Hypoxic microenvironment induced spatial transcriptome changes in pancreatic cancer

Abstract

Objective: Hypoxia is a significant feature of solid tumors, including pancreatic ductal adenocarcinoma (PDAC). It is associated with tumor invasion, metastasis, and drug resistance. However, the spatial distribution of hypoxia-related heterogeneity in PDAC remains unclear. Methods: Spatial transcriptomics (STs), a new technique, was used to investigate the ST features of engrafted human PDAC in the ischemic hind limbs of nude mice. Transcriptomes from ST spots in the hypoxic tumor and the control were clustered using differentially-expressed genes. These data were compared to determine the spatial organization of hypoxia-induced heterogeneity in PDAC. Clinical relevance was validated using the Tumor Cancer Genome Atlas and KM-plotter databases. The CMAP website was used to identify molecules that may serve as therapeutic targets for PDAC. Results: ST showed that the tumor cell subgroups decreased to 7 subgroups in the hypoxia group, compared to 9 subgroups in the control group. Different subgroups showed positional characteristics and different gene signatures. Subgroup 6 located at the invasive front showed a higher proliferative ability under hypoxia. Subgroup 6 had active functions including cell proliferation, invasion, and response to stress. Expressions of hypoxia-related genes, LDHA, TPI1, and ENO1, induced changes. CMAP analysis indicated that ADZ-6482, a PI3K inhibitor, was targeted by the invasive subgroup in hypoxic tumors. Conclusions: This study is the first to describe hypoxic microenvironment-induced spatial transcriptome changes in PDAC, and to identify potential treatment targets for PDAC. These data will provide the basis for further investigations of the prognoses and treatments of hypoxic tumors.

TAZ promotes vasculogenic mimicry in gastric cancer through the upregulation of TEAD4

“…25,26 Hypoxia, CSCs, and EMT are the main factors in VM formation. 27,28 VM formation in GC may involve a variety of molecules, including Lncrna-pvt1, galectin-1, and HMGA2, inducing VM by regulating EMT-related factors. [29][30][31] TAZ is highly expressed in many tumors and plays a key role in tumor cell proliferation, migration, stemness, and EMT.…”

“…Hypoxia, CSCs, and EMT are the main factors in VM formation 27,28 . VM formation in GC may involve a variety of molecules, including Lncrna‐pvt1, galectin‐1, and HMGA2, inducing VM by regulating EMT‐related factors 29–31 .…”

Spatial Transcriptomics for Tumor Heterogeneity Analysis

“…This study first describes the spatial gene expression changes of ductal adenocarcinoma of the breast induced by a hypoxic microenvironment, and it identifies its potential therapeutic targets, which can provide the foundation for further studies of prognosis and treatment of hypoxic tumors. Spatial heterogeneity of hypoxic tumors and control tissue in breast cancer was studied by Sun et al (2021) . ST results showed that tumor cell subgroups decreased to seven subsets compared to the nine subgroups of the normal control.…”

“…Different subsets exhibit positional features and different gene features. Next, subgroups located at the forefront of invasion exhibited active functions under hypoxic conditions, including cell proliferation, invasion, and stress response, as well as the uneven distribution of hypoxia-related genes across subsets ( Sun et al, 2021 ). These studies suggest that ST is able to dissect the heterogeneity in biopsy that cannot be detected by conventional transcriptome analysis, which may provide more detailed prognostic information.…”

Mapping Spatiotemporal Heterogeneity in Tumour Progression by Integrating High-Throughput Imaging and Omics Analysis

“…In a study involving engrafted human PDAC in ischemic hind limbs of nude mice, gene expression was observed to vary spatially depending on oxygenation of the microenvironment 78 . In the control group (normoxic conditions), the subgroups (SG) identified by spatial transcriptomics had diverse functions, such as enrichment of genes involved in proliferation in SG2, SG3, SG4 and SG11, but under hypoxic condition only SG6 showed properties of proliferation.…”