About this Research Topic
Pancreatic Ductal Adenocarcinoma (PDAC) is now on track to become the second commonest cause of cancer death in the world. Advances in surgery and the development of new chemotherapy regimens have markedly improved survival after surgery for PDAC. However, despite these advances the 5-year survival rate for the majority of unselected patients remains below 9%.
Large scale omics technologies have transformed our understanding of PDAC. These technologies have defined molecular phenotypes (genotypes) that now guide pre-clinical and clinical therapeutic development. Multimodal mapping of PDAC using single cell RNAseq and spatial transcriptomics has identified diverse cell populations resident in tumour samples providing unparalleled insight into PDAC tumour biology.
The development of advanced patient-derived organotypic models and new genetically engineered mouse models (GEMMs) of PDAC is driving the real time translation of emergent drug therapies into the clinic. Patient derived organoids, in particular, are emerging as a pre-eminent model system for PDAC translational research. Grown in 3D scaffolds, these organ-like tumour structures faithfully recapitulate patient sample phenotypes (genotypes) offering a tractable model system for high through-put pharmacogenomics and discovery.
This Research Topic focuses on key aspects of PDAC translational research and how organoids can be utilized to understand complex tumour biology, mechanisms of drug response and for the development/testing of new therapeutic opportunities. The application of emerging organotypic analysis platforms such as organ-on-a-chip platforms, ex vivo tissue culture and high-throughput pharmacogenomic drug screening will be discussed.
A distinguishing feature of PDAC is the abundance of stroma, the collective of non-tumor cells including cancer-associated fibroblasts (CAFs), immune cells, extracellular matrix, and endothelium that exceeds 80% of the tumor mass. Reciprocal signaling between stroma and tumor drives progression, metastasis, therapy resistance and bioavailability of chemotherapeutics. New models that better describe tumor-stroma interaction are required, including how different cellular origins of CAFs result in opposing stromal contributions and outcomes in PDAC. We will describe current advances in organoid-based co-culture model systems for PDAC and their advantages.
Intra-tumoral heterogeneity represents an important clinical challenge, with distinct populations of tumour cells providing a pool of genetic variation that may drive cancer progression and lead to the emergence of drug resistant sub-clones. Advances in genomics are providing new insights into the clonal architecture of PDAC and have defined tumour cell intrinsic phenotypes that exhibit remarkable plasticity. PDAC cells undergo epithelial-mesenchymal transition (EMT) in response to changes in the tumour microenvironment. EMT contributes to drug-resistant clonal expansions, the acquisition of stem cell features and metastatic colonization. Transcription factor networks governing PDAC cell plasticity, EMT, metastasis and drug resistance will be defined, and we will describe how organoid-based models, together with gene editing technologies, can be used to understand and target these transcription factor networks.
Selective targeting of specific immune cell populations and/or immunomodulatory mechanisms (e.g., myeloid cell inhibition and immune checkpoint inhibition) is a promising therapeutic strategy for PDAC. Despite the successful application of immune checkpoint (IC) inhibitors in several cancer types, IC therapies promote marginal responses in PDAC. Mechanisms governing response to immunotherapy and how organoid co-culture systems can be used to develop enhanced strategies for immunotherapy will be discussed. Finally, we will describe how tumour cell intrinsic innate immune pathways contribute to disease progression and how these pathways can be selectively targeted to promote the immune destruction of tumour cells.
Large scale omics technologies have transformed our understanding of PDAC. These technologies have defined molecular phenotypes (genotypes) that now guide pre-clinical and clinical therapeutic development. Multimodal mapping of PDAC using single cell RNAseq and spatial transcriptomics has identified diverse cell populations resident in tumour samples providing unparalleled insight into PDAC tumour biology.
The development of advanced patient-derived organotypic models and new genetically engineered mouse models (GEMMs) of PDAC is driving the real time translation of emergent drug therapies into the clinic. Patient derived organoids, in particular, are emerging as a pre-eminent model system for PDAC translational research. Grown in 3D scaffolds, these organ-like tumour structures faithfully recapitulate patient sample phenotypes (genotypes) offering a tractable model system for high through-put pharmacogenomics and discovery.
This Research Topic focuses on key aspects of PDAC translational research and how organoids can be utilized to understand complex tumour biology, mechanisms of drug response and for the development/testing of new therapeutic opportunities. The application of emerging organotypic analysis platforms such as organ-on-a-chip platforms, ex vivo tissue culture and high-throughput pharmacogenomic drug screening will be discussed.
A distinguishing feature of PDAC is the abundance of stroma, the collective of non-tumor cells including cancer-associated fibroblasts (CAFs), immune cells, extracellular matrix, and endothelium that exceeds 80% of the tumor mass. Reciprocal signaling between stroma and tumor drives progression, metastasis, therapy resistance and bioavailability of chemotherapeutics. New models that better describe tumor-stroma interaction are required, including how different cellular origins of CAFs result in opposing stromal contributions and outcomes in PDAC. We will describe current advances in organoid-based co-culture model systems for PDAC and their advantages.
Intra-tumoral heterogeneity represents an important clinical challenge, with distinct populations of tumour cells providing a pool of genetic variation that may drive cancer progression and lead to the emergence of drug resistant sub-clones. Advances in genomics are providing new insights into the clonal architecture of PDAC and have defined tumour cell intrinsic phenotypes that exhibit remarkable plasticity. PDAC cells undergo epithelial-mesenchymal transition (EMT) in response to changes in the tumour microenvironment. EMT contributes to drug-resistant clonal expansions, the acquisition of stem cell features and metastatic colonization. Transcription factor networks governing PDAC cell plasticity, EMT, metastasis and drug resistance will be defined, and we will describe how organoid-based models, together with gene editing technologies, can be used to understand and target these transcription factor networks.
Selective targeting of specific immune cell populations and/or immunomodulatory mechanisms (e.g., myeloid cell inhibition and immune checkpoint inhibition) is a promising therapeutic strategy for PDAC. Despite the successful application of immune checkpoint (IC) inhibitors in several cancer types, IC therapies promote marginal responses in PDAC. Mechanisms governing response to immunotherapy and how organoid co-culture systems can be used to develop enhanced strategies for immunotherapy will be discussed. Finally, we will describe how tumour cell intrinsic innate immune pathways contribute to disease progression and how these pathways can be selectively targeted to promote the immune destruction of tumour cells.
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