SMYD3-Driven Metabolic Rewiring in Colorectal Liver Metastases (AIRC_ IG 34634)

Targeting SMYD3-Driven Metabolic Rewiring and Oxidative Stress Adaptation in Colorectal Liver Metastases

This study focuses on patients with colorectal cancer undergoing surgery for the primary tumor and/or liver metastases. Tumor samples collected during surgery will be used to generate patient-derived models (primary cultures, spheroids, and organoids) to study colorectal cancer stem cells. The main objective is to investigate the role of the lysine methyltransferase SMYD3 in metabolic reprogramming and adaptation to oxidative stress that enable colorectal cancer cells to survive and grow in the liver. Previous work has shown that SMYD3 is overexpressed in colorectal cancer, promotes drug resistance, and regulates key oncogenic pathways, including c-MYC and the AMPK/mTOR axis. By identifying SMYD3-dependent pathways and pharmacologic vulnerabilities in cancer stem cells within liver metastases, this study aims to support the development of new therapeutic strategies that combine SMYD3 inhibitors with approved or experimental agents targeting tumor metabolism and oxidative stress responses

Study Overview

• Status: Not yet recruiting
• Conditions: CRC (Colorectal Cancer); Liver Metastases From Colorectal Primary Cancer

Detailed Description

Colorectal cancer represents one of the leading causes of cancer-related mortality worldwide. A significant proportion of patients develop distant metastases during the course of the disease. Liver metastases are among the main causes of death in patients with colorectal cancer. Despite advances in the genetic characterization of colorectal carcinoma, the biological mechanisms that enable tumor cells to adapt to the hepatic microenvironment and establish metastases remain only partially understood. In particular, increasing evidence suggests that subpopulations of tumor cells with cancer stem cell-like properties play a key role in tumor progression, treatment resistance, and metastatic dissemination.

The study of tumor tissues directly derived from patients is a fundamental tool for understanding the molecular mechanisms underlying metastatic progression and for developing clinically relevant experimental models, such as primary cell cultures, spheroids, and tumor organoids.

The collection of tumor samples from patients undergoing surgical resection of primary colorectal cancer and/or hepatic metastases will allow molecular, cellular, and transcriptomic analyses aimed at identifying new potential therapeutic targets.

In this context, we aim to investigate the role of the methyltransferase SMYD3 in metabolic and oxidative stress adaptation mechanisms in colorectal cancer and its derived liver metastases. Indeed, SMYD3 has recently emerged as a significant oncogenic driver, overexpressed in several tumor types. Our recent studies have revealed its contribution to drug resistance in response to genotoxic stress. Targeting SMYD3, in combination with standard or targeted therapies, has shown promise in overcoming drug resistance across various cancer types, including colorectal carcinoma, supporting the integration of SMYD3 inhibition into cancer treatment regimens.

Moreover, we have identified several SMYD3-interacting partners implicated in molecular processes related to the hallmarks of cancer. Among these are AMPK and mTOR: AMPK acts as the cell's main metabolic guardian, rewiring energy fluxes to sustain survival under stress, while mTOR regulates anabolic growth in response to nutrient availability. In this context, SMYD3 emerges as a key factor mediating processes encompassed within two major functional clusters - one involved in DNA damage repair and the other in sustaining oncogenic signaling.

Our investigations into the involvement of SMYD3 in cancer progression have advanced through an extensive molecular and functional characterization of its role in the biology of cancer stem cells, as this population is responsible for chemoresistance, recurrence, and metastasis in colorectal carcinoma. We have demonstrated that SMYD3 inhibition or stable genetic ablation affects the clonogenic and self-renewal potential of cancer stem cells and patient-derived organoids by altering their molecular signature. Furthermore, we discovered that both stable ablation and pharmacological inhibition drastically reduce the metastatic potential of cancer stem cells, identifying SMYD3 as a promising therapeutic target acting directly on the oncogene c-MYC, with potential implications for counteracting cancer stem cell proliferation and metastatic spread.

Based on this novel role of SMYD3 in cancer stem cells and metastatic dissemination, this project aims to define its contribution to the reprogramming processes that enable metastatic cells to adapt to the hepatic microenvironment under new and stressful conditions. Therefore, by delineating SMYD3-dependent pathways that promote cancer stem cell survival in liver metastases, we aim to exploit their pharmacological vulnerabilities for the development of new therapeutic strategies integrating SMYD3 inhibitors with clinically available or experimental compounds targeting tumor metabolism and oxidative stress adaptation

• Study Type: Observational
• Enrollment (Estimated): 156

Contacts and Locations

• Study Contact: Name: Cristiano Simone, MD; Phone Number: +390804994615; Email: cristiano.simone@irccsdebellis.it
• Study Contact Backup: Name: Martina Lepore Signorile, Biologist; Phone Number: +390804994615; Email: martina.lepore@irccsdebellis.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

This study is a multicenter prospective observational study and involves the collection of biological samples from patients undergoing surgery for CRC and/or liver metastases

Description

Inclusion Criteria:

Common criteria

• Age ≥ 18 years.
• Availability of residual tumor tissue from the surgical procedure that is not required for diagnostic purposes.
• Signed written informed consent for the use of biological samples for research purposes.

Cohort/Arm 1 (Colon-rectal tumor resection)

- Patients undergoing surgical resection of colorectal cancer.

Cohort/Arm 2 (Primary tumor and liver metastases resection) - Patients undergoing surgical resection of the primary colorectal tumor and liver metastases from colorectal carcinoma.

Cohort/Arm 3 (Liver metastases resection only)

- Patients undergoing surgical resection of liver metastases from colorectal carcinoma previously resected at the primary site.

Exclusion Criteria:

• Age < 18 years.
• Undergoing surgical intervention for a malignancy other than those specified in the inclusion criteria.
• Lack of signed informed consent

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Patients with CRC (colorectal cancer); Patients undergoing surgery for primary colorectal carcinoma, without liver metastases
Patients with colorectal cancer (CRC) and liver metastase; Patients undergoing surgery for primary colorectal carcinoma who simultaneously present liver metastases from colorectal carcinoma. In this case, tissue samples will be taken from both the colorectal carcinoma and the liver metastases
Patients with liver metastase; Patients undergoing surgery for the resection of liver metastases from previously operated colorectal cancer

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Molecular and Cellular mechanisms	Identification of the molecular and cellular mechanisms involved in metastatic progression that depend on the methyltransferase SMYD3	At the time of the surgery

Collaborators and Investigators

• Sponsor: Azienda Ospedaliera Specializzata in Gastroenterologia Saverio de Bellis
• Collaborators: University of Bari

Study record dates

Study Major Dates

• Study Start (Estimated): May 10, 2026
• Primary Completion (Estimated): May 10, 2027
• Study Completion (Estimated): May 10, 2028

Study Registration Dates

• First Submitted: March 23, 2026
• First Submitted That Met QC Criteria: March 23, 2026
• First Posted (Actual): March 27, 2026

Study Record Updates

• Last Update Posted (Actual): April 6, 2026
• Last Update Submitted That Met QC Criteria: March 31, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Colorectal cancer; liver metastases; liver metastases from colorectal cancer
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms
• Other Study ID Numbers: AIRC_ IG 34634

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No