Spatially-resolved transcriptomics analyses of invasive fronts in solid tumors

Abstract

Solid tumors are complex ecosystems, and heterogeneity is the major challenge for overcoming tumor relapse and metastasis. Uncovering the spatial heterogeneity of cell types and functional states in tumors is essential for developing effective treatment, especially in invasive fronts of tumor, the most active region for tumor cells infiltration and invasion. We firstly used SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq) with a nanoscale resolution to characterize the tumor microenvironment of intrahepatic cholangiocarcinoma (ICC). Enrichment of distinctive immune cells, suppressive immune microenvironment and metabolic reprogramming of tumor cells were identified in the 500µm-wide zone centered bilaterally on the tumor boundary, namely invasive fronts of tumor. Furthermore, we found the damaged states of hepatocytes with overexpression of Serum Amyloid A (SAA) in invasive fronts, recruiting macrophages for facilitating further tumor invasion, and thus resulting in a worse prognosis. We also confirmed these findings in hepatocellular carcinoma and other liver metastatic cancers. Our work highlights the remarkable potential of high-resolution-spatially resolved transcriptomic approaches to provide meaningful biological insights for comprehensively dissecting the tumor ecosystem and guiding the development of novel therapeutic strategies for solid tumors.

A Cellular Resolution Spatial Transcriptomic Landscape of the Medial Structures in Postnatal Mouse Brain

“…As expected, the distribution of specific brain cell markers ( Sst and Gfap ) exhibited remarkable similarity to in situ hybridization (ISH) data from P4 mice (Allen Institute) ( Lein et al, 2007 ) ( Figure 1D ). To evaluate the efficiency of the high-resolution in situ capture of Stereo-seq, we calculated the UMIs and gene counts of each bin (bin 50, 50 × 50 DNB bins, 25 µm diameter), which is an appropriate method to identify the different anatomical regions of the Stereo-seq data ( Chen et al, 2021 ; Wu et al, 2021 ). In section 1, 27,330 genes were detected, with an average of 6,425 UMI and 2,276 genes at bin 50 resolution ( Figures 1E,F and Supplementary Table S1 ).…”

Spatial transcriptomics technology in cancer research

“…Currently, neoplastic spatial heterogeneity has been reported in multiple malignant tumors, such as invasive micropapillary carcinoma (IMPC), gastric cancer (GC), glioblastoma (GBM), primary liver cancer and melanoma ( 19 , 52 – 55 ) ( Table 2 ). For instance, ERBB2 , the receptor of HER2, differentially expressed in multiple tumor areas on the same ST slide ( 15 ).…”

“…TLS was mostly found in para-tumor tissues ( 16 ). However, it also exists in tumor, leading-edge and para-tumor areas ( 19 , 98 ) ( Figure 1A ). Previous studies generally identify TLS by multiple IHC or multiplex IF staining ( 101 – 103 ), which is accurate but labor-consuming and low-throughput.…”

“…In the meanwhile, an increasing number of studies used ST to profile spatial heterogeneity of cancers (13,14). Currently, ST has been used to distinguish tumor and non-tumor tissues, special spatial areas such as tumor interface and tertiary lymphoid structures (TLSs) (15)(16)(17), and identify spatial-specific prognostic factors in cancer (18,19).…”

Spatial Transcriptomics Using Multiplexed Deterministic Barcoding in Tissue

“…Enabling, untargeted detection of mRNAs of the whole transcriptome. While commercially available technology resolves tissue spots with diameters of the order of tens of microns, recent technical improvements made in high-definition spatial transcriptomics (HDST) (Vickovic et al, 2019) and STEREO-seq (Wu et al, 2021a) resolve transcripts down to spot sizes of sub-microns. Alternative methods, including sci-SPACE (Srivatsan et al, 2021) and XYZeq (Lee et al, 2021) barcode biomolecules within tissue spots before retrieval.…”