Qin Zhu

"Mapping and modeling human colorectal carcinoma interactions with the tumor microenvironment"

Ning Li*, Qin Zhu#, Yuhua Tian, Kyung Jin Ahn, Kamyar Esmaeili Pourfarhangi, Xin Wang, Ian W. Folkert, Pengfei Yu, Justine Jou, Ben Z. Stanger, Anil Rustgi, Malay Haldar, Bryson W. Katona, Kai Tan*, and Christopher J. Lengner*

Colorectal adenocarcinoma (CRC) is a major cause of cancer incidence and cancer-associated deaths. Recent advances in organoid technology led to the establishment of patient-derived CRC tumor organoid models (tumoroids) that can predict drug sensitivity. However, current technologies preclude the long-term maintenance of tumor microenvironmental components (TME) in tumoroid culture.  Here we predict carcinoma-TME interactions from single cell transcriptomic maps of both human CRCs and mouse CRC models, ask how these interactions are altered upon establishing long-term human tumoroid cultures, and functionally recapitulate human myeloid-carcinoma interactions in vitro. Tumoroids suppress gene expression programs involved in communication with the TME, and 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 well-established pro-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.