Understanding intratumor heterogeneity to overcome drug resistance, a barrier to anti-cancer drug treatment
Cancer has been the leading cause of death in Japan since the early 1980s. Treatment approaches generally fall into three categories: surgery, radiation, and drug therapy, with anticancer drugs being the primary form of internal medical treatment. However, drug resistance remains a significant challenge, often making cancer difficult to cure. Associate Professor Ken Tajima of the Department of Respiratory Medicine at the School of Medicine balances basic research with his practice as a respiratory physician to address this issue. We spoke with him about the future of anticancer drug treatment in light of his research on intratumoral heterogeneity, which has been selected for the “Fusion Oriented Research for Disruptive Science and Technology” (FOREST) project.
Despite more than a century of anticancer drug development, achieving definitive cure remains elusive. While several challenges persist, anticancer drug resistance remains the primary obstacle. Extensive research has explored the mechanisms underlying this resistance, including reduced drug uptake by cells, enhanced drug efflux via pump functions from the cells, and acquired resistance to apoptosis (programmed cell death). In recent years, intratumoral heterogeneity has emerged as a key factor contributing to anticancer drug resistance.
Once believed to be a homogeneous cell population arising from a single cell, advanced gene sequencing technology, particularly next-generation sequencing, has revealed that each tumor cell in cancer exhibits distinct patterns of gene mutations and expression. This means that instead of a uniform population proliferating from a single cell, cancer consists of a diverse array of cells with significant heterogeneity.
In particular, anticancer drugs have been administered traditionally under the assumption that tumors are homogeneous. However, in reality, tumors contain thousands or even tens of thousands of genetically distinct cells, some of which lack the necessary drug targets or are inherently resistant to treatments. Without a deeper understanding of these resistance mechanisms, developing anticancer drugs that can overcome resistance and achieve a cure remains challenging. This heterogeneity not only differs between patients but also among cancer cells within the same tumor. In particular, intratumoral heterogeneity is a key factor contributing to the complexity of anticancer drug resistance, and understanding it is essential for advancing cancer treatment.
The research theme I am currently working on, “Understanding intratumor heterogeneity and overcoming drug resistance using a reversible differentiation model,” has been adopted as part of the Emergent Research Support Program from 2023, and is now in its second year. This research utilizes single-cell analysis, a cutting-edge genetic analysis technology that has advanced significantly over the past decade. Previously, bulk analysis was the primary method, where multiple cells were analyzed together. However, this approach only provided population-averaged data, making it difficult to identify heterogeneity among individual cells. The emergence of single-cell analysis technology has played a major role in improving our understanding of intratumor heterogeneity.
In this research, we focus on genetic analysis of cancer cells at the single-cell level to investigate the mechanisms underlying intratumoral heterogeneity. However, understanding heterogeneity alone is not sufficient to explain anticancer drug resistance. It is also crucial to determine how individual cells acquire resistance. We hypothesize that epigenetics—a regulatory mechanism that modifies gene expression without altering the DNA sequence, inherited by descendants and daughter cells—plays a key role in this process.
How does intratumoral heterogeneity arise, and how do individual cells develop drug resistance? By investigating these two fundamental questions, we aim to explore ways to prevent or eliminate resistance, ultimately contributing to novel drug development.
Bioinformatics technologies, such as next-generation sequencing and single-cell analysis, have advanced rapidly in recent years, allowing many researchers to investigate intratumoral heterogeneity. What sets my research apart is its focus on thoracic malignancies, including lung cancer, pleural mesothelioma, and thymic epithelial tumors—areas that align with my expertise as a respiratory physician.
Although intratumoral heterogeneity is a widely recognized concept, its complexity and degree of expression vary by cancer type. The challenges associated with sample collection make research on thoracic malignancies particularly difficult. My collaboration with the Thoracic Surgery Department, along with my clinical experience, provides a strong foundation for tackling these challenges. Additionally, the research environment at Juntendo, where basic science and clinical practice are closely integrated, enables me to push the boundaries of cancer treatment research.
Collaboration with researchers specializing in basic science has been invaluable in utilizing cutting-edge bioinformatics technologies, particularly for genetic analysis. While bioinformatics is becoming increasingly essential in medical research, there are very few experts in this field.
To stay at the forefront of technological advancements, we have actively expanded our information network and established collaborations not only within Juntendo but also with external companies and research platforms. Forming strong research partnerships was a key priority when launching this study, as external collaborations play a crucial role in driving progress. This holds true not only for future drug discovery and development but also for advancing research as a whole. Moving forward, expanding the scope of collaboration will be essential for progress in our work.
Among the thoracic malignancies studied in this research, lung cancer has the highest incidence and mortality rate. Notably, it exhibits exceptionally complex intratumoral heterogeneity. As research advances and the mechanisms of anticancer drug resistance become clearer, there is hope that this knowledge can be applied to prevent and overcome drug resistance in lung cancer.
The path ahead in this research will be challenging, but it holds the potential to drive the development of new treatments and could significantly benefit cancer patients and their families. The findings of our research will not only expand treatment options but also improve patients’ quality of life. As a physician and researcher engaged in both basic research and clinical practice, discovering a promising treatment that could transform clinical care and benefit my patients would be the greatest sense of accomplishment. While this is an ambitious goal, I am committed to pursuing it, focusing on both clinical and basic research to bring these findings to fruition.
Department of Respiratory Medicine, Juntendo University School of Medicine
Associate Professor
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