Immune evasion is a hallmark of KRAS-driven cancers, but the underlying causes remain unresolved. Here, we use a mouse model of pancreatic ductal adenocarcinoma to inactivate KRAS by CRISPR-mediated genome editing. We demonstrate that at an advanced tumor stage, dependence on KRAS for tumor growth is reduced and is manifested in the suppression of antitumor immunity. KRAS-deficient cells retain the ability to form tumors in immunodeficient mice. However, they fail to evade the host immune system in syngeneic wild-type mice, triggering strong antitumor response. We uncover changes both in tumor cells and host immune cells attributable to oncogenic KRAS expression. We identify BRAF and MYC as key mediators of KRAS-driven tumor immune suppression and show that loss of BRAF effectively blocks tumor growth in mice. Applying our results to human PDAC we show that lowering KRAS activity is likewise associated with a more vigorous immune environment.
Our study results demonstrate the feasibility of developing gastric cancer PDOs from EGD biopsies. These results also indicate that endoscopic-derived PDOs are accurate surrogates of the primary tumor and have the potential for drug sensitivity screening and personalized medicine applications.
Cancers arising from the bladder urothelium often exhibit lineage plasticity with regions of urothelial carcinoma adjacent to or admixed with regions of divergent histomorphology, most commonly squamous differentiation. To define the biologic basis for and clinical significance of this morphologic heterogeneity, here we perform integrated genomic analyses of mixed histology bladder cancers with separable regions of urothelial and squamous differentiation. We find that squamous differentiation is a marker of intratumoral genomic and immunologic heterogeneity in patients with bladder cancer and a biomarker of intrinsic immunotherapy resistance. Phylogenetic analysis confirms that in all cases the urothelial and squamous regions are derived from a common shared precursor. Despite the presence of marked genomic heterogeneity between co-existent urothelial and squamous differentiated regions, no recurrent genomic alteration exclusive to the urothelial or squamous morphologies is identified. Rather, lineage plasticity in bladder cancers with squamous differentiation is associated with loss of expression of FOXA1, GATA3, and PPARG, transcription factors critical for maintenance of urothelial cell identity. Of clinical significance, lineage plasticity and PD-L1 expression is coordinately dysregulated via FOXA1, with patients exhibiting morphologic heterogeneity pre-treatment significantly less likely to respond to immune checkpoint inhibitors.
Genomic analysis of a patients' tumor is the cornerstone of precision oncology, but it doesn't address whether metastases should be treated differently. Here we tested whether comparative scRNA-seq of a primary small intestinal neuroendocrine tumor to a matched liver metastasis could guide treatment of a patients' metastatic disease. Following surgery, the patient was put on maintenance treatment with a somatostatin analog. However, the scRNA-seq analysis revealed that the neuroendocrine epithelial cells in the liver metastasis were less differentiated and expressed relatively little SSTR2, the predominant somatostatin receptor. There were also differences in the tumor microenvironments. RNA expression of vascular endothelial growth factors was higher in the primary tumor cells, reflected by an increased number of endothelial cells. Interestingly, vascular expression of the major VEGF receptors was considerably higher in the liver metastasis, indicating that the metastatic vasculature may be primed for expansion and susceptible to treatment with angiogenesis inhibitors. The patient eventually progressed on sandostatin and although consideration was given to adding an angiogenesis inhibitor to her regimen, her disease progression involved non-liver metastases which had not been characterized. Although in this specific case comparative scRNA-seq did not alter treatment, its potential to help guide therapy of metastatic disease was clearly demonstrated.
The assembly of carbon nanomaterials into three-dimensional (3D) porous scaffolds is critical to harness their unique physiochemical properties for tissue engineering and regenerative medicine applications. In this study, we report the fabrication, characterization, and in vitro cytocompatibility of true 3D (>1 mm in all three dimensions), macroscopic (3-8 mm in height and 4-6 mm in diameter), chemically cross-linked graphene scaffolds prepared via radical initiated thermal cross-linking of single- and multiwalled graphene oxide nanoribbons (SWGONRs and MWGONRs). SWGONR and MWGONR scaffolds possess tunable porosity (∼65-80%) and interconnected macro-, micro-, and nanoscale pores. Human adipose derived stem cells (ADSCs) and murine MC3T3 preosteoblast cells show good cell viability on SWGONR and MWGONR scaffolds after 1, 3, and 5 days comparable to 3D poly(lactic-co-glycolic) acid (PLGA) scaffolds. Confocal live-cell imaging showed that cells were metabolically active and could spread on SWGONR and MWGONR scaffolds. Immunofluorescence imaging showed the presence of focal adhesion protein vinculin and expression of cell proliferation marker Ki-67 suggesting that cells could attach and proliferate on SWGONR and MWGONR scaffolds. These results indicate that cross-linked SWGONR and MWGONR scaffolds are cytocompatible and opens-avenues toward the development of 3D multifunctional graphene scaffolds for tissue engineering applications. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 73-83, 2017.
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