes that characterize spheroid re-adherence in EOC metastasis.
2024-01-26 | PXD043220 | Pride
Project description:Hematogenous metastasis of ovarian cancer: Re-thinking mode of spread
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Project description:For patients with unresectable colorectal cancer liver metastases, preclinical studies have shown that after the resistance of cetuximab, the treatment sensitivity can be restored by stopping cetuximab for a period of time. This is called the cetuximab re-challenge. And the circulating tumor DNA (ctDNA) test is reported a biomarker for the efficacy of cetuximab rechallenge. However, there is still no randomized controlled trial for verification. This study aims at patients after the first-line treatment of cetuximab has progressed. After the second-line non-cetuximab treatment has progressed, the effects of re-application of combined with cetuximab and chemotherapy alone are compared to verify the re-challenge effect.
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Project description:Emerging evidence suggest that many high-grade serous "ovarian" cancers (HGSOC) start in the fallopian tube. Cancer cells are then recruited to the ovary and then spread diffusely through the abdomen. The mechanism of ovarian cancer spread was thought to be largely due to direct shedding of tumor cells into the peritoneal cavity with vascular spread being of limited importance. Recent work challenges this dogma, suggesting hematogenous spread of ovarian cancer may play a larger role in ovarian cancer cell metastasis than previously thought. One reason the role of vascular spread of ovarian cancer has not been fully elucidated is the lack of easily accessible models of vascular ovarian cancer metastasis. Here, we present 3 metastatic models of ovarian cancer which confirm the ability of ovarian cancer to hematogenously spread. Strikingly, we observe a high rate of metastasis to the ovary with the development of ascites in these models. Interestingly, oophorectomy resulted in a complete loss of peritoneal metastases and ascites. Taken together, our data indicate that hematogenously disseminated HGSOC cells have a unique tropism for the ovary and that hematogenous spread in ovarian cancer may be more common than appreciated. Furthermore, our studies support a critical role for the ovary in promoting HGSOC cell metastasis to the abdomen. The models developed here represent important new tools to evaluate both the mechanism of cancer cell recruitment to the ovary and understand and target key steps in ovarian cancer metastasis.
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Project description:The mpox outbreak of 2022–2023 involved rapid global spread in men who have sex with men. We infected 18 rhesus macaques with mpox by the intravenous, intradermal, and intrarectal routes and observed robust antibody and T cell responses following all three routes of infection. Numerous skin lesions and high plasma viral loads were observed following intravenous and intradermal infection. Skin lesions peaked on day 10 and resolved by day 28 following infection. On day 28, we re-challenged all convalescent and 3 naive animals with mpox. All convalescent animals were protected against re-challenge. Transcriptomic studies showed upregulation of innate and inflammatory responses and downregulation of collagen formation and extracellular matrix organization following challenge, as well as rapid activation of T cell and plasma cell responses following re-challenge. These data suggest key mechanistic insights into mpox pathogenesis and immunity. This macaque model should prove useful for evaluating mpox vaccines and therapeutics.
2023-09-29 | GSE234118 | GEO
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