Abstract 5151: Deciphering the molecular mechanisms driving infiltrative histopathological type of colorectal cancer liver metastases
Bibliographic record
Abstract
Colorectal carcinoma (CRC) remains the second leading cause of cancer death in the western world. Over 50% of CRC patients develop liver metastases (LM) and 90% will succumb to their disease. Liver resection of the LMs provides the only possibility of cure, but only 20% of colorectal cancer liver metastases (CRCLM) patients are resectable. The combination of angiogenic inhibitors (AI: anti-VEGF) with chemotherapy is the current form of treatment. Unfortunately, 65-70% of the patients continue on chemotherapy until resistance develops and then are treated with second, third and some times a fourth line of treatment, with an expected median overall survival of 24-28 months. We have no way of identifying those CRCLM patients that would respond/benefit to the addition of anti-angiogenic therapies (e.g. Bevacizumab). Recently we have identified two CRCLM histologic growth patterns (HGP) that predict treatment response and survival: 1) Desmoplastic (DHGP), a desmoplastic ring separating cancer cells from the liver parenchyma and lesions grow by angiogenesis; 2) Replacement or infiltrative (RHGP), tumor cells infiltrate the parenchymal cells in the liver as the lesions grow by co-opting the sinusoidal blood vessels between the liver cell plates. We showed that CRCLM patients with predominantly desmoplastic HGP metastasis receiving AIs plus chemotherapy have more than double the 5-year overall survival compared to patients with replacement HGP who have received the same treatment. In addition, our clinical data revealed that Angiogenic Inhibitors could negatively affect outcomes in patients with replacement HGPs. These non-angiogenic lesions do not respond to angiogenic inhibitors. To further our understanding of the molecular differences between the two HGPs we demonstrated by knocking out ARPC3 (Actin-related protein 2/3 complex subunit 3, involved in actin polymerization) in the human colon cancer cell line, HT-29, that cancer cell motility is a crucial process that regulates histological growth pattern in CRCLM. HT29 CRC cells injected directly into the mouse liver grow into replacement HGPs, while HT29s silenced for ARPC3 grow into desmoplastic HGPs lesions. However, the molecular mechanisms that regulate ARPC3 in CRCLM remain unknown. To further dissect the molecular mechanisms differentiating desmoplastic from replacement HGPs, we performed RNA-seq analysis of CRCLM lesions from chemonaïve patients. Our data revealed that both TGFβ1 and RUNX1 were upregulated in RHGP comparing to DHGP lesions. This has been further validated by immunoblotting and immunohistochemistry. Consistently, RUNX1 has been reported as a downstream of TGFβ1 and transcriptional factor for ARPC3. Collectively, our data suggests that TGFβ1 and RUNX1 contribute to the formation of infiltrative type of colorectal cancer liver metastases possibly through upregulation of ARPC3.Note: This abstract was not presented at the meeting.Citation Format: Miran Rada, Anthoula Lazaris, Stephanie Petrillo, Abdellatif Amri, Peter Metrakos. Deciphering the molecular mechanisms driving infiltrative histopathological type of colorectal cancer liver metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5151.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 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".