Abstract 5089: The origin and contribution of the tumor stroma in colorectal cancer
Bibliographic record
Abstract
Abstract 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".