Xiaonan Zhang – Targeting therapy-evading cancer cells to enhance treatment efficacy and reduce the risk of relapse

The research group focuses on developing precision therapeutic strategies to overcome drug resistance and prevent tumour relapse. We are studying the biology of highly resistant and relapse-prone quiescent cancer cells, with the aim to uncover the fundamental mechanisms that drive cancer dormancy and treatment resistance. Our goal is to develop of more durable and effective treatments for these difficult-to-treat cancer populations.

Despite significant advances in cancer detection and treatment, mortality rates remain high – primarily due to tumour relapse and metastasis. A key driver of these challenges is the reactivation of quiescent cancer cells (QCCs). This is a small and treatment-resistant subpopulation of cells which is capable of entering a dormant state to evade therapy and later reinitiating tumour growth.

This phenomenon poses a particular threat to younger patients, who face a prolonged risk of recurrence throughout their lives following initial surgery or treatment. Progress in understanding QCC biology has been limited by the absence of effective experimental models, hindering efforts to fully characterize and target this elusive cell population.

The goal of our research is to overcome drug resistance and prevent tumour relapse by integrating insights from QCCs biology into next-generation diagnostic and therapeutic strategies. We aim to develop more durable and effective treatments for solid tumours that exhibit high recurrence rates and have a significant impact on young patients, including paediatric neuroblastoma, malignant cancers in women, e.g. triple-negative breast and early-onset ovarian cancer, and early-onset colorectal cancer.

Two hands with green gloves hold a pipette and a test tube.

Photo: Mikael Wallerstedt

Identifying novel molecular and phenotypic features of QCCs

Unlike actively proliferating cancer cells, QCCs remain metabolically active yet growth-arrested, allowing them to evade therapies that target dividing cells.

One of our key research focuses is to identify the unique features of QCCs that support their survival and reactivation pathways under stressed and unfavourable microenvironments. These characteristics may serve as potential therapeutic targets or biomarkers for early diagnostic approaches to detect and eliminate dormant cancer cells before relapse occurs. Our aim is to design targeted therapeutic strategies that specifically disrupt QCC survival and reactivation pathways.

Unexplored drug targets for solid tumour therapy

We have a strong and ongoing interest in identifying novel drug candidates capable of targeting both proliferative and quiescent cancer cell populations. To advance this goal, we have established a range of 3D-based cell culture models suitable for high-throughput chemical screening. This allows us to evaluate compounds in physiologically relevant tumour environments.

Through this approach, we aim to uncover previously unexplored drug targets revealed by newly identified compounds. Currently, our laboratory has discovered several small molecules that effectively target both proliferative and quiescent cancer cells, while also revealing novel therapeutic targets. They are now under further investigation.

Mitochondria a potential key to overcoming resistant QCCs

In our previous work, mitochondrial inhibition emerged as a promising strategy for targeting chemo resistant QCCs. QCCs residing in stressed and unfavourable microenvironments are greatly dependent on functional mitochondria for survival. However, the precise molecular targets involved remain unclear.

Our studies indicate that fatty acid metabolism plays a critical role in sustaining QCC survival, particularly through its contribution to ATP production. Given that cancer cells display high and specialized energy demands, exploring mitochondrial ATP supply provides a potential therapeutic window based on differential energy requirements between normal and cancer cells.

We are currently investigating both nuclear- and mtDNA-encoded mitochondrial proteins as potential therapeutic targets to disrupt QCC energy metabolism and overcome drug resistance.