Mapping and modeling human colorectal carcinoma interactions with the tumor microenvironment

Ning Li (), Qin Zhu, Yuhua Tian, Kyung Jin Ahn, Xin Wang, Zvi Cramer, Justine Jou, Ian W. Folkert, Pengfei Yu, Stephanie Adams-Tzivelekidis, Priyanka Sehgal, Najia N. Mahmoud, Cary B. Aarons, Robert E. Roses, Andrei Thomas-Tikhonenko, Emma E. Furth, Ben Z. Stanger, Anil Rustgi, Malay Haldar, Bryson W. Katona, Kai Tan () and Christopher J. Lengner ()
Additional contact information
Ning Li: University of Pennsylvania
Qin Zhu: University of Pennsylvania
Yuhua Tian: University of Pennsylvania
Kyung Jin Ahn: Children’s Hospital of Philadelphia
Xin Wang: University of Pennsylvania
Zvi Cramer: University of Pennsylvania
Justine Jou: University of Pennsylvania
Ian W. Folkert: University of Pennsylvania
Pengfei Yu: University of Pennsylvania
Stephanie Adams-Tzivelekidis: University of Pennsylvania
Priyanka Sehgal: Children’s Hospital of Philadelphia
Najia N. Mahmoud: University of Pennsylvania
Cary B. Aarons: University of Pennsylvania
Robert E. Roses: University of Pennsylvania
Andrei Thomas-Tikhonenko: Children’s Hospital of Philadelphia
Emma E. Furth: University of Pennsylvania
Ben Z. Stanger: University of Pennsylvania
Anil Rustgi: Columbia University Irving Medical Center
Malay Haldar: University of Pennsylvania
Bryson W. Katona: University of Pennsylvania
Kai Tan: University of Pennsylvania
Christopher J. Lengner: University of Pennsylvania

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract The initiation and progression of cancer are intricately 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 human tumor organoid (tumoroid) cultures, and functionally recapitulate human myeloid-carcinoma interactions in vitro. Tumoroid cultures suppress gene expression programs involved in inflammation and immune cell migration, 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 immunosuppressive and 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.

Date: 2023
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DOI: 10.1038/s41467-023-43746-6

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