Abstract 5089: The origin and contribution of the tumor stroma in colorectal cancer

Cancer-associated fibroblasts (CAFs) are a major constituent of the tumor microenvironment and play a critical part in cancer progression. However, the precise origin of the tumor stroma remains unknown, making it challenging to effectively target the cancer mesenchyme. Here, employing 4 different genetic fate mapping mouse models and a bone marrow transplantation model in combination with BrdU labeling, we uncovered a key contributor to the tumor stroma in colorectal cancer (CRC). We found that approximately half of a-smooth muscle actin (aSMA)+ CAFs emerge through proliferation in an AOM/DSS mouse model of CRC. Lineage tracing experiments revealed that intestinal leptin receptor (Lepr)-lineage stromal cells expanded and contributed to 75% of the aSMA+ proliferating CAFs. Notably, no aSMA+ CAFs in the tumor were derived from Krt19-lineage epithelial cells or bone marrow-transplanted cells, indicating no involvement of epithelial-mesenchymal transition and bone marrow recruitment to the tumor in this model. Moreover, RNA-sequencing of FACS-purified CRC mesenchymal cells identified MCAM (also known as CD146) as a CRC stroma-specific marker, which is expressed by Lepr-lineage cells. Analysis of human CRC samples showed that high MCAM expression was associated with a mesenchymal subtype of CRC and was independently prognostic of poor overall survival. Our data identify Lepr-lineage cells as a major source of the tumor stroma in CRC and suggest that targeting MCAM+ cells may serve as a novel therapeutic approach to restrain CRC progression. Citation Format: Hiroki Kobayashi, Krystyna A. Gieniec, Tamsin RM Lannagan, Tongtong Wang, Samuel Asfaha, Yoku Hayakawa, Simon J. Leedham, Nicholas Arpaia, Siddhartha Mukherjee, Timothy C. Wang, Atsushi Enomoto, Masahide Takahashi, Susan L. Woods, Daniel L. Worthley. The origin and contribution of the tumor stroma in colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5089.