Aberrant NOTUM+ Program Induced in LGR5+ Crypt Base Columnar Cells Maintains an Immunosuppressive Niche in Colorectal Cancer
Chua, J.; Sakthivel, P.; Kaur, A.; Allapitan, E.; Maqsood, A.; Bathe, O. F.; Minoo, P.; Ayyaz, A.
Show abstract
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with treatment failure largely driven by cancer stem-like cells that resist conventional chemoradiation and subsequently initiate tumor recurrence. While immune checkpoint blockade is effective in microsatellite instability-high (MSI-H) CRCs, the majority of CRCs are microsatellite stable (MSS) and exhibit immune exclusion, rendering them refractory to immunotherapy. Here, we identify a previously uncharacterized cancer cell subtype, which we term cancerous Crypt Base Columnar (canCBC) cells. These cells transcriptionally resemble normal LGR5+ CBC cells but activate an aberrant WNT/{beta}-catenin signalling inhibitory program, marked by NOTUM expression. We show that canCBC cells are specifically enriched in MSS tumors, where their presence correlates with reduced CD8 T cell infiltration, broader immune exclusion, and a propensity for regional lymphatic dissemination. Consistently, targeted ablation of canCBCs enhances the tumor-clearing potential of CD8 T cells. This study identifies a novel therapeutic target for overcoming immune exclusion and improving immunotherapy responses in MSS CRCs.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Mapping and modeling human colorectal carcinoma interactions with the tumor microenvironment 98%
- Single-Cell RNA Sequencing Reveals the Effects of Chemotherapy on Human Pancreatic Adenocarcinoma and its Tumor Microenvironment 98%
- Single-cell analysis of patient-derived PDAC organoids reveals cell state heterogeneity and a conserved developmental hierarchy 97%
Similar papers in this journal
Similar papers in this journal
- Multimodal Spatial Profiling Reveals Immune Suppression and Microenvironment Remodeling in Fallopian Tube Precursors to High-Grade Serous Ovarian Carcinoma 97%
- An in vivo KRAS allelic series reveals distinct phenotypes of common oncogenic variants 96%
- An immunomechanical checkpoint PYK2 governs monocyte-to-macrophage differentiation in pancreatic cancer 96%
Similar papers in this journal
- Cancer-associated fibroblast compositions change with breast cancer progression linking S100A4 and PDPN ratios with clinical outcome 97%
- Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma 96%
- Selenocysteine tRNA methylation promotes oxidative stress resistance in melanoma metastasis 95%
Similar papers in this journal
- Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer 97%
- Patient-derived xenografts and single-cell sequencing identifies three subtypes of tumor-reactive lymphocytes in uveal melanoma metastases 96%
- Unveiling the influence of tumor and immune signatures on immune checkpoint therapy in advanced lung cancer 96%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.