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Understanding mechanobiology of cancer cells can provide new solution 

Prof. Shamik Sen joined IIT Bombay in July 2010 in the Department of Biosciences and Bioengineering. Prof. Sen earned a B.E. in Mechanical Engineering from Jadavpur University, Kolkata, and a M. Tech in Mechanical Engineering from IIT Kanpur. He then completed his Ph.D. in Mechanical Engineering from University of Pennsylvania, where he worked in the area of mechanobiology. He is currently working in the area of mechanobiology where he is integrating mechanics and biology for probing stem cell biology and cancer cell biology. He is a Swarnajayanti fellowship recipient in the year 2016-17.

1.  Please tell us about your early days as a student and what motivated you to become a scientist and a professor?

I come from a family of academicians. My paternal grandfather was a teacher and a researcher. My father was a Professor of Applied Mathematics at the Calcutta University and my mother taught Education at Jaipuria College at the post-graduation level. My home environment thus exposed me to the responsibilities of a teacher/researcher as well as the intellectual freedom  associated with this job, and naturally nudged me towards a career in academia.

2.  Having done B. Tech., M. Tech., and a Ph.D. in Mechanical Engineering, how did you realize your interest lies in biosciences and bioengineering? 

Though I chose Statistics as my elective after Class 10, I did not dislike Biology. After my Masters at IIT Kanpur, I was offered a PhD position in the Mechanical Engineering department at the University of Pennsylvania in the area of cell biophysics. As I had already made up my mind to do a PhD, I accepted the position. Though the transition from a core Mechanical Engineering to Biology was tough, I started appreciating the field after overcoming the initial difficulty associated with learning the jargon. My research focuses on integrating concepts from mechanics with various cell biological processes.

3.  From your time at the University of Pennsylvania, and U.C. Berkeley what key differences do you find in the research environment and work ethic in Indian and American institutions. What is the one thing we can learn from each other?

The intrinsic motivation level of students in these institutes is very high. Undivided motivation/attention in their work combined with an enabling research environment (i.e., access to top notch facilities which are professionally managed) and exposure to international conferences together collectively maximizes their academic/research training and prepares them for the future. Building a robust research infrastructure with competent support staff here at IIT Bombay is critical for enabling our students to do cutting edge research.

4.  Can you describe your research work in Cell biology in a layman's language, which establishes that in addition to chemical cues, cell behavior is equally susceptible to physical cues of the environment, including the geometry, topography, and physical properties of the extracellular matrix (ECM)?

A cell inside our body is not a passive entity. Rather, it is an active entity that changes shape, divides, migrates and/or differentiates. It is increasingly understood that all these processes are dependent on the dynamic interaction of the cell with its microenvironment based on forces exerted by cells. While the microenvironment, or the ECM comprises of proteins secreted by cells themselves, the state of the cell is in turn dictated by the physicochemical properties of the ECM and its organization. In our lab, we study this dynamic crosstalk either by culturing cells on scaffolds mimicking physicochemical properties of specific organs/tissues, probing the biophysical properties of cells on these scaffolds and/or mapping cell-driven alterations in the ECM.

5.  Your most recent work was on the importance of phenotypic heterogeneity in enhancing cancer invasiveness. Could you tell us about it a little more?

Tumor heterogeneity, i.e., the presence of multiple different cell types, which are not only genetically distinct, but also phenotypically distinct, represents an attribute of cancer making it difficult to treat. In this work, we focused on how phenotypic heterogeneity can be a driver of cancer invasiveness. By focusing on size and deformability as two key attributes of phenotypic heterogeneity, we showed that phenotypic heterogeneity enhances cancer invasiveness by enabling spatio-temporal rearrangements of cells within the invading cluster. We also showed that this rearrangement leads to enrichment of cancer stem cells (CSCs) at the invasion front. CSCs are a sub-population of cancer cells implicated in cancer metastasis and drug resistance. Our study thus suggests that biophysical properties of CSCs enable their enrichment at the invasion front.

6.  Your lab uses a combination of cell and molecular biology tools with single-cell biophysics experiments and computational approaches. Please brief us about the work you and your team are doing in the field of cancer biology, stem cell biology, and tissue engineering, your three areas of emphasis, in these labs.

My lab is interested in probing the importance of cell-substrate interactions in the context of cancer cell biology, stem cell biology and tissue engineering. Here, our substrate corresponds to the extracellular matrix (ECM) in vivo, on which cells attach and perform their physiological functions.

In the area of cancer biology, we are studying how increased ECM stiffening drives cancer progression and tumor heterogeneity. By fabricating hydrogels recapitulating ECM stiffness of normal, pre-metastatic and metastatic cancers, we have shown that increase in ECM stiffness drives increased ECM degradation via a group of matrix degrading enzymes called matrix metalloproteinases (MMPs). We further showed that inhibition of MMP proteolytic activity induces a switch in the mode of invasion of cancer cells. We are now working towards parsing the proteolytic and non-proteolytic functions of MMPs. 

In the area of stem cell biology, we work with embryonic stem cells (ESCs) to understand the importance of cell-matrix interactions in regulation of ESC fate. Towards this, we have developed cell derived matrices which can either maintain ESC pluripotency or drive their differentiation, which maintaining genomic integrity. This holds tremendous importance for cell therapy applications where genomically stable cells need to be generated prior to their transplantation in our bodies.

In the area of tissue engineering, we are specifically focused on developing solutions for wound healing applications in healthy and diabetic subjects. Beyond a critical size, wounds do not self-heal. As an alternative to sutures which cause scarring, we are trying to develop tissue adhesives which can drive scarless wound healing. Recently, we have identified an enzyme which enhances motility of primary diabetic fibroblasts in vitro. We are currently trying to incorporate this enzyme in a hydrogel and develop it as a product and test the efficacy of our product in an animal model.

7.  Please share a turning point or defining moment in your research career.

I consider joining my PhD lab as the defining moment of my research career. It is in the lab of my PhD supervisor, Prof. Dennis Discher—a world-renowned scientist, that I got exposed to the interdisciplinary field of mechanobiology. The depth and breadth of his knowledge, his keenness in integrating insights from disparate fields and his work ethic left an indelible impression on my mind. During my tenure in his lab, our lab published a paper on the role of ECM stiffness in regulating mesenchymal stem cell differentiation. This paper has emerged as a groundbreaking work in the field of mechanobiology garnering more than 10000 citations till date.

8.  Do you have any dream project that you would really like to explore?

Cancer metastasis, i.e., the spread of cancer cells from their tissue of origin to distant tissues, is responsible for the high mortality in cancer patients. One very interesting aspect of cancer metastasis is the phenomenon of organ tropism, i.e., specific cancers metastasize to specific secondary organs. However, the mechanisms mediating organ-specific metastasis remains incompletely understood. Our recent in vitro findings suggest that mesenchymal stem cells (MSCs) which reside in the bone marrow may play an important role in mediating metastasis of breast cancer cells, to bones. We are very interested in pursuing these initial findings further so that we can contribute to this area of research. However, for doing this work, we need to perform animal experiments.

9.  What is your best experience as a professor? What type of student-guide relationship you share with your students?

I cannot recall any specific “best experience”. However, exchanging ideas with students, seeing them grow in confidence and ability, provides me with immense happiness. Being able to mold the thought process of the young generation is a gift in itself.

I believe in cultivating a candid relationship with my students. While I want my students to excel in their research work, I urge them to strike a work-life balance, do things outside of lab work so that they can be content and well rested, but raring to go when they enter the lab.

10.  What do you have to say to a young student who aspires to pursue research? How to find out the thing that interests you, and choose projects? And what’s one piece of advice you’d like them to stick by?

For pursuing research, a student should be open to learn new things, be patient and not expect instant gratification. Every field requires an energy barrier to be crossed before finding the concepts/ideas interesting. Based on broad interest, one can choose one or two areas to work in; after exercising this decision, one needs to learn the basics to be able to appreciate the chosen field and then gradually develop the maturity to define a research question to pursue.