GIS/BII Fellow, Genome Institute of Singapore / Bioinformatics Institute 

Colorectal cancer (CRC) is a clinically and molecularly heterogeneous disease. Single-cell RNA-sequencing (scRNA-seq) has enabled us to describe the diverse cell types within the CRC tumor microenvironment. However, the complex interplay between heterogeneous epithelial cell states and their spatial niches remains poorly understood. To address this, we employ state-of-the-art spatial omics technologies to generate high-resolution maps of primary CRC tumors, comprising over 9 million cells from 63 samples and 34 patients. Our results reveal how the organized architecture of the normal colon becomes disrupted in cancer. We identify molecular markers related to biological signatures such as stem-like properties and response to hypoxia that exhibit spatial patterning within tumor glands. We also identify tumor-enriched spatial neighborhoods, including a tumor budding neighborhood enriched at the tumor-normal interface of invasive samples, and that is associated with SPP1+ macrophages and an invasive epithelial cell state. In vitro validation using primary patient-derived organoids shows that this invasive state can be induced by synergistic TGFβ and IL1β signaling. Our study provides a valuable resource for investigating the spatial organization of tumor epithelial states in CRC.