Unraveling genetic and pathogen-associated mechanisms in occult lymph node metastasis of tongue squamous cell carcinoma:
We are keen to address a critical issue of occult lymph nodal metastases in tongue squamous cell carcinoma (TSCC), which occurs in approximately 30% of early-stage (pT1 or pT2) patients and is undetectable by MRI/CT. This poses a unique challenge compared to other oral cancer subsites. Neck dissection in 70% of patients without nodal metastases increases morbidity, cost, and poor overall survival, highlighting the need for reliable prognostic biomarkers to stratify patients likely to have adverse clinical outcomes.
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Figure: We developed an orthotopic tongue cancer mouse model (right panel) to predict nodal metastasis in oral cancer: an unmet clinical need (shown in left panel)
We presented the first landscape of genetic alterations among tongue cancer patients of Indian origin, showing a lack of HPV infection and a tobacco-associated signature. We identified NOTCH1 alterations and MMP10 overexpression as promising prognostic biomarkers, potentially sparing many early-stage tongue cancer patients from mandatory elective neck dissection. More recently, we demonstrated that miR-944 negatively regulates MMP10 by targeting its 3'-UTR. Overexpression of MMP10 induces EMT, upregulating the tyrosine kinase gene AXL, which is essential for the functional consequences of miR-944 downregulation or MMP10 overexpression. Our work characterizes the miR-944/MMP10/AXL axis's role in lymph node metastasis using an orthotopic in vivo tongue cancer mouse model.
Figure: Genome-based discovery of MMP10 as a biomarker to predict nodal metastasis in tongue cancer was validated through rigorous in vitro and in vivo approaches.
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Recently, our work led to the identification of a novel fusion transcript, UBE3C-LRP5, in head and neck cancer, with potential clinical relevance. This fusion activates the Wnt/β-catenin pathway, driving cancer cell behaviors. The FDA-approved drug pyrvinium pamoate shows promise in inhibiting tumor growth linked to this fusion. Patient survival data suggests its importance. This finding proposes a new therapeutic angle for head and neck cancer, warranting larger clinical trials. Overall, his work illustrates a unique blending of basic and translational cancer genomics research and detailed functional mechanistic insight.
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Figure: Genome-based discovery of UBE3C-LRP5 as a novel therapeutically relevant fusion transcript in tongue cancer, as validated through rigorous in vitro and in vivo approaches.
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Additionally, we described the first comprehensive landscape of infectious pathogens across various cancers, establishing a significant prevalence of Fusobacterium nucleatum in tongue tumors among Indian patients. This bacterium occurs mutually exclusively with HPV in Caucasian samples and is associated with poor survival and nodal metastases, defining a distinct subgroup of head and neck cancer. Our work blends basic and translational cancer genomics research with detailed functional mechanistic insights.
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Figure: Genome-based discovery of the association of Fusobacterium nucleatum with tongue tumors. These Fusobacterium-positive tumors lacked HPV infection and showed distinct features, including increased inflammatory markers and immune cells, and more lymph node involvement.
Currently, we are investigating the intricate interactions between Fusobacterium nucleatum and oral cancer, with a particular focus on the microorganism's spatial characteristics within the tumor microenvironment. By addressing key questions such as the impact of Fusobacterium nucleatum on tumor growth and invasion, the molecular mechanisms behind its promotion of tumor development, and its role in modulating the immune response, we seek to elucidate the microorganism's influence on cancer progression. Additionally, we are exploing the spatial heterogeneity and colonization patterns of Fusobacterium nucleatum across different subtypes, stages, and age groups of oral cancer. A significant outcome of this work will be the development of an automated computational pipeline and web tool for detecting oral cancer stages, enhancing diagnostic capabilities and potentially informing therapeutic strategies.
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Publications:
8. Dharavath B, Butle A, Chaudhary A, Pal A, Desai S, Chowdhury A, Thorat R, Upadhyay P, Nair S, Dutt A. Recurrent UBE3C-LRP5 translocations in head and neck cancer with therapeutic implications. NPJ Precis Oncol. 2024 Mar 4;8(1):63.
7. Dharavath B, Butle A, Pal A, Desai S, Upadhyay P, Rane A, Khandelwal R, Manavalan S, Thorat R, Sonawane K, Vaish R, Gera P, Bal M, D'Cruz AK, Nair S, Dutt A. Role of miR-944/MMP10/AXL- axis in lymph node metastasis in tongue cancer. Commun Biol. 2023 Jan 17;6(1):57.
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6. Desai S, Dharavath B, Manavalan S, Rane A, Redhu AK, Sunder R, Butle A, Mishra R, Joshi A, Togar T, Apte S, Bala P, Chandrani P, Chopra S, Bashyam MD, Banerjee A, Prabhash K, Nair S, Dutt A. Fusobacterium nucleatum is associated with inflammation and poor survival in early-stage HPV-negative tongue cancer. NAR Cancer. 2022 Mar 4;4(1):zcac006.
5. Togar T, Desai S, Mishra R, Terwadkar P, Ramteke M, Ranjan M, Kawle D, Sahoo B, Pal A, Upadhyay P, Dutt A. Identifying cancer driver genes from functional genomics screens. Swiss Med Wkly. 2020 Feb 21;150:w20195.
4. Upadhyay P, Gardi N, Desai S, Chandrani P, Joshi A, Dharavath B, Arora P, Bal M, Nair S, Dutt A. Genomic characterization of tobacco/nut chewing HPV-negative early stage tongue tumors identify MMP10 asa candidate to predict metastases. Oral Oncol. 2017 Oct;73:56-64.
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3 Upadhyay P, Nair S, Kaur E, Aich J, Dani P, Sethunath V, Gardi N, Chandrani P, Godbole M, Sonawane K, Prasad R, Kannan S, Agarwal B, Kane S, Gupta S, Dutt S, Dutt A. Notch pathway activation is essential for maintenance of stem-like cells in early tongue cancer. Oncotarget. 2016 Aug 2;7(31):50437-50449.
2. Chandrani P, Upadhyay P, Iyer P, Tanna M, Shetty M, Raghuram GV, Oak N, Singh A, Chaubal R, Ramteke M, Gupta S, Dutt A. Integrated genomics approach to identify biologically relevant alterations in fewer samples. BMC Genomics. 2015 Nov 14;16:936.
1. Chandrani P, Kulkarni V, Iyer P, Upadhyay P, Chaubal R, Das P, Mulherkar R, Singh R, Dutt A. NGS-based approach to determine the presence of HPV and their sites of integration in human cancer genome. Br J Cancer. 2015 Jun 9;112(12):1958-65.
