UNDERSTANDING HUMAN CERVICAL CANCER PROGRESSION AND BUILDING A BIOLOGY-MEDICINE INTERPHASE

Our group has two interests, i) understanding the nature of human cervical cancer progression with a particular focus on sub-sets of CD66+ cells ii) and enabling inter-campus bio-medical efforts spanning diverse areas such as hematology, HLA platforms, Dengue vaccines etc.

Human cervical cancers constitute a major burden of female malignancies in our country and are caused by papillomaviruses of the highly oncogenic type. Our cumulative data over decades has led us to suggest that ligand dependent Notch pathway activation acts as a “second signal” in human cervical cancer progression (reviewed in Maliekal T. et. al., Oncogene 2008). Subsequently, we have identified a sub-set of CD66+ cells with distinctive promoting properties and is dependent on Notch signaling (Bajaj J. et al., Cancer Research 2011 and Pattabiraman C. et al., Cancer Research 2014). Currently, following the work of Aswathy Ammothumkandy and collaborators from Kidwai Memorial Hospital showing that CD66+ cells are associated with metastasis progression and have distinct roles in migration, Calvin Rodrigues and Leanna Rose Joy are exploring the role of epigenetic regulators in cervical cancer progression and analyzing antibodies that target CD66+ proteins.

Since 2008, we have been working intensively with the St. John’s medical college campus and built extensive research laboratories, explored joint teaching programs with medical colleagues, developed gene editing and NGS platforms that will enable better HLA typing (Gowda, M. et al., 2016) and supported Chitra Pattabiraman and colleagues in developing a viral genomics program.

Exploring the pathobiology of CD66+ cells in human cervical cancers and setting up a biology-medicine interphase program

Exploring the pathobiology of CD66+ cells in human cervical cancers:

Cervical cancers, a major cause of cancer associated female mortality in the developing world, is caused by high risk human papillomaviruses. Papillomavirus belong to the family of small DNA tumor viruses and the study of these agents have been extraordinarily influential in driving key concepts in cancer biology. Our laboratory for over two decades has been interested in the signals that complement the function of papillomavirus oncogenes (for review see Malliekal T. et al., Oncogene 2008) and our focus has been on the role of Notch signaling.

Our work on Notch signaling led us to identify a distinctive tumorigenic sub-set of cells that are CD66+ and are dependent on this pathway in human cervical cancers (Bajaj J. et al., Cancer Research, 2011). Following our initial characterization of these cells in cancers, we have extended this observation to define a role for CD66+ cells in cervical pre-cancers in collaboration with Laimonis Laimin’s laboratory. A particularly intriguing observation has been the relationship of CD66+ cells and the papillomavirus life cycle (Pattabiraman C. et al., Cancer Research, 2014).

An important challenge was to examine the role of CD66+ cells in the process of metastasis by looking at outcomes in  a reasonable sized retrospective study in collaboration with the Adyar Cancer Centre. We found an association of CD66+ and CD49f cells with metastasis and local recurrence respectively. In parallel, there are very distinctive associations of CD66 and CD49f cells in the various layers of cohesive cell migration (Ammothumkandy, A., et al., European Journal of Cancer, 2016). In the absence of effective implementation of cervical cancer prevention in India for some time to come, CD66+ cells will be a potential major target for novel therapeutic and diagnostic approaches. With the emerge of migration of human cervical cancer cells  as a major theme in the group, Calvin Rodrigues and Leanna Rose Joy are examinging various aspects of epigenetic regulation (Rodrigues C. et al., In preparation) and the  dependence on the CD66+ protein on migration respectively in human cervical cancers.

SETTING UP A OFF CAMPUS BIOLOGY-MEDICINE INTERPHASE PROGRAM

2005 Meeting on translational research organized by S. Krishna and I. Verma (Salk Institute) initiated and supported by the Department of Biotechnology,

2005-2008 The planning process

2008-2011 Several joint courses with clinicians and scientists with a focus on hematological malignancies with St. John’s Medical College

2011-16 Parallel lab infrastructure at St. John’s medical college: supported by NCBS and DBT through the Glue grant program

Molecular biology labs, confocal, flow cytometry and tissue culture

2011-16: Research focus; hematology centric and platform oriented, in particular gene editing and HLA platforms towards enabling national registries:

Key publications:

Gowda, M.,  Ambardar, S.,  Dighe, N., Manjunath, A.,  Shankaralingu, C.,  Hallappa, P.,   Harting, J.,  Ranade, S., Jagannathan, L. &  Krishna, S (2016). Comparative analyses of low, medium and high-resolution HLA typing technologies for human populations. Journal of Clinical and Cellular Immunology, 7, 399-406.

Arya, D.,  Sasikala, P. S., Ross, C., , Dasaradhi, P., Shang, L. &  Krishna, S (2017).

MiR-182  regulates percentage of myeloid and erythroid cells in chronic myeloid leukemia. Cell death and disease: 8, e2547; doi:10.1038/cddis.2016.471

Sasikala, P. S.,  Arya, D., Shuling, Z., Deepak, P. B., Dasaradhip, P.,  Mock, B. and Krishna, S. (2017). HES-1, a bHLH transcription factor regulates cell proliferation and promotes apoptosis in Multiple Myeloma cells. In preparation.

2016 onwards: Two faculty appointments  (Sweta Srivastava and Neha Vyas) St. John’s campus  from the NCBS campus

2015 onwards: Chitra Pattabiraman with St. John’s Medical College initiates a Dengue

Sequencing program: so far over 100 genomes sequenced

2017:  Under discussion: Philanthropic commitments towards a Dengue vaccine trial site:

Suggestion is two sites, one in India and the other in Africa with Program anchor: NCBS campus

AWARD OF INDIA ALLIANCE CLINICAL RESEARCH FELLOWS
Maria Bukelo and and Sanjay Chilbule were awarded Wellcome trust-DBT clinical alliance research fellowships to work with our group. Maria and Sanjay are a trained pathologist and paediatric orthopaedic surgeon from St. John’s Medical College and CMC, Vellore respectively. This process strengthens their existing research programs on Hirschprung’s disease and bone cancer stem cells respectively. We  also helped Archana Puroshottam of InStem set up a novel “clinical dialogues” course.

Overall, we have gathered deep insights on how biomedical education can be reconfigured to make it inter-disciplinary and innovative, integrating aspects of various streams of Indian medicine, basic science, bio-design, humanities, health economics, public health etc. We have floated a preliminary “ideas proposal” on developing such a novel biomedical campus.