Sox9: Can this protein enable a molecular reversal that could lead to colorectal cancer? Nilay Sethi MD

Nilay Sethi, MD, PhD, discusses Sox9: Can this protein enable a molecular reversal that could lead to colorectal cancer?


SOX9: Can this protein enable a molecular reversal that could lead to colorectal cancer? Nilay Sethi MD

By Nilay Sethi, MD, PhD
Assistant Professor at Dana-Farber Cancer Institute

SOX9 (gene) is a developmental transcription factor that is usually active in the stem cell compartment of colon tissue. However, when cancer initiates with the loss of APC (the most common first mutation in colon cancer), levels and expression of SOX9 increase. This is what cancer prefers, and we have elucidated the reasons for this in our recent study.


How does the SOX9 protein enable molecular time travel, and what does this mean for cancer treatment? 

What we observed was that, as SOX9 (gene) expression levels increased in cancerous tissue across various model systems (including mouse models and samples from colorectal cancer or pre-cancer), it was bound to and activating genes that are typically active during intestinal development. This implies that when the intestines were forming during embryo development, these genes played a role in shaping the organ that would eventually form in adult tissue.


Now, in adult tissue, these same genes were being inappropriately reactivated at the very beginning of cancer initiation. In a sense, this transported the cells back in time to an earlier stage in development. We provided evidence in the study that this allowed for greater plasticity or flexibility in the cell states that could be achieved during cancer initiation.


What are the implications of this study for cancer diagnosis and prevention? 

I believe that one of the early and important implications of this work is in cancer detection. Developmental genes are typically active during embryonic development and then turned off in adult tissue. However, their reactivation in pre-cancerous tissue could provide a unique diagnostic window for detecting molecules that are specific to pre-cancerous tissue. Therefore, this could be a valuable marker for diagnosing pre-malignant cancers. Additionally, this study provides further evidence that SOX9 could be a therapeutic target in cancer treatment. Previous research showed that depleting SOX9 or interfering with its function in cancer cell lines and models led to tumor regression by promoting differentiation (or differently expressed genes).


In the current study, we demonstrate that blocking SOX9 expression using genetic tools prevented adenoma formation. These two studies combined suggest that SOX9 plays an essential role in both cancer initiation and maintenance. Targeting SOX9 therapeutically could be a way to treat colon cancer by promoting differentiation and pushing the cancer back into the normal life cycle of the colon, which relies on a balance between stem cells and differentiated cells.


How does this research expand our understanding of the molecular mechanisms that lead to cancer development? 

I believe that our study adds value to the field by demonstrating that cellular plasticity, which is currently a hot topic and an important area of research, is predominantly being studied in the context of cancer progression, cancer metastasis, and therapeutic resistance. Cellular plasticity refers to the ability of pre-cancer and cancer cells to alter their cell state in response to various stressors, making it a critical area of research.


Our study indicates that this phenomenon can occur even before cancer initiation, specifically during the first stage of colon cancer. We observed that a level of plasticity is achieved by reactivating developmental genes. This finding has significant implications for researchers interested in studying cancer initiation, pre-malignancy, and cell state plasticity.


Overall, our study sheds light on the importance of understanding cellular plasticity in cancer research, and provides valuable insights into the early stages of colon cancer initiation.


What further research needs to be done in order to fully understand the role of SOX9 in cancer and its potential as a target for therapy?

I believe that there are two main areas that need to be explored immediately following the study. Firstly, we need to understand whether developmental reprogramming is a functional component, and identify the essential functional mediators required for this plasticity to occur at an early stage. Although we have nominated a few markers, we have yet to test whether there are any functional components involved in this developmental reprogramming.


Secondly, I think more effort should be directed towards targeting genes and transcription factors, such as SOX9, with drugs. Previous research and paradigms have suggested that transcription factors may be too challenging to target. However, this notion should be challenged and actively changed. Therefore, renewed efforts and inspiration should be made to target transcription factors such as SOX9, and our lab will collaborate with other groups of experts in chemical biology and structural biology to achieve this goal.


What challenges might arise in developing treatments that target SOX9, and how might these be addressed?

I believe there may be some challenges in targeting SOX9, particularly when considering its effect on normal tissue or the blocking of its activity in normal tissue. This has been studied to some extent in the intestines, where the deletion of SOX9 led to the loss of a specific cell type in the colon. However, these mice were viable and had a normal lifespan without any defects.


Therefore, it seems that the loss of SOX9 in colon tissue may be well-tolerated, but the question remains as to whether inhibiting SOX9 levels in other tissues will have an impact. There appears to be a therapeutic window, and more sophistication may be needed in terms of dosing and scheduling for drugs targeting SOX9.


However, these are some of the unknown questions that need to be addressed before moving forward with this approach in patients.


How might this research impact our understanding of other types of cancer beyond colorectal cancer?

We have noticed that developmental genes, which are active during development and silenced in adult tissue, are reactivated in cancer across the board. This signal has been observed in cancer subtypes such as prostate cancer and breast cancer, indicating that developmental genes are inappropriately activated and developmental programs are being utilized by cancer.


Therefore, our research emphasizes the need to understand the regulators, specifically transcription factors and chromatin modifiers, involved in this developmental reprogramming as they could be potential therapeutic targets for further study and investigation. Identifying these regulators is a crucial next step that may apply across cancer types.


How might this research be applied to personalized medicine and precision oncology?

The fortunate thing about SOX9 research is that our goal is ultimately to target the cell lines and models that depend on high levels of SOX9 expression. This is intuitive and serves as a good biomarker with predictive value for the drug we hope to develop in the future, which will target SOX9. We will be able to use SOX9 expression levels in patient biopsies to guide who is most likely to benefit from the drug and who may not.


How might this research contribute to our overall understanding of cancer biology and help inform future cancer research and treatment?

As alluded to earlier, I believe there is an observation that developmental programs are being activated in cancer and inappropriately co-opted for the purpose of cancer. One reason for this could be the increased plasticity that allows cancer cells to survive in different organs in the body and withstand the therapeutic pressures exerted on them by our treatments.


Therefore, understanding how these programs are being molecularly activated and identifying the important regulators is going to be the next step for studying other cancers where this observation has been made. However, we still do not fully understand how these programs are activated and how they functionally promote cancer progression in colon tissue.

Our study brings an important conceptual advance to light, that these programs can occur even before the formation of cancer. If good model systems of premalignancy exist for these other cancer types, they can be readily studied using single-cell RNA sequencing techniques, as well as standard chromatin biology techniques.


Final thoughts about the SOX9 protein

I believe the overarching concept that our study sheds light on, particularly in relation to colon cancer, is that the process of differentiation, whereby stem cells give rise to specialized cells responsible for the absorption and secretion of hormones in the intestines, is impaired at an early stage in cancer development. If we can devise strategies to induce differentiation or redifferentiate colon cancer cells, this could represent a promising therapeutic approach.

Our data strongly suggest that the key lies in preventing cells from halting differentiation and instead promoting their continued differentiation and eventual death, which is the natural lifecycle of colon tissue. Whether through activating stem cell programs or developmental genes, the ultimate goal is to coax colon cancer cells back to a differentiated state.


Such an approach could prove to be a valuable monotherapy targeting SOX9 or in combination with other drugs that promote the same mechanism.


What is the SOX9 protein?

SOX9 is a protein that plays a crucial role in embryonic development and the differentiation of various cell types in the body. It belongs to the Sox family of transcription factors, which are proteins that bind to (genomic) DNA and regulate the expression of genes.

During embryonic development, SOX9 is involved in the formation of many different tissues and organs, including the testes, cartilage, and nervous system. It is particularly important in the development of the skeletal system, where it helps to stimulate the production of cartilage cells that later become bone.

In addition to its role in embryonic development, SOX9 is also involved in the maintenance of tissues and the repair of damaged tissue. For example, it is important in the regeneration of cartilage in the joints, and it plays a role in the development of some types of cancer.

Mutations in the SOX9 gene can lead to a variety of developmental disorders, including campomelic dysplasia, a rare genetic condition characterized by skeletal abnormalities and other symptoms (human genetics).

Research into the function of SOX9 is ongoing, and it is likely that further discoveries about this protein will continue to shed light on the processes that govern development and disease in the human body.


10 Key Takeaways from the SOX9 Study

  1. Colorectal cancer is one of the leading causes of cancer-related deaths worldwide, and identifying the molecular mechanisms underlying its initiation and progression is crucial for developing effective prevention and treatment strategies.

  2. The study found that aberrant cell state plasticity, a phenomenon where cells can switch between different cellular states, mediated by developmental reprogramming precedes colorectal cancer initiation.

  3. This developmental reprogramming is characterized by the activation of a gene expression program that is normally active during embryonic development but is silenced in adult tissues.

  4. The activation of this gene expression program leads to the acquisition of stem cell-like properties by adult cells, which allows them to divide and proliferate (or cell proliferation) rapidly, leading to the formation of pre-cancerous lesions.

  5. The study also found that the reactivation of this embryonic gene expression program is mediated by specific transcription factors, including SOX2 and SOX9.

  6. Inhibiting the activity of these transcription factors or their downstream targets can prevent the activation of the embryonic gene expression program and the acquisition of stem cell-like properties by adult cells.

  7. These findings suggest that targeting the aberrant cell state plasticity mediated by developmental reprogramming may be a promising approach for preventing the initiation of colorectal cancer.

  8. The study also identified specific markers that can be used to identify cells that have undergone developmental reprogramming and acquired stem cell-like properties.

  9. These markers could be used for early detection of pre-cancerous lesions and for developing targeted therapies that specifically target these cells.

  10. Overall, the study highlights the importance of understanding the molecular mechanisms underlying the initiation and progression of colorectal cancer, and suggests new avenues for developing effective prevention and treatment strategies.


Nilay Sethi, MD, PhD - About The Author, Credentials, and Affiliations

Nilay Sethi, MD, PhD, is a devoted physician-scientist who specializes in treating patients with gastrointestinal cancer. In addition to his clinical work, he conducts basic and translational research in the laboratory. His primary focus is to gain a deeper understanding of the specific genomic alterations and fundamental molecular mechanisms that drive gastrointestinal cancers, with the ultimate goal of translating this knowledge into clinical advances that improve patient outcomes.


His passion for research is rooted in its ability to enhance our understanding of human disease and ultimately improve patient care. He is driven by a strong determination to make a meaningful difference in the lives of patients with gastrointestinal cancers, and he is committed to achieving this through my clinical and research efforts.