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).

We are currently examining in detail the nature of cohesive cell migration of CD66+ cells in the invasive phase of cervical cancers (Ammothumkandy, A., et al., manuscript in preparation). In addition to our long standing collaboration with the Kidwai Memorial Institute of Oncology, we are working with the Adyar Cancer Centre in Chennai on this project. 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.

In parallel, Sweta Srivastava, Calvin Rodrigues and Leanna Rose Joy are examinging various aspects of radioresistance, epigenetics and CD66+ dependence on migration respectively in human cervical cancers.

SETTING UP A BIOLOGY-MEDICINE INTERPHASE PROGRAM

The broad aim is to enable deep clinical resources for a basic science campus with positive ongoing outcomes for the clinicians

The program is primarily with St. John's Medical College and is currently undergoing extension with other academic medical campuses

Sweta Srivastava (Research Co-ordinator) and Cecil Ross

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
Broad goals:
1.    Can we develop biomedical projects of national importance

2.    Can we develop the careers of young clinical scientists ?

3.    Can we develop novel training techniques

2011 onwards:
1.    Established infrastructure for Confocal microscopy, FISH, high end flow cytometry, molecular biology and tissue culture for both research and “continuous hands on” courses in an inter-departmental setting. Setting up infrastructure which would allow a continuous inter-campus course structure and research program. The intermediate aim  to consolidate this process would be to develop a joint PhD program with medical campuses.

Hematological malignancy research
Deepak Arya and Anita Chacko. In collaboration with R. Sowdhamini
Chronic Myeloid Leukemia has emerged as a major treatable disease using drugs such as Imatinib which are novel tyrosine kinase inhibitors. However, over time there are broadly two forms of resistance that can emerge i) due to mutations in the BCR-ABL gene and ii) abrogation of the drug response due to a possible expansion of a CML stem cell like pool.

We were interested in characterizing the stem cell like pool and also analyzing potential other mutations that might aid the generation of resistance.
The two major projects underway are an analysis of microRNA 182 in the context of imatinib resistance and a longitudinal analysis of mutations using whole exome sequencing. Deepak with the support of Li Shang from Singapore has successfully developed the use of Crisper for mir-182 knockouts.
Srinag is also engaged in a clinical platelet study in various disorders.

DEVELOPMENT OF A NATIONAL HLA REGISTRY BY NGS (DUAL SERVICE AND RESEARCH)

A major project that we have undertaken primarily with the TTK blood bank (Drs. LathaJaganathan and NutanDighe) and CCAMP (MalaliGowda and colleagues) is to lay the foundation for a national HLA registry by Next Gen Sequencing.  This would have a invaluable role in serving to sustain a bone marrow transplant program which is a critical need for leukemia and other therapies. In addition, this would serve to lay the stage for research in infectious disease progression, next generation vaccines etc. The NGS approach can also be used for population evolution studies and multiplexing is a useful tool to study any gene variants at a large level.

Currently, we have sequenced 80 donors with a very high quality by NGS and are aiming to lay the foundation for a one million donor registry in a multi-centric manner. We have recently also by Pacbio sequencing generate large read lengths successfully of the HLA region.

DEVELOPMENT OF A NGS BASED PATHOGEN DISCOVERY GROUP

Chitra Pattabiraman working with St. John’s and NIMHANS and the help of Malali Gowda from CCAMP has set up a viable pathogen characterization program using NGS. She can use this to develop an independent NGS based discovery program.

AWARD OF INDIA ALLIANCE CLINICAL RESEARCH FELLOWS

Maria Bukelo and and Sanjay Chilbule have been 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. They will strengthen their existing research programs on Hirschprung’s disease and bone cancer stem cells respectively. We are also helping Archana Puroshottam of InStem set up a novel “clinical dialogues” course.