Mapping and modeling human colorectal carcinoma interactions with the tumor microenvironment

Abstract

SummaryThe initiation and progression of cancer are inextricably linked to the tumor microenvironment (TME). Understanding the function of specific cancer-TME interactions poses a major challenge due in part to the complexity of the in vivo microenvironment. Here we predict cancer-TME interactions from single cell transcriptomic maps of both human colorectal cancers (CRCs) and mouse CRC models, ask how these interactions are altered in established, long-term human tumor organoid (tumoroid) cultures, and functionally recapitulate human myeloid-carcinoma interactions in vitro. Tumoroid cultures suppress gene expression programs involved in promoting inflammation and immune cell migration through receptor-ligand interactions, providing a reductive platform for re-establishing carcinoma-immune cell interactions in vitro. Introduction of human monocyte-derived macrophages into tumoroid cultures instructs macrophages to acquire pro-tumorigenic gene expression programs similar to those observed in vivo. This includes hallmark induction of SPP1, encoding Osteopontin, an extracellular CD44 ligand with established oncogenic effects. Taken together, these findings offer a framework for understanding CRC-TME interactions and provide a reductionist tool for modeling specific aspects of these interactions.

Niche differential gene expression analysis in spatial transcriptomics data identifies context-dependent cell-cell interactions

“…One application of such contrast testing is niche marker gene identification, which we perform on the liver metastasis data to delineate tumor-associated versus normal macrophage markers. The markers we identify corroborate with published findings on macrophage subtypes in liver metastases [ [17] and primary colorectal carcinoma [ [27], not only at the gene level but also at the level of cellular processes inferred through a Reactome analysis.…”

APCandP53mutations synergise to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer

“…Further, NOTUM expression is significantly elevated in colon and rectal cancers in the human Cancer Genome Atlas 3 (TCGA colon adenocarcinoma (COAD) and rectal adenocarcinoma (READ), respectively) relative to normal tissue ( figure 1C ). We also examined single cell transcriptome profiles of primary human COAD 18 and confirmed that NOTUM expression is largely restricted to carcinoma cells and almost entirely absent in the tumour microenvironment ( figure 1D ).…”

“…Finally, examining a group of paired human primary tumours and their cognate liver metastases 18 revealed further increases in NOTUM expression in the metastatic lesions ( online supplemental figure 1D ). These findings confirm published findings that NOTUM expression is induced in response to APC inactivation, and demonstrate that it remains elevated throughout the transition from adenoma to invasive adenocarcinoma, and becomes even further upregulated in metastatic lesions.…”

Organoids as an in vitro model to study human tumors and bacteria

“…These data indicate that PDO can predict the responses of clinical patients to radiotherapy and chemotherapy, potentially serving as a valuable tool in cancer diagnosis and treatment 12 . Li et al 18 utilized intestinal organoid models to recapitulate the cellular composition, stromal structure, and immune cell infiltration of primary tumor tissues, providing a robust framework for in‐depth investigation into the biological characteristics of tumors. Zhou et al, by coculturing cholangiocarcinoma organoids with immune cells and simulating the tumor immune microenvironment, quantified direct and indirect antitumor immune responses within the bile duct cancer organoid model.…”