Research Summary: This study reveals that myofibroblastic CAF-specific Tie2 signaling contributes to poor prognosis in oral cancer. Targeting Tie2 signaling may offer a promising therapeutic strategy for patients with high levels of these stromal cells.
Author interview: Ms. Paromita Mitra was born and raised in Krishnanagar. She completed her Bachelor’s and Master’s in Zoology from University of Kalyani. In 2019, she joined as a PhD candidate under Prof. Sandeep Singh at the National Institute of Biomedical Genomics, Kalyani. Her research focuses on understanding how stem-like cancer cells and their surrounding microenvironment contribute to the progression and poor prognosis of oral carcinoma.
Lab: Prof. Sandeep Singh, BRIC-National Institute of Biomedical Genomics (NIBMG), Kalyani
What was the core problem you aimed to solve with this research?
Oral cancer is the most prevalent cancer among Indian men and the fourth most common among women. Despite advances in treatment, the 5-year survival rate in India remains low at approximately 36%. Prognosis worsens considerably when the disease is diagnosed at an advanced stage or recurs after therapy, with a marked decline in median survival. A major contributor to therapy resistance, recurrence, and poor clinical outcomes is a subpopulation of cancer cells with stem-like properties. These cells are supported by myofibroblastic cancer-associated fibroblasts (CAFs)—non-malignant stromal cells. In this study, we sought to identify the molecular drivers within myofibroblastic CAFs that enhance stemness in oral cancer cells and to investigate whether targeting myofibroblastic CAF-specific drivers could provide novel therapeutic strategies, particularly for patients with tumors enriched in myofibroblastic CAFs.
How did you go about solving this problem?
We have discovered the expression and function of Tie2 protein in myofibroblastic CAF. Specifically, autocrine or exogenous TGFβ-induction in CAF led to the recruitment of histone deacetylase 2 (HDAC2) on the promoter of Tie2-antagonist, Angiopoietin-2 (ANGPT2), resulting in its downregulation, leading to phosphorylation of Tie2 (Y992) and subsequent activation of SRC (Y418). This led to SRC/ROCK mediated αSMA-positive stress-fiber formation with gain of myofibroblast phenotype. We have developed an in-vitro model system that mimics the in-vivo tumor microenvironment to study the reciprocal interaction between myofibroblastic CAF and cancer cells. Through extensive cellular and molecular study, coupled with bulk RNA sequencing and single cell RNA sequencing of CAF and cancer cells, we identified The CAF-specific Tie2-signaling was responsible for producing embryonic-like cell state in co-cultured cancer cells; with enhanced tumor initiating ability. We used small molecule inhibitors as well as gene silencing targeting Tie2 in myofibroblastic CAF and found this CAF-specific Tie2 inhibition reverses these fibroblasts towards less aggressive type and suppressing tumor growth in preclinical models. We have identified CAF-specific Tie2 activity may serve as a direct stromal target against cancer cell plasticity.
How would you explain your research outcomes (Key findings) to the non-scientific community?
Oral cancer in India is steadily increasing and expected to reach 210k by 2040. Major risk factors include widespread use of tobacco, betel nut and areca nuts which contribute to chronic inflammation in the oral sub-mucosal tissue. Increased inflammation causes resident fibroblasts, a non-malignant cell type converted into activated myofibroblasts which play an important role in metastasis, recurrence, therapeutic failure and poor survival. Even after conventional therapies, which include surgery, chemotherapy and radiotherapy, the tumor comes back. Stem-like cancer cells escape these therapies by increasing drug efflux and come out with more aggressive phenotypes. Currently, there are no therapies that could eliminate stem-like cancer cells from the tumor. Here, we showed that disrupting Tie2 activity in myofibroblastic CAF not only reverted their behavior towards less aggressive CAF type but also reversed the reprogramming of stem-like cancer cells. Therefore, targeting non-malignant cells could be a new strategy to reshape the tumor microenvironment from permissive to suppressive one.
“As the company is, so is the character”; this was found true in the tumor microenvironment of oral cancer patients.
What are the potential implications of your findings for the field and society?
New target identified: We identified Tie2 signaling in cancer-associated fibroblasts (CAFs) as a key driver of cancer stemness and therapy resistance. This opens up a novel stromal target that could complement existing cancer therapies, which mostly focus only on the tumor cells themselves. This deeper understanding may shift future research toward targeting the tumor ecosystem, not just the tumor.
- Biomarker potential: Tie2 activation and CAF subtype signatures may serve as biomarkers to identify high-risk oral cancer patients who are more likely to relapse—paving the way for personalized treatment strategies.
- Better survival prospect: This research encourages a shift in treatment design—from focusing only on killing cancer cells to also disrupting the cells that help cancer survive. This may be especially impactful in tumors that are resistant to current treatments.
- Faster clinical translation: Drugs like Rebastinib, which inhibit Tie2 and are already in clinical trials for other cancers, could potentially be repurposed for oral cancer—accelerating the translation of our findings into patient care.
What was the exciting moment during your research?
One of the most exhilarating moments in my research was discovering that Tie2 signaling is present in CAF. This protein has long been regarded as an endothelial specific protein. When we used a small molecule inhibitor to block Tie2 signaling, we could see dramatic reduction in the number of myofibroblastic CAF, indicated reversing aggressive CAF phenotype towards less aggressive state. It was thrilling to see such a clear shift in behavior with a targeted intervention!
Another truly memorable moment was when we visualized, at the single-cell level, how Tie2-positive myofibroblastic CAFs were driving cancer cells to reprogram into embryonic-like stem cells—a major reason for therapy resistance. Even more exciting was that CAF-specific Tie2 inhibition successfully blocked this transformation even in pre-clinical models. It felt like witnessing a molecular switch being flipped in real-time and gave us confidence that our findings could one day translate to real therapeutic impact.
I am deeply grateful to my supervisor Prof. Sandeep Singh for his constant encouragement, guidance and insightful mentorship throughout this journey. Research can be challenging but it becomes immensely joyous when you have a PI like him and extremely loving lab mates who made the entire experience deeply fulfilling and memorable. This work was made possible through the collaborative efforts of all collaborators and co-authors. The shared insights and teamwork throughout the project were truly invaluable.
Paper reference: Mitra P, Saha U, Stephen KJ, Prasad P, Jena S, Patel AK, Bv H, Mondal SK, Kurkalang S, Roy S, Ghosh A, Roy SS, Das Sarma J, Biswas NK, Acharya M, Sharan R, Arun P, Jolly MK, Maitra A, Singh S. J Exp Clin Cancer Res. 2025 May 10;44(1):142. doi: 10.1186/s13046-025-03405-8. PMID: 40349056. Journal of Experimental and Clinical Cancer Research (2025). https://link.springer.com/article/10.1186/s13046-025-03405-8
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