| 1. |
- Binzer-Panchal, Amrei, et al.
(författare)
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Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes
- 2019
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Ingår i: Clinical Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 1078-0432 .- 1557-3265. ; 25:7, s. 2155-2165
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Undifferentiated uterine sarcomas (UUS) are rare, extremely deadly, sarcomas with no effective treatment. The goal of this study was to identify novel intrinsic molecular UUS subtypes using integrated clinical, histopathologic, and molecular evaluation of a large, fully annotated, patient cohort.Experimental Design: Fifty cases of UUS with full clinicopathologic annotation were analyzed for gene expression (n = 50), copy-number variation (CNV, n = 40), cell morphometry (n = 39), and protein expression (n = 22). Gene ontology and network enrichment analysis were used to relate over-and underexpressed genes to pathways and further to clinicopathologic and phenotypic findings.Results: Gene expression identified four distinct groups of tumors, which varied in their clinicopathologic parameters. Gene ontology analysis revealed differential activation of pathways related to genital tract development, extracellular matrix (ECM), muscle function, and proliferation. A multivariable, adjusted Cox proportional hazard model demonstrated that RNA group, mitotic index, and hormone receptor expression influence patient overall survival (OS). CNV arrays revealed characteristic chromosomal changes for each group. Morphometry demonstrated that the ECM group, the most aggressive, exhibited a decreased cell density and increased nuclear area. A cell density cutoff of 4,300 tumor cells per mm(2) could separate ECM tumors from the remaining cases with a sensitivity of 83% and a specificity of 94%. IHC staining of MMP-14, Collagens 1 and 6, and Fibronectin proteins revealed differential expression of these ECM-related proteins, identifying potential new biomarkers for this aggressive sarcoma subgroup. Conclusions: Molecular evaluation of UUS provides novel insights into the biology, prognosis, phenotype, and possible treatment of these tumors.
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| 2. |
- Gultekin, Okan, et al.
(författare)
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FOXP3+ T cells in uterine sarcomas are associated with favorable prognosis, low extracellular matrix expression and reduced YAP activation
- 2021
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Ingår i: npj Precision Oncology. - : Springer Nature. - 2397-768X. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Uterine sarcomas are rare but deadly malignancies without effective treatment. Immunotherapy is a promising new approach to treat these tumors but has shown heterogeneous effects in sarcoma patients. With the goal of identifying key factors for improved patient treatment, we characterized the tumor immune landscape in 58 uterine sarcoma cases with full clinicopathological annotation. Immune cell characterization revealed the overall prevalence of FOXP3+ cells and pro-tumor M2-like macrophages. Hierarchical clustering of patients showed four tumor type-independent immune signatures, where infiltration of FOXP3+ cells and M1-like macrophages associated with favorable prognosis. High CD8+/FOXP3+ ratio in UUS and ESS correlated with poor survival, upregulation of immunosuppressive markers, extracellular matrix (ECM)-related genes and proteins, and YAP activation. This study shows that uterine sarcomas present distinct immune signatures with prognostic value, independent of tumor type, and suggests that targeting the ECM could be beneficial for future treatments.
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| 3. |
- Moyano-Galceran, Lidia, et al.
(författare)
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Adaptive RSK-EphA2-GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer.
- 2020
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- Metastatic cancers commonly activate adaptive chemotherapy resistance, attributed to both microenvironment-dependent phenotypic plasticity and genetic characteristics of cancer cells. However, the contribution of chemotherapy itself to the non-genetic resistance mechanisms was long neglected. Using high-grade serous ovarian cancer (HGSC) patient material and cell lines, we describe here an unexpectedly robust cisplatin and carboplatin chemotherapy-induced ERK1/2-RSK1/2-EphA2-GPRC5A signaling switch associated with cancer cell intrinsic and acquired chemoresistance. Mechanistically, pharmacological inhibition or knockdown of RSK1/2 prevented oncogenic EphA2-S897 phosphorylation and EphA2-GPRC5A co-regulation, thereby facilitating a signaling shift to the canonical tumor-suppressive tyrosine phosphorylation and consequent downregulation of EphA2. In combination with platinum, RSK inhibitors effectively sensitized even the most platinum-resistant EphA2high , GPRC5Ahigh cells to the therapy-induced apoptosis. In HGSC patient tumors, this orphan receptor GPRC5A was expressed exclusively in cancer cells and associated with chemotherapy resistance and poor survival. Our results reveal a kinase signaling pathway uniquely activated by platinum to elicit adaptive resistance. They further identify GPRC5A as a marker for abysmal HGSC outcome and putative vulnerability of the chemo-resistant cells to RSK1/2-EphA2-pS897 pathway inhibition.
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| 4. |
- Moyano Galceran, Lidia
(författare)
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Receptor tyrosine kinase signaling and extracellular matrix cues in ovarian cancer metastasis and drug resistance
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Albeit many studies have contributed towards understanding the origin, development, treatment response and evolution of high-grade serous ovarian carcinoma (HGSC), the exact supporting mechanisms are still not fully understood, and the disease remains a clinical challenge with low 5-year survival and high recurrence rate. The purpose of this thesis was to study the dynamic communication between the cancer cells and the tumor microenvironment (TME) to understand how these influence and are affected by disease progression and chemotherapy in the context of HGSC. In Paper I we uncovered a robust platinum chemotherapy-induced ERK1/2-RSK1/2-EphA2- GPRC5A signaling switch associated with cancer cell intrinsic and acquired chemoresistance. Mechanistically, RSK inhibition halted this signaling switch and even restored the canonical, tumor-suppressive EphA2 signaling, resulting in the efficient sensitization of HGSC cells to platinum treatment in vitro and in vivo. In addition, we described GPRC5A association to chemotherapy response, overall and progression-free survival in HGSC patients. In Paper II we reported that the ligand ephrinA5 was highly expressed in the most aggressive ovarian cancer type (i.e. HGSC) and further upregulated both at the protein and mRNA levels upon disease progression. Functionally, ephrinA5 left unaffected or even impaired EphA2 tumorsuppressive signaling. In Paper III we characterized the matrisome of HGSC solid tumors (primary and different metastatic sites) and ascites, pre- and post-chemotherapy. We showed that extracellular matrix (ECM) stiffness promoted cell proliferation and spreading (via focal adhesion kinase and YAP/TAZ signaling), and protected HGSC cells against cisplatinmediated, apoptosis-inducing DNA damage. In addition, we reported that different ECM components altered cell adhesion, migration and chemoresistance in diverse ways. In particular, collagen VI enhanced the chemoresistance of disease-recurrent, patient-derived organoids, was upregulated in HGSC patients upon chemotherapy and associated to poor survival. In conclusion, the findings of this thesis help us to better understand how ovarian cancer cells activate specific signaling mechanisms and engage in altered ECM remodeling and TME interactions that enhance cancer cell growth, metastatic and chemoresistance capabilities.
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| 5. |
- Schoutrop, Esther, et al.
(författare)
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Mesothelin-Specific CAR T Cells Target Ovarian Cancer
- 2021
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Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 81:11, s. 3022-3035
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Tidskriftsartikel (refereegranskat)abstract
- New therapeutic options for patients with ovarian cancer are urgently needed. Therefore, we evaluated the efficacy of two second-generation mesothelin (MSLN)-directed CAR T cells in orthotopic mouse models of ovarian cancer. Treatment with CAR T cells expressing an MSLN CAR construct including the CD28 domain (M28z) significantly prolonged survival, but no persistent tumor control was observed. Despite lower response rates, MSLN-4-1BB (MBBz) CAR T cells induced long-term remission in some SKOV3-bearing mice. Tumor-infiltrating M28z and MBBz CAR T cells upregulated PD-1 and LAG3 in an antigen-dependent manner while MSLN+ tumor cells expressed the corresponding ligands (PD-L1 and HLA-DR), demonstrating that coin-hibitory pathways impede CAR T-cell persistence in the ovarian tumor microenvironment. Furthermore, profiling plasma soluble factors identified a cluster of M28z- and MBBz-treated mice characterized by elevated T-cell secreted factors that had increased survival, higher CD8(+) T-cell tumor infiltration, less exhausted CAR T-cell phenotypes, and increased HLA-DR expression by tumor cells. Altogether, our study demonstrates the therapeutic potential of MSLN-CAR T cells to treat ovarian cancer. Significance: These findings demonstrate that MSLN-directed CAR T cells can provide antitumor immunity against ovarian cancer.
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