Molecular Biology of the cells attracted me since my days through B.Sc. in Zoology honors from Presidency College (not a University then) and later on, M.Sc. in Biochemistry from the University of Calcutta. Following this, I got trained in the areas of Molecular Biology through PhD from CSIR-Indian Institute of Chemical Biology and post-doctoralship from University of Texas Medical Branch at Galveston and University of Nebraska Medical Centre at Omaha. I started my independent research career from Saroj Gupta Cancer Centre & Research Institute, till joining Presidency University from where I continue pursuing my research works on “Basic and Translational Cancer Biology”.
My ongoing research areas of interests are as follows:
'Endocrine therapy responsiveness in breast cancer'
Clinically, breast cancer is marked by the presence of hormone receptors and more importantly, positive cases are successfully treated with endocrine therapy. However, while hormone receptor negative cases do not even come under the privilege of this therapy, positive cases frequently show resistance to ongoing endocrine therapy upon gradual loss of hormone receptors. Our ongoing works aim to dissect the molecular mechanism of restoration of endocrine therapy among breast cancer subtypes, emphasizing on a hormone-receptor-degrading-protein, CUEDC2.
In this search, we have found a crosstalk between hormone receptor status and aneuploidy in breast cancer. Aneuploidy in breast cancer is a frequent phenomenon and it varies among breast cancer subtypes. Maintenance of the ploidy status largely depends largely on a cell surveillance mechanism during cell division, namely spindle assembly checkpoint (SAC). However, the efficiency of SAC among breast cancer subtypes remains largely unknown. In our ongoing studies, we are exploring i) the molecular crosstalk between hormone receptors and SAC and, ii) its relevance on aneuploidy in breast cancer.
'Front-line therapy resistance in chronic myeloid leukemia (CML)'
The hematopoietic stem cell disorder CML is characterized by the presence of Philadelphia chromosome. This occurs through a reciprocal translocation generating BCR-ABL1 oncoprotein. Front-line (Imatinib) therapy directed against BCR-ABL1 tyrosine kinase activity showed a paradigm shift in CML management. However, resistance to front-line TKI is often encountered and mutations in the BCR-ABL1 kinase domain (KD) have been detected as a major determinant of this resistance. Indeed, a significant proportion of resistant cohorts do not show any candidate KD mutations and the resistance mechanism remains here mostly unresolved. Through our study, we explore molecular mechanism of TKI resistance in this pool.
'Ploidy status of breast cancer stem cells'
Among the malignant solid tumors, the presence of breast cancer stem cells, also known as tumor initiating cells (TIC), is well documented in breast cancer. These TIC populations are held responsible for disease recurrence and drug resistance in breast cancer. However, existing cancer therapies are unable to target these cell populations.
Aneuploidy is a prominent feature among mature malignant cells, little is known about the background ploidy status of TIC of breast cancer origin. In our study, we aim to determine the ploidy status of TIC populations from malignant primary breast malignancies as well as breast cancer cell lines. Based on these information, we aim to develop therapeutic strategy for imposing aneuploidy burden in breast-TICs as a preventive measure.
Administrative Experience:
Technical Director, Molecular Diagnostics Laboratory, Saroj Gupta Cancer Centre & Research Institute, November, 2020 – June, 2022
Research Experience:
I. As Assistant Professor (Institute of Health Sciences, Presidency University, Kolkata, from July, 2022 – till date) and as a Scientist (at Saroj Gupta Cancer Centre & Research Institute, Kolkata, August, 2015 to June, 2022)
After completing my post-doctoral work, I returned to India and joined Saroj Gupta Cancer Centre and Research Institute, Kolkata in August 2015 as a scientist in the Basic and Translational Research division and worked there till June, 2022. Following this, I joined the Institute of Health Sciences, Presidency University, Kolkata, as an Assistant Professor. I am working on the following areas:
- Endocrine therapy responsiveness in breast cancer
- Front-line resistance therapy resistance in chronic myeloid leukemia (CML)
- Ploidy status of breast cancer stem cells
These research works were/are being carried by from the following grants:
Ongoing:
1. Grant Title: To develop therapeutic leads to counter PD-L1 mediated suppression of immune system in cancer microenvironment
Reference Number: NCD/Ad-hoc/189/2022-23; Role as investigator: Co-Investigator; Funding agency: ICMR; Award period: 2023-2026
2. Grant Title: Clinical role of a pair of novel mutations in BCR-ABL1 towards therapy switch in imatinib-resistant chronic myeloid leukemia
Application No: 3330; Role as investigator: Principal Investigator; Funding agency: Lady Tata Memorial Trust (Institutional Research Grant); Award period: 2021-2024
Completed:
1. Grant title: Impact of BCR-ABL mutations on front-line tyrosine kinase inhibitor therapy: an East Indian cohort study
Grant number: ST/P/S&T/9G-21/2016; Role as investigator: Principal Investigator
Funding agency: Department of Science, Technology and Biotechnology (DSTBT), Govt. of West Bengal; Award period: 2018-2022
2. Grant Title: Delineating a novel transcriptional regulatory role of APC/C-Cdc20 complex and its impact on chromosomal instability in oral cancer (EMR/2015/001835)
Role as investigator: Co-Investigator; Funding agency: Science & Engineering Research Board (SERB)-Dept. of Science and Technology (DST), Govt. of India; Award period: 2019-2022
3. Grant title: Deciphering CUEDC2-mediated molecular crosstalk between aneuploidy and receptor status of breast tumors (ECR/2015/000206)
Role as investigator: Principal Investigator; Funding agency: Science & Engineering Research Board (SERB)-Dept. of Science and Technology (DST), Govt. of India; Award period: 2016-2019
II. Post-doctoral work (carried out in UTMB & UNMC, USA):
After completing my pre-doctoral work, I pursued his research work as a post-doctoral fellow from University of Texas Medical Branch at Galveston, Texas and University of Nebraska Medical Centre at Omaha, Nebraska, USA. During this tenure, I investigated two novel aspects of DNA damage repair enzyme APE1: the functional relevance of secretory APE1 and the role of APE1 acetylation in potentiating cell survival.
A) The secretion of DNA damage repair protein APE1 by monocytes induces IL-6 production: implication of extracellular role of APE1 in inflammation
Apurinic/apyrimidinic endonuclease 1 (APE1) is a pleiotropic nuclear protein with roles in DNA base excision repair (BER) pathway as well as in transcriptional regulation. The extracellular release of APE1 in plasma has also been reported. However, the physiological importance of this secretion remained elusive. We showed that monocytes secrete APE1 upon inflammatory challenges. This secretion follows a non-classical route of transportation through microvesicle shedding and requires ATP-binding cassette transporters. Furthermore, challenging the monocytes with APE1 (recAPE1) increased expression and secretion of pro-inflammatory cytokine IL6. Phosphorylation of transcription factor NF?B-p65 upon APE1 treatment preceded increased occupancy to IL6 promoter resulting in the induced expression of the cytokine. This pool of APE1-induced IL6 further served to elicit immunological responses in both autocrine and paracrine fashions. Moreover, the extracellular IL6 promoted the secretion of APE1, thus indicating a functional positive feedback loop in this pathway. Additionally, the release of APE1 by necrotic cells indicates stress responsive behavior of this secretion. Together, this study demonstrated a novel role of extracellular APE1 and identified secretory APE1 as a mediator of IL6 dependent inflammatory responses (published in Cell Signal, 2017).
B) The role of acetylated APE1 in mitotic bookmarking of genes, DNA damage repair, and cell proliferation
Lineage maintenance of cells following mitotic exit relies on re-establishing gene expression patterns in progeny cells. Here, we showed that mammalian APE1, when acetylated (AcAPE1), constitutively associates with thousands of gene promoters and enhancer regions, and persists throughout mitosis. Notably, mitotic retention of AcAPE1 contributes to rapid post-mitotic reactivation of target genes via preferential repair of the specific region of the active genes. Tumor cells exhibit higher level of AcAPE1 and maintain full length APE1, which otherwise undergoes limited proteolytic-cleavage by a serine protease when un-acetylated. The results demonstrated a critical requirement of AcAPE1 for sustained cell proliferation (published in Oncotarget, 2016a), DNA damage repair (published in Oncotarget, 2016b) and a novel role of AcAPE1 in bookmarking of active genes through mitosis, potentially facilitating the inheritance of gene expression patterns in progeny cells (published in Mol Cell Biol, 2017).
III. Pre-doctoral work (carried out at CSIR-IICB, Kolkata, India):
A) Study of the regulation of spindle assembly checkpoint gene, UBCH10 and its role in genomic instability in human cancer
I completed his thesis work on the topic of “Study of the regulation of spindle assembly checkpoint gene, UBCH10 and its role in genomic instability in human cancer” from CSIR-Indian Institute of Chemical Biology, Kolkata, India. To study the regulation of mitotic ubiquitin carrier protein UbcH10, we identified a novel role of spindle assembly checkpoint (SAC) protein Cdc20 in transcription regulation of UbcH10. Proper mitotic progression depends on orderly ubiquitination and degradation of various mitotic inhibitors. At molecular level, Cdc20 activates the ubiquitin ligase APC/C that along with ubiquitin conjugating enzyme, UbcH10, executes this function. This is monitored by SAC that ensures accurate chromosome segregation. Both Cdc20 and UbcH10 are overexpressed in many cancer types and associated with defective SAC and chromosomal instability. The precise mechanism of correlated over-expression of these proteins remained elusive. We dissected that Cdc20 is a novel transcription factor regulating UBCH10 expression in a cell cycle specific manner by acetylation dependent chromatin remodelling. The WD40 domain of Cdc20 is required for this activity. Physical interaction between Cdc20 and APC/C-CBP/p300 complex and its subsequent recruitment to UBCH10 promoter is involved in this transactivation. We identified that Cdc20, in combination with mitotic ubiquitin ligase APC/C and co-activator CBP/p300, transcriptionally regulates UbcH10 expression (published in J Biol Chem., 2011). However, this Cdc20 transcription complex does not have any DNA binding domain. Towards this, we found a novel role of Rb-E2F1 axis in Cdc20-mediated UBCH10 transcription regulation. E2F1 interacts with and modulates the activity of Cdc20-transcription complex. Physical recruitment of Cdc20-transcription complex on UBCH10 promoter occurs through E2F1 consensus element. Furthermore, we provided evidence for the occurrence of mitotic abnormalities upon E2F deregulation. We showed that upregulated E2F1 activity drives mitotic slippage in Cdc20 and UbcH10 dependent manner, and associates with increased mitotic abnormalities in cancer cells (published in Mol Cell Biol, 2015). It could be speculated that Cdc20 overexpression and thus UbcH10 up-regulation synergistically cause the onset of aneuploidy and tumorigenesis. Further, this study contributes to the enrichment of information on E2F1 mediated cell cycle regulation and open therapeutic avenues in tumorigenesis.
B) Germline transmission of MAD2 deletion is associated with human foetal abortions
During my Ph.D. tenure, I also worked on a parallel project investigating the involvement of a functional spindle assembly checkpoint (SAC) in the maintenance of foetal growth during pregnancy. Germline transmission of a mutation is likely to be a prominent cause of recurrent abortions and birth defects. Mad2 is one of the crucial SAC molecules. Deregulated Mad2 has been associated with defective SAC and abnormal meiotic progression. We reported the germline transmission of a MAD2 copy number deletion in three trisomic aborted fetuses (published in Mol Hum Reprod, 2012). To the best of knowledge, no such germline human mutations have been reported for any of the SAC genes in aborted foetal samples. This study implicates the possible involvement of the SAC genes in pregnancy loss.
C) Additional participation:
During my PhD tenure, I also participated in projects investigating the role of p53 in the regulation of Cdc20 (published in Nucleic Acids Res, 2009) and UbcH10 (published in J Biol Chem, 2016), and the role of microRNA-125b in the regulation of mitotic cell death (published in Cell Death Differ, 2013). These important findings have broader implications in understanding the regulation of cell cycle and the nature of origin of chromosomal instability in human cancer.
Original Article: (* corresponding author)
1. Barik GK, Sahay O, Mukhopadhyay A, Manne RK, Islam S, Roy A, Nath S, Santra MK. FBXW2 suppresses breast tumorigenesis by targeting AKT-Moesin-SKP2 axis. Cell Death Dis. 2023 Sep 22;14(9):623. doi: 10.1038/s41419-023-06127-x
2. Kar S, Maji N, Sen K, Roy S, Maity A, Ghosh Dastidar S, Nath S, Basu G, Basu M. Reprogramming of glucose metabolism via PFKFB4 is critical in FGF16-driven invasion of breast cancer cells. Biosci Rep. 2023 24:BSR20230677. doi: 10.1042/BSR20230677
3. Saha S, Mukherjee M, Basak D, Panja P, Mondal PK, Ghosh R, Halder A, Chowdhury A, Dhali GK, Chattopadhyay BK, Ghosh S, Nath S, Datta S. High expression of mesothelin in plasma and tissue is associated with poor prognosis and promotes invasion and metastasis in gastric cancer. Adv Cancer Biol Metastasis. 2023, doi: https://doi.org/10.1016/j.adcanc.2023.100098.
4. Sengupta D, Mukhopadhyay P, Banerjee S, Ganguly K, Mascharak P, Mukherjee N, Mitra S, Bhattacharjee S, Mitra R, Sarkar A, Chaudhuri T, Bhattacharjee G, Nath S, Roychoudhury S, Sengupta M. Identifying polymorphic cis-regulatory variants as risk markers for lung carcinogenesis and chemotherapy responses in tobacco smokers from eastern India. Sci Rep. 2023 Mar 10;13(1):4019. doi: 10.1038/s41598-023-30962-9.
5. Mukhopadhyay A, Roy S, Saha S, Majumder S, Dey S, Bhattacharyya S, Gupta A, Nath S*. A comparative analysis of features and outcome of breast cancer in younger versus older women: A single center experience from Eastern Indian subcontinent. J Can Res Ther 2023 Apr;19(Supplement):S59-S66. doi: 10.4103/jcrt.jcrt_664_22.
6. Chakraborty P, Paul R, Chowdhury A, Mukherjee N, Nath S*, Roychoudhury S. The anaphase promoting complex/cyclosome ubiquitylates histone H2B on the promoter during UbcH10 transactivation. FEBS Lett. 2022 Feb;597(3):437-447. doi: 10.1002/1873-3468.14563
7. Dey S, Basu S, Shah S, Bhattacharyya D, Gupta PP, Acharjee M, Roychoudhury S, Nath S*. Deep sequencing reveals the spectrum of BCR-ABL1 mutations upon front-line therapy resistance in chronic myeloid leukemia: an Eastern-Indian cohort study. Cancer Treat Res Commun. 2022 Sep 15;33:100635. doi: 10.1016/j.ctarc.2022.100635
8. Roy S, Saha S, Dhar D, Chakraborty P, Singha Roy K, Mukherjee C, Gupta A, Bhattacharyya S, Roy A, Sengupta S, Roychoudhury S, Nath S*. Molecular crosstalk between CUEDC2 and ERα influences the clinical outcome by regulating mitosis in breast cancer. Cancer Gene Ther. 2022 Nov;29(11):1697-1706. doi: 10.1038/s41417-022-00494-x
9. Saha T, Bhowmick B, Sengupta D, Banerjee S, Mitra R, Sarkar A, Chaudhuri T, Bhattacharjee G, Nath S, Roychoudhury S, Sengupta M. No association of the common Asian mitochondrial DNA haplogroups with lung cancer in East Indian population. J Basic Clin Physiol Pharmacol. 2022 Mar 28. doi: 10.1515/jbcpp-2021-0352
10. Ghuwalewala S, Ghatak D, Das S, Roy S, Das P, Butti M, Gorain M, Nath S, Kundu GC, Roychoudhury S. MiRNA-146a/AKT/β-catenin activation regulates cancer stem cell phenotype in oral squamous cell carcinoma by targeting CD24. Front Oncol. 2021 Oct 12;11:651692. doi: 10.3389/fonc.2021.651692
11. Dey S, Bhattacharyya D, Gupta PP, Nath S*. Long-term Outcome of Philadelphia Chromosome Positive Leukemia from Eastern Indian Sub-continent: An Experience in the Era of Tyrosine Kinase Inhibitor (TKI) Therapy. Clin Lymphoma Myeloma Leuk. 2021 Nov; 21(11):e8 doi: https://doi.org/10.1016/j.clml.2021.06.026
12. Sengupta D, Banerjee S, Mukhopadhyay P, Mitra R, Chaudhuri T, Sarkar A, Bhattacharjee G, Nath S, Roychoudhury S, Bhatatcharjee S, Sengupta M. A comprehensive meta-analysis and a case-control study give insights into genetic susceptibility of lung cancer and subgroups. Sci Rep. 2021 Jul 16;11(1):14572. doi: 10.1038/s41598-021-92275-z
13. Nath S, Roychoudhury S, Kling MJ, Song H, Biswas P, Shukla A, Band H, Joshi S, Bhakat KK. The extracellular role of DNA damage repair protein APE1 in regulation of IL-6 expression. Cell Signal. 2017 Nov; 39:18-31. doi: 10.1016/j.cellsig.2017.07.019.
14. Roychoudhury S, Nath S, Song H, Hegde ML, Bellot LJ, Mantha AK, Sengupta S, Ray S, Natarajan A, Bhakat KK. Human AP-endonuclease (APE1) is acetylated at DNA damage sites in chromatin and acetylation modulates its DNA repair activity. Mol Cell Biol. 2017 Mar 1;37(6):e00401-16. doi: 10.1128/MCB.00401-16.
15. Sengupta S, Mantha AK, Song H, Roychoudhury S, Nath S, Ray S, Bhakat KK. Elevated level of acetylation of APE1 in tumor cells modulates DNA damage repair. Oncotarget. 2016 Nov 15;7(46):75197-75209. doi: 10.18632/oncotarget.12113
16. Bajaj S, Alam SK, Singha Roy K, Datta A, Nath S, Roychoudhury S. E2-ubiquitin conjugating enzyme, UBE2C, is reciprocally regulated by wild-type and gain-of-function mutant p53. J Biol Chem. 2016 Jul 1;291(27):14231-47. doi: 10.1074/jbc.M116.731398
17. Bhakat KK, Sengupta S, Adeniyi V, Roychoudhury S, Nath S, Bellot LJ, Feng D, Mantha AK, Sinha M, Luxon B. Regulation of limited N-terminal proteolysis of APE1 in tumor via acetylation and its role in cell proliferation. Oncotarget. 2016 Apr 19;7(16):22590-604. doi: 10.18632/oncotarget.8026
18. Nath S, Chowdhury A, Dey S, Roychoudhury A, Ganguly A, Bhattacharyya D, Roychoudhury S. Deregulation of Rb-E2F1 axis causes chromosomal instability by engaging the transactivation function of Cdc20-APC/C complex. Mol Cell Biol. 2015 Jan 15; 35(2):356-69. doi: 10.1128/MCB.00868-14
19. Bhattacharjya S, Nath S, Ghose J, Maiti G, Biswas N, Bhattacharyya NP, Bandopadhyay S, Panda CK, Roychoudhury S. miR-125b promotes cell death by targeting Spindle Assembly Checkpoint gene MAD1 and modulating mitotic progression. Cell Death Differ. 2013 Mar;20(3):430-42. doi: 10.1038/cdd.2012.135
20. Nath S, Moghe M, Chowdhury A, Godbole K, Godbole G, Doipodhe M, Roychoudhury S. Is Germline transmission of MAD2 gene deletion associated with human foetal loss? Mol Hum Reprod. 2012 November;18(11):554–562. doi: 10.1093/molehr/gas031
21. Nath S, Banerjee T, Sen D, Das T, Roychoudhury S. Spindle assembly checkpoint protein Cdc20 transcriptionally activates expression of ubiquitin carrier protein UbcH10. J Biol Chem. 2011 May 6;286(18):15666-77. doi: 10.1074/jbc.M110.160671
22. Banerjee T, Nath S, Roychoudhury S. DNA damage induced p53 downregulates Cdc20 by direct binding to its promoter causing chromatin remodeling. Nucleic Acids Res. 2009 May;37(8):2688-98. doi: 10.1093/nar/gkp110
Review Article: (* corresponding author)
1. Saha S, Dey S, Nath S*. Steroid hormone receptors: links with cell cycle machinery and breast cancer progression. Front Oncol. 2021. Mar 12;11:620214. doi: 10.3389/fonc.2021.620214
2. Nath S, Ghatak D, Das P, Roychoudhury S. Transcriptional control of mitosis: deregulation and cancer. Front Endocrinol (Lausanne). 2015 May 5;6:60. doi: 10.3389/fendo.2015.00060
Book Chapter: (* corresponding author)
Nath S*, Roy S. (2021) Genomic Instability in Carcinogenesis: the role of oxidative stress. In: Chakraborti S., Ray B.K., Roychowdhury S. (eds) Handbook of Oxidative Stress in Cancer: Mechanistic Aspects. Springer, Singapore. https://doi.org/10.1007/978-981-15-4501-6_155-1
Roychoudhury S, Banerjee T, Nath S. CDC20 (cell division cycle 20 homolog (S. cerevisiae)). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(2):104-105. doi: 10.4267/2042/44399
Editorial: (* corresponding author)
Nath S and Agarwal P (2023), Editorial: Genetic regulation of mitosis and ploidy in cancer. Front Genet. 14:1264772. doi: 10.3389/fgene.2023.1264772
Conference publication:
1. D. Bhattacharyya, S. Dey, R. N. Ghosh, P. P. Gupta, A. Gupta, S. Roychoudhury, S. Nath. PB2498 Diagnosis of acute leukemia and its impact in a resource poor centre of Eastern India: A retrospective overview. Hemasphere. 2020; 4:S1, 1106
2. D. Bhattacharyya, R. N. Ghosh, P. P. Gupta, A. Gupta, S. Roy, S. Roychoudhury, S. Nath. PB1972 Prevalence of imatinib resistance in chronic myeloid leukemia (CML): experience from a tertiary care centre in Eastern India. Hemasphere. 2020; 4:S1, 897
3. S. Nath. 65P Investigating the molecular connection between hormone receptor status and ploidy management in breast cancer. Annals Oncol. Volume 31, Supplement 2, S37, May 01, 2020. https://doi.org/10.1016/j.annonc.2020.03.199
4. D. Bhattacharyya, R. Ghosh, P. Gupta, A. Gupta, S. Roychoudhury, S. Nath. 1098P - Incidence of imatinib resistance in chronic myeloid leukemia (CML) patients: Experience from resource poor center of eastern India. Annals Oncol. Volume 30, Supplement 5, October 2019, Page v445, doi:10.1093/annonc/mdz251
5. S Nath, A Shukla, S Joshi, K K Bhakat. DNA damage repair enzyme APE1 is a non-classical secretory protein and acts as a mediator of IL6 dependent inflammatory responses (IRM11P.626). J Immunol. May 1, 2015, 194 (1 Supplement) 132.
6. Sengupta, S., Bellot, L., Nath, S., Bhakat, K. K. Mitotic bookmarking of genes- a novel dimension of epigenetic memory in cancer. Anticancer Res. October, 2014 34(10); 5835
7. S Nath, T Banerjee, D Sen, T Das, S Roychoudhury. Abstract 3075: A novel transcriptional role of spindle assembly checkpoint protein Cdc20 regulating the expression of mitotic ubiquitin carrier protein UbcH10, Cancer Res. April 15, 2011 71; 3075
8. S Bajaj, S Nath, S Roychoudhury. Abstract # 4269 - Novel TP53 gain-of-function mutations that activate the cell cycle regulatory gene, UBE2C, Cancer Res. May 1, 2009 69; 4269
9. T Banerjee, S Nath, S Roychoudhury. Repression of the spindle assembly checkpoint gene CDC20 by p53 upon DNA damage, Cancer Res. May 1, 2008 68; 2597
Presidency University Students Corner