Profile
Research Interest
Aggressive nature of cancer has been correlated with heterogeneity among cancer cells which is collectively ascribed to the genetic diversity along with gene-environment interaction established between cancer and stromal cells that constitute tumor microenvironment (TME). Our research interest is to comprehend the mechanisms responsible for cellular and functional heterogeneity in solid tumors through cancer stem cell model. Taking help of technologies which facilitate studies at holistic level; we are emphasizing on the biology of stemness maintenance in cancer, interactions between cells within TME and identification of therapeutic targets.
Selected publications
Vipparthi, K., Hari, K., Chakraborty, P., Ghosh, S., Patel, A.K., Ghosh, A., Biswas, N.K., Sharan, R., Arun, P., Jolly, M.K., Singh, S., Emergence of hybrid states of stem- like cancer cells correlates with poor prognosis in oral cancer, ISCIENCE. 2022 25(5), 104317
Vipparthi K, Patel AK, Ghosh S, Das S, Das C, Das K, Sarkar A, Thattikonda V, Pal B, Remani ASN, Arora N, Parihar M, Vijayakumar MV, Bhat MK, Boppana R, Bhattacharjee S, Biswas NK, Arun P, Sharan R, Singh S. Two novel cell culture models of buccal mucosal oral cancer from patients with no risk-habits of tobacco smoking or chewing. Oral Oncology. 2021 Feb;113:105131
Patel AK, Singh S. Cancer associated fibroblasts: phenotypic and functional heterogeneity. Front Biosci (Landmark Ed). 2020 Mar 1;25:961-978.
Patel AK, Vipparthi K, Thatikonda V, Arun I, Bhattacharjee S, Sharan R, Arun P, Singh S. A subtype of cancer-associated fibroblasts with lower expression of alpha-smooth muscle actin suppresses stemness through BMP4 in oral carcinoma. Oncogenesis. 2018 Oct 5;7(10):78.
Research
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Link : https://youtu.be/N3fLKbOULDU
This video is created to summarise the current understanding of cancer stem cell biology. I have talked about history of the discovery of cancer stem cells, the current excitement in the field and avenues for future research. Graduate and undergraduate students may watch this video as introductory lecture.
Recent Research Highlights:
CAF-specific Tie2-signaling in cancer cell reprogramming:
Based on mechanistic investigation and validation in oral cancer patient cohort, at both bulk and single cell levels we have found that the Tie2-signaling is activated in myofibroblasts which impacts the behaviour of malignant cells by inducing cellular plasticity to acquire stemness. We are for the first-time reporting that the cancer-associated fibroblasts (CAFs) express Tie2-receptor-tyrosine kinase upon acquiring TGFb-induced myofibroblastic phenotype. Mechanistically, HDAC mediated epigenetic downregulation of ANGPT2 was accountable for CAF-specific Tie2 activation in oral-CAFs. The CAF-specific Tie2 signaling was found to induce plasticity in cancer cells led to the emergence of embryonic-like cell state in co-culture experiments. CAF-specific Tie2-activity was targetable by small molecule inhibitor, resulted in reversal of CAF-induced-acquisition of stemness in oral cancer cells. The Tie2-specific gene expression signature in CAFs as well as reprogrammed cancer cell specific gene expression modules were validated in earlier reported, two independent scRNAseq studies of HNSCC tumors. The CAF-induced reprogramming led to the transcriptional evolution in cancer cells which was associated with poor prognosis of oral cancer patients. These findings are out as preprint (https://www.biorxiv.org/content/10.1101/2024.06.29.601319v1).
Cancer stem cells diversity is responsible for poor survival of oral cancer patients:
High-intratumoral heterogeneity (ITH) has been the clinically important factor, impacting aggressive cancer behaviour, drug tolerance and overall poor prognosis among patients. Recent advancement in cancer research using high-throughput technologies have provided better resolution of ITH at cellular and molecular levels. However, these studies could not provide the composition and characteristics of critical subpopulations, responsible for global tumor behaviour. By multiplexing phenotypic markers of cancer stem cells, we have defined four subpopulations of oral cancer cells. These subpopulations showed stochastic inter-conversions as well as a strict non-interconvertible transition among them to achieve cellular heterogeneity. Importantly, RNA-sequencing of these subpopulations demonstrated the alternate states of putative stemness, maintained within these subpopulations. Also, our group has observed conversions of these subpopulations as rapid and reversible strategy to respond to chemotherapy induced stress; accumulating drug-tolerant subpopulation. We went ahead and mapped the transcriptional states of these subpopulations to discover clinically relevant signatures, suggesting the poor prognosis in oral cancer patients. To emphasize, we have provided solid contributions to the growing field of non-genetic cellular plasticity, which is one of the emerging hallmarks of cancer. This work is published in ‘iScience’, in April 2022. (https://doi.org/10.1016/j.isci.2022.104317)
Two novel oral cancer cell lines established from Indian patients having no risk-habits of tobacco smoking or chewing:
We have reported the establishment of two novel oral cancer cell lines from primary tumor samples. These two cell lines are among very few oral cancer cell lines which are established from India and first reported cell lines in the world which are from buccal mucosal oral cancer patients who were not having the risk habit of tobacco usage. These cell lines are comprehensively characterized for the genomic perturbations and their functions related to aggressive cancer behaviours including cell proliferation, migration, drug sensitivity, stemness and tumor formation. Using these primary cultures derived from tumor samples, we have generated the method to enrich cancer cells with stem cell like activity. Using this methodology we are screening anti-cancer stem cell drug in collaboration with IISER-Kolkata (https://doi.org/10.1039/d0cc00472c). Further, these cell cultures are serving as valuable resource for testing our hypothesis related to functions of genetic and molecular changes identified in large scale genomic studies of ICGC and TCGA. Overall, towards making the precision medicine a reality for oral cancer patients; these cell culture models are creating an avenue to move forward and I am eager to collaborate. (https://doi.org/10.1016/j.oraloncology.2020.105131)
Heterocellular reciprocation in oral tumor microenvironment:
Despite the improvement in the standard treatment strategies, the 5-years survival rate for oral cancer patients has remained around 50% since decades. Patients frequently show resistance to the given treatment or local recurrence. With the framework of stem cell biology of cancer, we have carried out in-depth investigations on oral tumor biology emphasizing on gingivobuccal oral cancer. Our work has revealed the surprising diversity among fibroblast within the microenvironment of oral tumor as responsible factor for differences in stemness of oral cancer cells. Study suggests that myofibroblast differentiation of stromal-fibroblast provide more conducive environment for aggressive self-renewal of oral-cancer stem cells through differential expression of certain genes. By discovering the CAFs-mediated mechanisms which might restrain cancer cells to a less-aggressive state, our work has provided an opportunity for prognostic classification of patients, who might get better response to the given treatment as well as opened an avenue for targeting tumor-stroma interactions in aggressive tumors. (https://doi.org/10.1038/s41389-018-0087-x)
CV
Education
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Year
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University
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Degree
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2007
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National Centre for Cell Science (NCCS), Pune
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Ph.D
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2001
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Himachal Pradesh University, Shimla
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M.Sc
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1999
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Udai Pratap College, Varanasi
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B.Sc
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Professional Appointments
Postdoctoral fellow, Dept. of Tumor Biology, Moffitt Cancer Center, Tampa, FL, USA (2007-2012)
Professional Memberships
Life member; Society of Biological Chemist (SBC), India
Life member; Indian Society of Human Genetics (ISHG), India
Life Member; Indian Association for Cancer Research (IACR), India
Active member; American Association for Cancer Research (AACR), USA
IACR-Executive Committee Member (East Zone) 2022-2025 (Elected)
Awards/Honors
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Year |
Award |
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2001-2006 |
Research Scholarship, Dept. of Biotechnology, Govt. of India |
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2013-2018 |
Intermediate Fellowship and research grant from Wellcome Trust/DBT India Alliance |
Extramural projects:
DBT PI-driven Grant (CRG/2021/005556)
Project start date: June 21, 2024 (3 Years)
Amount: INR 80 Lakh
Role: PI
Title: Study on the epigenetic mechanism of JAK-STAT driven plasticity in oral cancer stem cells for its therapeutic value
SERB CRG Support (CRG/2021/005556)
Project start date: December 28, 2021 (3 Years)
Amount: INR 58,35,628
Role: PI
Title: Discovery of potential molecular targets against NOTCH- active and inactive states of stemness in gingivobuccal oral cancer
Intermediate Grant (IA/I/13/1/500908) from Wellcome Trust/DBT India Alliance
Period: 10/01/13 - 09/30/19 (Completed)
Amount: INR 3,15,60,000.00
Role: PI
Title: Understanding the biology of stem-like cancer cells from human oral tumor
Publications
URL: https://www.ncbi.nlm.nih.gov/myncbi/1RM2yPw8WGckeC/bibliography/public/
Kumari P, Ghosh S, Acharya S, Mitra P, Roy S, Ghosh S, Maji M, Singh S, Mukherjee A. Cytotoxic Imidazolyl-Mesalazine Ester-Based Ru(II) Complexes Reduce Expression of Stemness Genes and Induce Differentiation of Oral Squamous Cell Carcinoma. J Med Chem. 2023 Oct 26;66(20):14061-14079. doi: 10.1021/acs.jmedchem.3c01092. Epub 2023 Oct 13. PubMed PMID: 37831489.
Ghosh S, Mitra P, Saha U, Nandi R, Jena S, Ghosh A, Roy SS, Acharya M, Biswas NK, Singh S. NOTCH pathway inactivation reprograms stem-like oral cancer cells to JAK-STAT dependent state and provides the opportunity of synthetic lethality. Transl Oncol. 2023 Jun;32:101669. doi: 10.1016/j.tranon.2023.101669. Epub 2023 Apr 11. PubMed PMID: 37054548; PubMed Central PMCID: PMC10122064.
Ghosh S, Mitra P, Saha U, Vipparthi K, Singh S. Characterizing diversity among human oral stem-like cancer cells using flow cytometry. STAR Protoc. 2022 Oct 11;3(4):101763. doi: 10.1016/j.xpro.2022.101763.
Vipparthi K, Hari K, Chakraborty P, Ghosh S, Patel AK, Ghosh A, Biswas NK, Sharan R, Arun P, Jolly MK, Singh S. Emergence of hybrid states of stem-like cancer cells correlates with poor prognosis in oral cancer.iScience. 2022 May 20;25(5):104317. eCollection 2022 May 20.
Vipparthi K, Patel AK, Ghosh S, Das S, Das C, Das K, Sarkar A, Thatikonda V, Pal B, Remani ASKN, Arora N, Parihar M, Vijayakumar MV, Bhat MK, Boppana R, Bhattacharjee S, Biswas NK, Arun P, Sharan R, Singh S. Two novel cell culture models of buccal mucosal oral cancer from patients with no risk-habits of tobacco smoking or chewing. Oral Oncol. 2021 Feb;113:105131. doi: 10.1016/j.oraloncology.2020.105131. Epub 2020 Dec 30. PubMed PMID: 33387705.
Lab members
Postdoctoral Fellow:
Dr. Priyanka Prasad, CSIR-RA
PhD students:
Paromita Mitra, CSIR-SRF
Subhashree Jena, INSPIRE-SRF
Rimpa Nandi, UGC-SRF
Uday Saha, UGC-JRF (NIBMG-iPhD)
Priyanshi Sisodia, NIBMG iPhD
Bhagyashree Pradhan, UGC-JRF (NIBMG-iPhD)
Lab alumni:
Subhashis Ghosh, DBT-SRF (Currently at Tufts University, Massachusetts, USA as postdoctoral fellow)
Kavya Vipparthi, INSPIRE-SRF (Currently at Cleveland Clinic, Ohio, USA as postdoctoral fellow)
Ankit K Patel, ICMR-SRF (Currently at Umeå University, Sweden as postdoctoral fellow)
