Abstract 6557: Human 16p11.2 microdeletion suppresses malignant progression of colon cancer through dysregulation of the tumor microenvironment
Bibliographic record
Abstract
Abstract Colorectal cancer (CRC) is the third most diagnosed malignancy in Canada, where nearly half of diagnoses occur at late stages. The tumor microenvironment (TME), including host mesenchymal, immune, and endothelial cells, is an important driver of colorectal tumor progression toward late-stage disease. Tumor cells can instruct the TME to support invasion and metastasis via angiogenesis, immunosuppression, and extracellular matrix (ECM) remodeling. Next-generation cancer therapeutics must account for the complexities of the TME. Thus, the discovery of vulnerabilities therein is of critical importance. Our group contributed to a study showing that the hemi-deletion of the 16p11.2 locus (16p11.2+/-), associated with the autism spectrum disorder, significantly impairs cortical vascularization. Given that several genes within 16p11.2 are critical to CRC development, we found that primary CRC tumors with high 16p11.2 locus activity correlated with shorter overall survival rates than low 16p11.2 activity tumors. Pan-cancer hazard ratio analysis showed this relationship with 16p11.2 gene expression is specific to CRC. To study the role of the 16p11.2 locus in CRC tumor progression, we introduced a monoallelic deletion of the 7F3 locus (homologous to human 16p11.2 and termed h16p11.2 for clarity) in the APCmin/AOM tumorigenesis model. CRC tumors developing in the h16p11.2-deficient animals showed a significantly reduced size. Similarly, syngeneic CRC tumor engraftment assays using MC38 cells (h16p11.2 wt) showed delayed tumor growth in h16p11.2-deficient recipients compared to wt controls. CRC tumors developing in an h16p11.2-deficient niche presented significant disruptions in critical elements of the TME. Specifically, 3D mapping of CD31-positive endothelial structures revealed a 50% reduction in blood vessel density for tumors engrafted into h16p11.2-deficient animals. Transcriptome profiling of tumor and tumor-adjacent tissues identified several aspects of the TME perturbed by the h16p11.2-deficient niche, such as extracellular matrix (ECM) composition and enhanced adaptive immune response in macrophages. Polarized light microscopy and immunohistochemistry confirmed ECM gene regulation by showing a reorganization of collagen fiber and SPARCL1 deposition inside CRC tumor mass. Moreover, macrophage infiltration is enhanced within CRC tumors grown in a h16p11.2-deficient TME, with enhanced M1 anti-tumor and reduced M2 pro-tumor polarization. Overall, our data support that a 16p11.2-deficient TME represents an inhospitable niche for CRC tumor growth and progression. Gaining a better understanding of the biological mechanisms associated with lower 16p11.2 locus activity in CRC will reveal novel treatment modalities targeting both tumor and TME tissues. Citation Format: Jacob L. Billingsley, Joshua Haebe, Chris Bergin, Tanguy Fenouil, Baptiste Lacoste, Yannick Benoit. Human 16p11.2 microdeletion suppresses malignant progression of colon cancer through dysregulation of the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6557.
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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 | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".