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Supplemental Tables 1-8 from Colorectal Cancer Metastases in the Liver Establish Immunosuppressive Spatial Networking between Tumor-Associated SPP1+ Macrophages and Fibroblasts

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posted on 2023-04-01, 00:01 authored by Anuja Sathe, Kaishu Mason, Susan M. Grimes, Zilu Zhou, Billy T. Lau, Xiangqi Bai, Andrew Su, Xiao Tan, HoJoon Lee, Carlos J. Suarez, Quan Nguyen, George Poultsides, Nancy R. Zhang, Hanlee P. Ji

Supplemental Table 1: Antibodies, reporters, imaging order and exposure times used in CODEX imaging. EPCAM, SPP1, CD163 were excluded from downstream analysis due to non-specific staining; Supplemental Table 2: Sequencing metrics for scRNA-seq; Supplemental Table 3: Absolute number of cells detected from each sample per cell lineage; Supplemental Table 4: Differentially expressed genes belonging to respective macrophage clusters compared by site of sample origin. pct.1, pct.2 indicate percentage of cells expressing given gene in the cluster of interest and all other comparison clusters respectively; Supplemental Table 5: Enriched reactome pathways in differentially expressed genes in tumor macrophages; Supplemental Table 6: Gene signatures for Foam cells (Fernandez et.al., 2020, PMID 31591603) and scar-associated macrophages (Ramachandran et. al., 2020, PMID 31597160); Supplemental Table 7: Annotation of differentially expressed genes in CAFs with the components of the matrisome expression program; Supplemental Table 8: Spatial proximity analysis examining whether fibroblasts are more proximal to macrophages than any other cell type.

Funding

National Institutes of Health (NIH)

National Cancer Institute (NCI)

United States Department of Health and Human Services

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American Cancer Society (ACS)

Stanford University (SU)

U.S. Department of Energy (DOE)

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ARTICLE ABSTRACT

The liver is the most frequent metastatic site for colorectal cancer. Its microenvironment is modified to provide a niche that is conducive for colorectal cancer cell growth. This study focused on characterizing the cellular changes in the metastatic colorectal cancer (mCRC) liver tumor microenvironment (TME). We analyzed a series of microsatellite stable (MSS) mCRCs to the liver, paired normal liver tissue, and peripheral blood mononuclear cells using single-cell RNA sequencing (scRNA-seq). We validated our findings using multiplexed spatial imaging and bulk gene expression with cell deconvolution. We identified TME-specific SPP1-expressing macrophages with altered metabolism features, foam cell characteristics, and increased activity in extracellular matrix (ECM) organization. SPP1+ macrophages and fibroblasts expressed complementary ligand–receptor pairs with the potential to mutually influence their gene-expression programs. TME lacked dysfunctional CD8 T cells and contained regulatory T cells, indicative of immunosuppression. Spatial imaging validated these cell states in the TME. Moreover, TME macrophages and fibroblasts had close spatial proximity, which is a requirement for intercellular communication and networking. In an independent cohort of mCRCs in the liver, we confirmed the presence of SPP1+ macrophages and fibroblasts using gene-expression data. An increased proportion of TME fibroblasts was associated with the worst prognosis in these patients. We demonstrated that mCRC in the liver is characterized by transcriptional alterations of macrophages in the TME. Intercellular networking between macrophages and fibroblasts supports colorectal cancer growth in the immunosuppressed metastatic niche in the liver. These features can be used to target immune-checkpoint–resistant MSS tumors.

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