SMYD3-Driven Metabolic Rewiring in Colorectal Liver Metastases

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

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