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Dr. Sharmila Bapat

Scientist 'F',
National Centre for Cell Science,
NCCS Complex, Pune University Campus
Ganeshkhind, Maharashtra, Pune- 411 007, India
Ph.: +91-020-25708074, 25708089, 25708000
Fax: +91-020-25692259
E-mail: lsl, lsl

DrBapat

 

 

Education |Research Interest | Publicatons | Awards and Achievements | Memberships of Scientific Societies | Lab Members | Lab Alumni | Collaborations

 

 

Education

 

Ph.D., 1992, National Chemical Laboratory, Pune.

M.Sc., 1987, Microbiology, Pune University, Pune

 

 

Research Interests

 

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Ovarian cancer stem cells and Tumor-derived Endothelial Stem Cells

Cancers like normal adult organs seem to be maintained by a hierarchical organization that includes three cell types: slow cycling, cancer stem cells (CSCs); rapidly dividing, transit amplifying / progenitor cells; and differentiated cells. Presence of the small CSC population of might explain why several tumors recur after radio- and/or chemo-therapy even when the tumor shrinks for a brief span of time after the treatment.

Our lab provided the first evidence that human ovarian cancer may be a result of stem cell dysfunction. We initially established a novel, in vitro model comprising of 19 immortalized stem and progenitor clones derived from a single sample of human ovarian cancer (malignant grade IV serous adenocarcinoma).  Extensive analyses of these clones that display stem cell properties, forms the mainstay of the Cancer Stem Cell projects in the lab.  We initially identified that five of these clones had a mutant mitochondrial DNA profile and were tumorigenic, while the remaining 14 clones had a germline mitochondrial DNA profile, expressed the stem cell marker CD133 and were not tumorigenic.  The former transformed clones were concluded to represent CSCs because (a) they self-renew and are clonogenic, (b) differentiate in vitro to form organized spheroids in suspension, (c) express multipotency and tissue-specific differentiation markers, (d) express self-renewal mechanisms in vivo (sequential tumorigenicity), and (e) undergo in vivo differentiation to produce a disease similar to that in the patient.

The CD133-expressing clones were initially puzzling – they were present in physical association with the CSCs in situ, i.e. in the patient-derived malignant ovarian cancer ascites. Further studies revealed that depending on the local micro-environmental cues, these cells could either remain quiescent, or commit towards endothelial differentiation. In vitro stage-specific immuno-phenotyping during this differentiation using stem and endothelial cell markers correlated with a definitive progression of the CD133 expressing endothelial stem cells to progenitors at varying levels of specification. This provides the first evidence of a tumor-specific endothelial hierarchy that could play a crucial role in ensuring long-term tumor survival and complement CSC-driven tumor development and progression, by establishing its vasculature.

 

 

CSCs and Tumor-derived Aneuploid Cells Determine Dormancy and Heterogeneity  

 

Cancer dormancy reflects an ability of certain residual tumor cells to persist within the patient in a state of reversible quiescence without any clinical evidence of disease. A lack of functional characterization of such dormant tumor cells has limited our understanding of the full complexity of the phenomenon, although CSCs are speculated to be a major player. Most human cancers are characterized by an inherent genomic instability that leads to aneuploidy. Whether aneuploidy drives required for tumorigenesis is subject to debate, but it almost certainly imparts selective / adaptive advantages under certain stress condition. It thus seemed apparent to us that CSCs and aneuploid cells were quite likely to be involved in such processes that ensure tumor survival.

Towards providing the proof for this, we demonstrated that CSCs enter a quiescent state through their isolation as long-term label retaining cells from primary tumors and metastases. Such CSCs also exhibited therapeutic refractoriness. Additionally, the label-retaining fractions also identified aneuploid cell populations as a potential contributor to cancer dormancy.  Thereby, tumor heterogeneity contributes to tumor dormancy and drug resistance.  Understanding the biological variations within tumors is crucial to resolve the response of subsets within the stem cell hierarchies and aneuploid clone(s) could provide definitive targets for tumor progression.  This is currently, an area of interest in the lab. 

 

Epigenetic changes in ovarian cancer

 

Epigenetic changes in cancer involve global hypomethylation with localized promoters CpG island hypermethylation. Using the progression models of ovarian cancer established in our lab, we have been profiling the changes in DNA methylation and post-translational histone modifications and integrating this information with the corresponding gene expression patterns. These approaches reveal the aberrant regulation of certain genes in ovarian cancer. In order to further resolve molecular signatures that delineate ovarian tumor cells from CSCs, our priority lies in applying high-throughput technologies complemented by bioinformatics to handle the complexity of the cancer epigenome and the various networks that coordinate disease initiation and progression.

 

Systems Networks identifies Transformation Associated Molecules and Pathways

 

Multiple, dissimilar genetic defects in cancers of the same origin contribute to heterogeneity in tumor phenotypes and therapeutic responses of patients, yet the associated molecular mechanisms remain elusive. We have recently shown at the systems level, serous ovarian carcinoma is marked by activation of interconnected modules associated with a specific gene signature. Network prediction algorithms combined with pre-established protein interaction networks and known functionalities affirmed importance to genes associated with ovarian cancer as predictive biomarkers, besides 'discovering' novel ones purely on the basis of interconnectivity, whose precise involvement remains to be investigated. Copy number alterations and aberrant epigenetic regulation were identified and validated as significant influences on gene expression. More importantly, the involvement of three functional modules centering on c-Myc activation, altered retinoblastoma signaling and p53/cell cycle/DNA damage repair pathways was identified as transformation-associated events. Further studies will assign significance to, and aid the design of a panel of specific markers predictive of individual- and tumor-specific pathways. In the parlance of this emerging field, such networks of gene-hub interactions may define personalized therapeutic decisions.

 

Protein profiling of ovarian cancer stem cells

 

In our proteomics aproaches, we are trying to identify to identify differentially expressed proteins in ovarian cancer. Purification and molecular fingerprinting of the identified proteins will be essential to identify therapeutic targets at and/or disease-associated biomarkers. A molecular understanding of protein-protein interactions of such key biomarkers may further provide a valuable framework for an enhanced understanding of the functional organization of the proteome. Predicting protein-protein interaction is critical to success in many therapeutic research areas such as antibody modeling, elucidation of signal transduction pathways, and identification / optimization of peptide or protein inhibitors or activators for drug discovery.

Another strategy involves the generation of monoclonal antibodies targeting the surface antigens on cancer cell membrane, and further evaluation of their therapeutic potential. Some novel proteins have been identified and further resolution of their functions and interacting partners will be undertaken through a combination of surface Plasmon resonance (SPR), 2-DE, MS/MS, others and in silico method.

 

Epithelial-mesenchymal Transitions (EMT) in the context of CSCs

 

The exact molecular events leading to ovarian tumor metastases have not yet been elucidated, although it is recognized that the acquisition of capacity for migration and invasiveness would be a necessary prerequisite. These processes involve a change in morphology of the rigid, cuboidal and cobble-stone epithelia to a mesenchymal form through a process referred to as: epithelial-mesenchymal transition (EMT). EMT is initiated through the dissolution of cell-cell junctions viz., adherens, tight and desmosomal junctions between adjacent epithelial cells, followed by cytoskeleton reorganization, degradation of base membranes and stroma and an enhanced growth rate. Our initial work demonstrated the involvement of two transcriptional repressors - Snail and Slug in EMT-mediated invasion and metastases of ovarian cancer cells.

We further extended this understanding to demonstrate the involvement of Snail and Slugh in the development of resistance to radiation and paclitaxel. The process is orchestrated through the acquisition of a novel subset of gene targets that is repressed under conditions of stress, effectively inactivating p53-mediated apoptosis, while another subset of targets continues to mediate EMT. Repressive activities are complemented by a concurrent derepression of specific genes resulting in the acquisition of stem cell-like characteristics. Such cells are bestowed with three critical capabilities, namely EMT, resistance to p53-mediated apoptosis, and a self-renewal program, that together define the functionality and survival of metastatic CSCs. Our findings, besides achieving considerable expansion of the inventory of direct genes targets, more importantly demonstrate that such elegant cooperative modulation of gene regulation mediated by Snail and Slug is critical for a cancer cell to acquire radio- or chemo- resistance, and this may be a determinative aspect of aggressive cancer metastases.  We are currently trying to identify novel protein interactions in these processes that could lead to better understanding of EMT and these repressor molecules in cancer.

 

 

 

Publications

 

Books

 

 

book

Sharmila A. Bapat (Editor)
Hardcover

 

1. Edition - November 2008
276 Pages, Hardcover
- Professional Book -
ISBN-10: 0-470-12201-3
ISBN-13: 978-0-470-12201-3 - John Wiley & Sons

 

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Book Chapters

 

  1. Sagar MM, Kusumbe AP, Vemuganti GK,  Bapat SA. Cancer Stem Cells.  In: Regenerative Medicine, 2011, Gustav Steinhoff (Ed.), Springer Verlag Publishers,

  2. Bapat SA. Stem Cells in Human Epithelial Ovarian Cancer. In: Stem cells: organogenesis and cancer, S.R. Singh & P.K. Mishra(Eds.), Research Signpost/ Transworld Research Network (Publishers), 2010.

  3. Sharmila Bapat, Anne Collins, Michael Dean, Kenneth Nephew, Suraiya Rasheed. Cancer Stem Cells (CSCs): Similarities and Variation of the Theme of Normal Stem Cells In : Cancer Stem Cells: Identification and targets; Pages 1-26; 2008, Bapat SA (Ed), John Wiley & Sons (Publishers)

  4. Sharmila Bapat. Leukemic Stem Cells. In: Cancer Stem Cells: Identification and targets; Pages 1-26; 2008, Bapat SA (Ed), John Wiley & Sons (Publishers).

  5. Anjali Kusumbe, Sharmila Bapat. Ovarian Stem Cell Biology and the emergence of Ovarian Cancer Stem Cells. In: Cancer Stem Cells: Identification and targets; Pages 1-26; 2008, Bapat SA (Ed), John Wiley & Sons (Publishers).

  6. Bapat SA, Mishra GC. Pharmacogenomics Based Emerging Drug Discovery Strategies. In : Advances in Biochemistry and Biotechnology; Volume 1 Pages 245-280; 2005, Chakraborty C (Ed), Daya Publishing House, India.

Research Articles

  1. Sharmila A. Bapat, Victor Jin, Nicholas Berry, Curt Balch, Neeti Sharma, Nawneet Kurrey, Shu Zhang, Fang Fang, Xun Lan, Meng Li, Brian Kennedy, Robert M. Bigsby, Tim H M. Huang and Kenneth P. Nephew, “Multivalent epigenetic marks confer microenvironment-responsive epigenetic plasticity to ovarian cancer cells” Epigenetics 5:8, 1-14; November 16, 2010. PMID: 20676026 [Link]

  2. Neeti Sharma, Avinash M. Mali, Sharmila Bapat “Spectrum of CREBBP mutations in Indian patients with Rubinstein-Taybi syndrome” J.Biosci.35(2), June 2010,187-202 PMID: 20689175 [Link]

  3. Sharmila A. Bapat, Anagha Krishnan, Avinash D. Ghanate, Anjali P. Kusumbe, and Rajkumar S. Kalra “Gene Expression: Protein Interaction System Network Modeling Identifies Transformation-Associated Molecules and Pathways in Ovarian Cancer” Cancer Research, June 8, 2010. PMID: 20530682 [Link]

  4. Bapat SA Human Ovarian Cancer Stem Cells. Reproduction, July 2010;140(1):33-41. PMID: 20368192 [Review][Link]

  5. Sharma Neeti, Jadhav Shweta and Bapat SA "CREBBP Re-Arrangements affect Protein Function and lead to aberrant Neuronal Differentiation" Differentiation. 2010 Apr-Jun; 79(4-5):218-31, PMID: 20207472. [Link]

  6. Bapat SA Modulation of Gene Expression in Ovarian Cancer by Active and Repressive Histone Marks. Epigenomics 2010 Feb 10 ; 2(1):39-51 (Invited Review) [Link]

  7. Kusumbe AP, Bapat SA, Cancer stem cells and aneuploid populations within developing tumors are the major determinants of tumor dormancy. Cancer Research. 2009 Dec 15;69(24):9245-53. Epub .PMID: 19951996 [Link]

  8. Kurrey NK, Jalgaonkar SP, Joglekar AV, Ghanate AD, Chaskar PD, Doiphode RY, Bapat SA. Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells. 2009 Sep;27(9):2059-68.PMID: 19544473 [Link] [Citation]

  9. Kusumbe AP, Mali AM, Bapat SA. CD133-expressing stem cells associated with ovarian metastases establish an endothelial hierarchy and contribute to tumor vasculature. Stem Cells. 2009 Mar;27(3):498-508.PMID: 19253934 [Link][Citation]

  10. Berry NB, Bapat SA, Ovarian cancer plasticity and epigenomics in the acquisition of a stem-like phenotype. J Ovarian Res.2008 Nov 24; 1(1):8. [Epub ahead of print] PMID: 19025622. [Link] [Citation]

  11. Wani AA, Rangrez AY, Kumar H, Bapat SA, Suresh CG, Barnabas S, Patole MS, Shouche YS. Analysis of reactive oxygen species and antioxidant defenses in complex I deficient patients revealed a specific increase in superoxide dismutase activity. Free Radic Res.2008 May;42(5):415-27. PMID: 18551809. [Link] [Citation]

  12. Wani AA, Ahanger SH, Bapat SA, Rangrez AY, Hingankar N, Suresh CG, Barnabas S, Patole MS, Shouche YS. Analysis of mitochondrial DNA sequences in childhood encephalomyopathies reveals new disease-associated variants. PLoS ONE. 2007 Sep 26;2 (9):e942. PMID: 17895983 [Link] [Citation]

  13. Balch C, Nephew KP, Huang TH, Bapat SA. Epigenetic "bivalently marked" process of cancer stem cell-driven tumorigenesis. Bioessays. 2007 Sep;29(9):842-5. PMID: 17688287 [Link] [Citation]

  14. Bapat SA. Evolution of Cancer Stem Cells. Invited review for Seminars in Cancer Biology; 2006 May 20; [Epub ahead of print] PMID: 16787749 [Link] [Citation]

  15. Wani AA, Sharma N, Shouche YS and Bapat SA. Nuclear-mitochondrial genomic profiling reveals a pattern of evolution in epithelial ovarian tumor stem cells. PMID: 16732329 [Link] [Citation]

  16. Bapat SA and Mishra GC. Stem Cell Pharmacogenomics: A Reality Check on Stem Cell Therapy; Curr. Opin. Mol. Ther. 2005; 7(6):551-6. PMID: 16370378 [Link]

  17. Bapat SA and Galande S. Association by guilt: identification of DLX5 as a target for MeCP2 provides a molecular link between genomic imprinting and Rett syndrome. Bioessays 2005; 27(7), 676-680. PMID: 15954098 [Link] [Citation]

  18. Bapat SA, Mali AM, Koppikar CB and Kurrey NK. Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Cancer Research 2005; 65(8): 3025 - 3029. PMID: 15833827 [Link] [Citation]

  19. Kurrey NK, Amit K and Bapat SA. Snail and Slug are major determinants of ovarian cancer invasiveness at the transcription level. Gynecologic Oncology 2005, 97, (1): 155-165. PMID: 15790452. [Link] [Citation]

  20. Bapat SA & Mishra GC. Stem Cell Pharmacogenomics, Current Topics in Medicinal Chemistry 2004; 4(13): 1371-83. PMID: 15379651 [Link] [Citation]

     

 

 

Awards and Achievements

2005               International Travel Award, Department of Biotechnology
2006               Short-term Overseas Fellowship, Department of Biotechnology availed at Indiana University, Bloomington, Indiana, US
2008               National Woman Bioscientist Award
2010               R.M. Tiwari Research Oration Award
2010               Elected Fellow of the National Academy of Sciences, Allahabad

 

Membership of Scientific Societies

  1. Active Member of American Association of Cancer Research (AACR).

  2. Active Member of International Society for Stem Cell Research (ISSCR).

  3. Life Member of Indian Association of Cancer Research (IACR).

  4. Member, Executive Committee of the Indian Association of Cancer Research (2009-2012)

  5. Life Member of Indian Society of Cell Biology (ISCB).

  6. Member- International Epigenetics Society (earlier DNA Methylation Society).

  7. Life Member of Indian Women Scientists Association.

  8. Life Member of International Federation of Head and Neck Oncology 

 

 

 

Lab Members

 

 

 

group

 

 

 

avinash

Avinash  M.  Mali
Lab Technician
E-mail: avinahrajmali@rediffmail.com

 

 

Ph.D. Students
raj

Rajkumar Singh
Ph.D. Student (DBT - SRF)
E-mail: raj@nccs.res.in

anand

Anand Kamal Singh
Ph.D. Student (CSIR - JRF)
E-mail: anandkamalsingh@yahoo.com

brijesh

Brijesh Kumar
Ph.D. Student (CSIR-JRF)
E-mail:brijsbt@gmail.com, brijesh_sbt06@yahoo.co.in

rutika

Rutika Naik
Ph.D. Student (UGC-JRF)
E-mail:rutikanaik@yahoo.co.in

swapnil

Swapnil Kamble
Ph.D. Student (CSIR-JRF)
E-mail: swapn_net@yahoo.co.in

 

 

Project Staff
rohini

Rohini Kshirsagar
Research Associate
E-mail:rohinivet@gmail.com


tejaswini

Tejaswini U. Deshpande
Project-JRF
E-mail: tejaswiniud@gmail.com

nilesh

Nilesh L. Gardi

Project-JRF

E-mail: nilesh.gardi2688@gmail.com

 

 

M. Sc. Project Scholar
sagar

Sagar Varankar

E-mail : sagarvarankar@gmail.com

   

 

 

 

Lab Alumni

 

Visiting Scientist   Ph.D. Students   M.Sc. Project Scholars  

Dr. Nicholas Berry

 

Nawneet K. Kurrey
Neeti Sharma
Anjali P. Kusumbe

 

Ms. Deepali Korade
Supriya Nachegiriwar
Kiran Bagal
R. M. Aruna Devi
Savita Marathe
Rajesh Sarkar
Abhishek
Anshu Chhatrapal
Shyamala Rao
Sunita Narayan
Varsha Naik
Nimisha Singh
Shweta Jadhav
Swati Jalgaonkar
Rahul Doiphode
Alok Joglekar
Anagha Krishnan
Avinash D. Ghanate
Prasad D. Chaskar
Divya R. Iyer
Mihir Metkar

 

 

 

Collaborations

  1. Prof. Kenneth Nephew, Indiana University, Bloomington, USA.

  2. Dr. Matthias Nees, VTT, Turku, Finland.

  3. Dr. Renu Wadhwa, AIST, Japan

  4. Dr. Sunil Kaul, AIST, Japan

 

 

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NCCS Complex,University of Pune Campus,Ganeshkhind,Pune 411007,Maharashtra,India Phone: +91-20-25708000 Fax:+91-20-25692259 Gram:ATCELL