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.
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.
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)
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)
National Centre for Cell Science (NCCS), Pune
Himachal Pradesh University, Shimla
Udai Pratap College, Varanasi
Postdoctoral fellow, Dept. of Tumor Biology, Moffitt Cancer Center, Tampa, FL, USA (2007-2012)
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)
|2001-2006||Research Scholarship, Dept. of Biotechnology, Govt. of India|
|2013-2018||Intermediate Fellowship and research grant from Wellcome Trust/DBT India Alliance|
Intermediate Grant (IA/I/13/1/500908) from Wellcome Trust/DBT India Alliance
Period: 10/01/13 - 09/30/19
Amount: INR 3,15,60,000.00
Title: Understanding the biology of stem-like cancer cells from human oral tumorSERB CRG Support (CRG/2021/005556)
Project start date: December 28, 2021
Amount: INR 58,35,628
Title: Discovery of potential molecular targets against NOTCH- active and inactive states of stemness in gingivobuccal oral cancer
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.
- Acharya S, Ghosh S, Maji M, Parambil ARU, Singh S, Mukherjee A. Inhibition of 3D colon cancer stem cell spheroids by cytotoxic RuII-p-cymene complexes of mesalazine derivatives. Chem Commun (Camb). 2020 May 19;56(40):5421-5424. doi: 10.1039/d0cc00472c. PubMed PMID: 32292957.
- Patel AK, Singh S. Cancer associated fibroblasts: phenotypic and functional heterogeneity. Front Biosci (Landmark Ed). 2020 Mar 1;25:961-978. PubMed PMID: 32114420.
- 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. doi: 10.1038/s41389-018-0087-x. PubMed PMID: 30287850; PubMed Central PMCID: PMC6172238.
- Bora-Singhal N, Nguyen J, Schaal C, Perumal D, Singh S, Coppola D, Chellappan S. YAP1 Regulates OCT4 Activity and SOX2 Expression to Facilitate Self-Renewal and Vascular Mimicry of Stem-Like Cells. Stem Cells. 2015 Jun;33(6):1705-18. doi: 10.1002/stem.1993. PubMed PMID: 25754111; PubMed Central PMCID: PMC4441573.
- Pillai S, Trevino J, Rawal B, Singh S, Kovacs M, Li X, Schell M, Haura E, Bepler G, Chellappan S. β-arrestin-1 mediates nicotine-induced metastasis through E2F1 target genes that modulate epithelial-mesenchymal transition. Cancer Res. 2015 Mar 15;75(6):1009-20. doi: 10.1158/0008-5472.CAN-14-0681. Epub 2015 Jan 19. PubMed PMID: 25600647; PubMed Central PMCID: PMC4359962.
- Singh S, Chellappan S. Lung cancer stem cells: Molecular features and therapeutic targets. Mol Aspects Med. 2014 Oct;39:50-60. doi: 10.1016/j.mam.2013.08.003. Epub 2013 Sep 7. Review. PubMed PMID: 24016594; PubMed Central PMCID: PMC3949216.
- Treviño JG, Verma M, Singh S, Pillai S, Zhang D, Pernazza D, Sebti SM, Lawrence NJ, Centeno BA, Chellappan SP. Selective disruption of rb-raf-1 kinase interaction inhibits pancreatic adenocarcinoma growth irrespective of gemcitabine sensitivity. Mol Cancer Ther. 2013 Dec;12(12):2722-34. doi: 10.1158/1535-7163.MCT-12-0719. Epub 2013 Oct 9. PubMed PMID: 24107447; PubMed Central PMCID: PMC3858536.
- Singh S, Bora-Singhal N, Kroeger J, Laklai H, Chellappan SP. βArrestin-1 and Mcl-1 modulate self-renewal growth of cancer stem-like side-population cells in non-small cell lung cancer. PLoS One. 2013;8(2):e55982. doi: 10.1371/journal.pone.0055982. Epub 2013 Feb 13. PubMed PMID: 23418490; PubMed Central PMCID: PMC3572139.
- Treviño JG, Pillai S, Kunigal S, Singh S, Fulp WJ, Centeno BA, Chellappan SP. Nicotine induces inhibitor of differentiation-1 in a Src-dependent pathway promoting metastasis and chemoresistance in pancreatic adenocarcinoma. Neoplasia. 2012 Dec;14(12):1102-14. doi: 10.1593/neo.121044. PubMed PMID: 23308043; PubMed Central PMCID: PMC3540937.
- Singh S, Trevino J, Bora-Singhal N, Coppola D, Haura E, Altiok S, Chellappan SP. EGFR/Src/Akt signaling modulates Sox2 expression and self-renewal of stem-like side-population cells in non-small cell lung cancer. Mol Cancer. 2012 Sep 25;11:73. doi: 10.1186/1476-4598-11-73. PubMed PMID: 23009336; PubMed Central PMCID: PMC3497614.
- Perumal D, Singh S, Yoder SJ, Bloom GC, Chellappan SP. A novel five gene signature derived from stem-like side population cells predicts overall and recurrence-free survival in NSCLC. PLoS One. 2012;7(8):e43589. doi: 10.1371/journal.pone.0043589. Epub 2012 Aug 29. PubMed PMID: 22952714; PubMed Central PMCID: PMC3430700.
- Alamanda V, Singh S, Lawrence NJ, Chellappan SP. Nicotine-mediated induction of E-selectin in aortic endothelial cells requires Src kinase and E2F1 transcriptional activity. Biochem Biophys Res Commun. 2012 Feb 3;418(1):56-61. doi: 10.1016/j.bbrc.2011.12.127. Epub 2012 Jan 3. PubMed PMID: 22240023; PubMed Central PMCID: PMC3273677.
- Singh S, Pillai S, Chellappan S. Nicotinic acetylcholine receptor signaling in tumor growth and metastasis. J Oncol. 2011;2011:456743. doi: 10.1155/2011/456743. Epub 2011 Mar 30. PubMed PMID: 21541211; PubMed Central PMCID: PMC3085312.
- Singh S, Davis R, Alamanda V, Pireddu R, Pernazza D, Sebti S, Lawrence N, Chellappan S. Rb-Raf-1 interaction disruptor RRD-251 induces apoptosis in metastatic melanoma cells and synergizes with dacarbazine. Mol Cancer Ther. 2010 Dec;9(12):3330-41. doi: 10.1158/1535-7163.MCT-10-0442. Epub 2010 Dec 7. PubMed PMID: 21139044; PubMed Central PMCID: PMC3058238.
- Singh S, Johnson J, Chellappan S. Small molecule regulators of Rb-E2F pathway as modulators of transcription. Biochim Biophys Acta. 2010 Oct-Dec;1799(10-12):788-94. doi: 10.1016/j.bbagrm.2010.07.004. Epub 2010 Jul 15. Review. PubMed PMID: 20637913; PubMed Central PMCID: PMC2997897.
- Ajay AK, Upadhyay AK, Singh S, Vijayakumar MV, Kumari R, Pandey V, Boppana R, Bhat MK. Cdk5 phosphorylates non-genotoxically overexpressed p53 following inhibition of PP2A to induce cell cycle arrest/apoptosis and inhibits tumor progression. Mol Cancer. 2010 Jul 31;9:204. doi: 10.1186/1476-4598-9-204. PubMed PMID: 20673369; PubMed Central PMCID: PMC2922192.
- Upadhyay AK, Ajay AK, Singh S, Bhat MK. Cell cycle regulatory protein 5 (Cdk5) is a novel downstream target of ERK in carboplatin induced death of breast cancer cells. Curr Cancer Drug Targets. 2008 Dec;8(8):741-52. doi: 10.2174/156800908786733405. PubMed PMID: 19075597.
- Singh S, Upadhyay AK, Ajay AK, Bhat MK. Gadd45alpha does not modulate the carboplatin or 5-fluorouracil-induced apoptosis in human papillomavirus-positive cells. J Cell Biochem. 2007 Apr 1;100(5):1191-9. doi: 10.1002/jcb.21111. PubMed PMID: 17063488.
- Singh S, Upadhyay AK, Ajay AK, Bhat MK. p53 regulates ERK activation in carboplatin induced apoptosis in cervical carcinoma: a novel target of p53 in apoptosis. FEBS Lett. 2007 Jan 23;581(2):289-95. doi: 10.1016/j.febslet.2006.12.035. Epub 2006 Dec 29. PubMed PMID: 17208232.
- Upadhyay AK, Singh S, Chhipa RR, Vijayakumar MV, Ajay AK, Bhat MK. Methyl-beta-cyclodextrin enhances the susceptibility of human breast cancer cells to carboplatin and 5-fluorouracil: involvement of Akt, NF-kappaB and Bcl-2. Toxicol Appl Pharmacol. 2006 Oct 15;216(2):177-85. doi: 10.1016/j.taap.2006.05.009. Epub 2006 May 19. PubMed PMID: 16806341.
- Singh S, Chhipa RR, Vijayakumar MV, Bhat MK. DNA damaging drugs-induced down-regulation of Bcl-2 is essential for induction of apoptosis in high-risk HPV-positive HEp-2 and KB cells. Cancer Lett. 2006 May 18;236(2):213-21. doi: 10.1016/j.canlet.2005.05.024. Epub 2005 Jul 5. PubMed PMID: 15996812.
- Vijayakumar MV, Singh S, Chhipa RR, Bhat MK. The hypoglycaemic activity of fenugreek seed extract is mediated through the stimulation of an insulin signalling pathway. Br J Pharmacol. 2005 Sep;146(1):41-8. doi: 10.1038/sj.bjp.0706312. PubMed PMID: 15980869; PubMed Central PMCID: PMC1576255.
- Chhipa RR, Singh S, Surve SV, Vijayakumar MV, Bhat MK. Doxycycline potentiates antitumor effect of cyclophosphamide in mice. Toxicol Appl Pharmacol. 2005 Feb 1;202(3):268-77. doi: 10.1016/j.taap.2004.06.025. PubMed PMID: 15667832.
- Singh S, Bhat MK. Carboplatin induces apoptotic cell death through downregulation of constitutively active nuclear factor-kappaB in human HPV-18 E6-positive HEp-2 cells. Biochem Biophys Res Commun. 2004 May 28;318(2):346-53. doi: 10.1016/j.bbrc.2004.04.037. PubMed PMID: 15120608.
Subhashis Ghosh, DBT-SRF
Paromita Mitra, CSIR-SRF
Uday Saha, iPhD
Subhashree Jena, INSPIRE Fellow
Rimpa Nandi, UGC-JRF
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)