Investigation of MTDH and SND1 Expression and Inhibition in Ovarian Cancer

Abstract

High-grade serous ovarian cancer (HGSOC) is the most lethal subtype of ovarian cancer and remains a major clinical challenge due to frequent late diagnosis and limited treatment options. This study investigates the therapeutic potential of targeting the oncogenic interaction between metadherin (MTDH) and staphylococcal nuclease domain-containing 1 (SND1) which are proteins known to promote tumor progression, metastasis and immune evasion. Using gene expression data from The Cancer Genome Atlas (TCGA) and protein-level analysis via multiplex immunofluorescence (mIF) on tissue microarrays (TMAs) from ovarian cancer patients, the expression patterns and prognostic implications of MTDH and SND1 were examined. While analysis of RNA expression data revealed minimal co-expression between the two genes, protein-level analysis revealed frequent co-expression. Importantly, co-expression of MTDH and SND1, as well as high SND1 expression alone, was associated with poorer overall survival. These findings support the hypothesis that the MTDH-SND1 complex and SND1 alone may play a role in driving disease progression. To complement the patient analysis and to explore treatment strategies, tissue from a syngeneic mouse model treated with the MTDH/SND1 inhibitor C26A6, the PARP inhibitor Olaparib or both was analyzed. Preliminary observations provided supportive though limited insights into treatment response. Overall, this study suggests that dual expression of MTDH and SND1 may define a subgroup of HGSOC patients with poorer prognosis and highlights the potential for targeting this interaction as a therapeutic strategy. Further investigation into MTDH/SND1 inhibition, particularly in combination with immune therapies, could contribute to improved outcomes for ovarian cancer patients.

Popular Abstract

Targeting Key Protein Interactions to Suppress Tumors - New Clues in the Fight Against Ovarian Cancer

Ovarian cancer is a deadly disease often discovered too late with an urgent need for new treatments. This thesis explores whether a protein duo might be part of the problem, and more importantly, part of the solution.

Ovarian cancer is one of the deadliest cancers and causes almost 13,000 deaths every year in the United States, mainly because it’s hard to detect early and tough to treat once it spreads. This is especially true for the most common and fast-growing form called high-grade serous ovarian cancer (HGSOC). Despite advances in treatment, many patients still face poor odds of long-term survival. That’s why we need new ways of understanding and fighting this disease.

This project investigated two proteins called MTDH and SND1 that help tumors grow, spread and escape the body’s defense systems. You can think of them as part of the tumor’s internal communication network. If we can disrupt their “conversation”, we may slow down the cancer or even stop it. We analyzed patient samples using data from a large international cancer database (TCGA) and performed lab-based analysis on tissue samples from ovarian tumors. Our goal was to find out if MTDH and SND1 could be used as warning signals, or even better, as weak points that could be
targeted by new treatments.

The surprising finding? These two proteins don’t necessarily “talk” to each other at genetic level, but when we looked at the actual tumor cells they often showed up together. This suggests that MTDH and SND1 may work together after the gene stage, like secret agents meeting up behind the scenes. Even more importantly, patients whose tumors had high levels of both proteins tended to have shorter survival times. This points to a powerful possibility: if we can block the interaction between MTDH and SND1, we may be able to weaken the tumor.

So, how can this information be used? Treatments that target specific molecules in cancer cells, socalled “targeted therapies”, are one of the most promising areas in modern medicine. Today, most ovarian cancer patients receive general treatments like chemotherapy which can be tough on the whole body. A new experimental drug, called C26A6, has been developed to interrupt the communication between MTDH and SND1. If successful, it could make the tumor weaker and more visible to the body’s immune system, like turning off a stealth mode. This opens the door for combining it with other treatments, such as immunotherapy, which has not worked well on its own in this cancer type.

In short, this study looks at ovarian tumors not just as a mass of cells, but as a system with vulnerabilities. By focusing on the proteins they depend on, we may be able to design smarter and more precise treatments to help more patients live longer. It's a step forward in the engineering of personalized ovarian cancer therapy.

• author: Hansson, Andreas and Lagergren, Linn
• supervisor: Anna Sandström Gerdtsson; Asger Meldgaard Frank; Parisa Esmaeili
• organization: Department of Immunotechnology
• course: KIMM05 20251
• year: 2025
• type: H2 - Master's Degree (Two Years)
• subject: Biology and Life Sciences; Technology and Engineering; Medicine and Health Sciences
• keywords: Cancer, Oncology, Gene expression, Ovarian Cancer, MTDH, SND1, TCGA, Immunofluorescense, PARP
• language: English
• id: 9196368
• date added to LUP: 2025-06-10 20:24:08
• date last changed: 2025-06-10 20:24:08