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1.
PLoS One ; 19(4): e0301413, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38635728

RESUMO

Incidence of endometrial cancer (EC) is rising in the developed world. The current standard of care, hysterectomy, is often infeasible for younger patients and those with high body mass index. There are limited non-surgical treatment options and a lack of biologically relevant research models to investigate novel alternatives to surgery for EC. The aim of the present study was to develop a long-term, patient-derived explant (PDE) model of early-stage EC and demonstrate its use for investigating predictive biomarkers for a current non-surgical treatment option, the levonorgestrel intra-uterine system (LNG-IUS). Fresh tumour specimens were obtained from patients with early-stage endometrioid EC. Tumours were cut into explants, cultured on media-soaked gelatin sponges for up to 21 days and treated with LNG. Formalin-fixed, paraffin embedded (FFPE) blocks were generated for each explant after 21 days in culture. Tumour architecture and integrity were assessed by haematoxylin and eosin (H&E) and immunohistochemistry (IHC). IHC was additionally performed for the expression of five candidate biomarkers of LNG resistance. The developed ex vivo PDE model is capable of culturing explants from early-stage EC tumours long-term (21 Days). This model can complement existing models and may serve as a tool to validate results obtained in higher-throughput in vitro studies. Our study provides the foundation to validate the extent to which EC PDEs reflect patient response in future research.


Assuntos
Neoplasias do Endométrio , Dispositivos Intrauterinos Medicados , Feminino , Humanos , Levanogestrel/farmacologia , Neoplasias do Endométrio/patologia , Histerectomia , Biomarcadores
2.
Cancers (Basel) ; 13(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067833

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and no significant improvement in patient survival has been seen in the past three decades. Treatment options are limited and selection of chemotherapy in the clinic is usually based on the performance status of a patient rather than the biology of their disease. In recent years, research has attempted to unlock a personalised treatment strategy by identifying actionable molecular targets in tumour cells or using preclinical models to predict the effectiveness of chemotherapy. However, these approaches rely on the biology of PDAC tumour cells only and ignore the importance of the microenvironment and fibrotic stroma. In this review, we highlight the importance of the microenvironment in driving the chemoresistant nature of PDAC and the need for preclinical models to mimic the complex multi-cellular microenvironment of PDAC in the precision medicine pipeline. We discuss the potential for ex vivo whole-tissue culture models to inform precision medicine and their role in developing novel therapeutic strategies that hit both tumour and stromal compartments in PDAC. Thus, we highlight the critical role of the tumour microenvironment that needs to be addressed before a precision medicine program for PDAC can be implemented.

3.
Cancer Res ; 81(13): 3461-3479, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33980655

RESUMO

Cancer-associated fibroblasts (CAF) are major contributors to pancreatic ductal adenocarcinoma (PDAC) progression through protumor signaling and the generation of fibrosis, the latter of which creates a physical barrier to drugs. CAF inhibition is thus an ideal component of any therapeutic approach for PDAC. SLC7A11 is a cystine transporter that has been identified as a potential therapeutic target in PDAC cells. However, no prior study has evaluated the role of SLC7A11 in PDAC tumor stroma and its prognostic significance. Here we show that high expression of SLC7A11 in human PDAC tumor stroma, but not tumor cells, is independently prognostic of poorer overall survival. Orthogonal approaches showed that PDAC-derived CAFs are highly dependent on SLC7A11 for cystine uptake and glutathione synthesis and that SLC7A11 inhibition significantly decreases CAF proliferation, reduces their resistance to oxidative stress, and inhibits their ability to remodel collagen and support PDAC cell growth. Importantly, specific ablation of SLC7A11 from the tumor compartment of transgenic mouse PDAC tumors did not affect tumor growth, suggesting the stroma can substantially influence PDAC tumor response to SLC7A11 inhibition. In a mouse orthotopic PDAC model utilizing human PDAC cells and CAFs, stable knockdown of SLC7A11 was required in both cell types to reduce tumor growth, metastatic spread, and intratumoral fibrosis, demonstrating the importance of targeting SLC7A11 in both compartments. Finally, treatment with a nanoparticle gene-silencing drug against SLC7A11, developed by our laboratory, reduced PDAC tumor growth, incidence of metastases, CAF activation, and fibrosis in orthotopic PDAC tumors. Overall, these findings identify an important role of SLC7A11 in PDAC-derived CAFs in supporting tumor growth. SIGNIFICANCE: This study demonstrates that SLC7A11 in PDAC stromal cells is important for the tumor-promoting activity of CAFs and validates a clinically translatable nanomedicine for therapeutic SLC7A11 inhibition in PDAC.


Assuntos
Sistema y+ de Transporte de Aminoácidos/antagonistas & inibidores , Anticorpos Monoclonais/farmacologia , Fibroblastos Associados a Câncer/efeitos dos fármacos , Carcinoma Ductal Pancreático/prevenção & controle , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pancreáticas/prevenção & controle , Microambiente Tumoral , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/imunologia , Animais , Apoptose , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/patologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias Pancreáticas
4.
Sci Rep ; 11(1): 1944, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33479301

RESUMO

The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is attributed to the highly fibrotic stroma and complex multi-cellular microenvironment that is difficult to fully recapitulate in pre-clinical models. To fast-track translation of therapies and to inform personalised medicine, we aimed to develop a whole-tissue ex vivo explant model that maintains viability, 3D multicellular architecture, and microenvironmental cues of human pancreatic tumours. Patient-derived surgically-resected PDAC tissue was cut into 1-2 mm explants and cultured on gelatin sponges for 12 days. Immunohistochemistry revealed that human PDAC explants were viable for 12 days and maintained their original tumour, stromal and extracellular matrix architecture. As proof-of-principle, human PDAC explants were treated with Abraxane and we observed different levels of response between patients. PDAC explants were also transfected with polymeric nanoparticles + Cy5-siRNA and we observed abundant cytoplasmic distribution of Cy5-siRNA throughout the PDAC explants. Overall, our novel model retains the 3D architecture of human PDAC and has advantages over standard organoids: presence of functional multi-cellular stroma and fibrosis, and no tissue manipulation, digestion, or artificial propagation of organoids. This provides unprecedented opportunity to study PDAC biology including tumour-stromal interactions and rapidly assess therapeutic response to drive personalised treatment.


Assuntos
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Técnicas de Cultura de Células , Organoides/patologia , Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Matriz Extracelular/patologia , Matriz Extracelular/ultraestrutura , Humanos , Organoides/ultraestrutura , Pâncreas/patologia , Pâncreas/ultraestrutura , Microambiente Tumoral/genética
5.
Biomaterials ; 240: 119742, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32088410

RESUMO

Pancreatic cancer is predicted to be the second leading cause of cancer-related death by 2025. The best chemotherapy only extends survival by an average of 18 weeks. The extensive fibrotic stroma surrounding the tumor curbs therapeutic options as chemotherapy drugs cannot freely penetrate the tumor. RNA interference (RNAi) has emerged as a promising approach to revolutionize cancer treatment. Small interfering RNA (siRNA) can be designed to inhibit the expression of any gene which is important given the high degree of genetic heterogeneity present in pancreatic tumors. Despite the potential of siRNA therapies, there are hurdles limiting their clinical application such as poor transport across biological barriers, limited cellular uptake, degradation, and rapid clearance. Nanotechnology can address these challenges. In fact, the past few decades have seen the conceptualization, design, pre-clinical testing and recent clinical approval of a RNAi nanodrug to treat disease. In this review, we comment on the current state of play of clinical trials evaluating siRNA nanodrugs and review pre-clinical studies investigating the efficacy of siRNA therapeutics in pancreatic cancer. We assess the physiological barriers unique to pancreatic cancer that need to be considered when designing and testing new nanomedicines for this disease.


Assuntos
Nanopartículas , Neoplasias Pancreáticas , Preparações Farmacêuticas , Inativação Gênica , Humanos , Nanomedicina , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Interferência de RNA , RNA Interferente Pequeno/genética
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