Mechanobiology: Mechanical force-induced selective cancer cell killing

Dr. Ajay Tijore’s interview with Bio Patrika hosting “Vigyaan Patrika”, a series of author interviews. Dr. Tijore completed his doctoral studies in stem cell bioengineering field from Nanyang Technological University, Singapore. He is currently working as a Post-Doctoral Research Fellow in the lab of Prof. Michael Sheetz at Mechanobiology Institute, National University of Singapore. His research focus lies in cancer mechanobiology area. Currently, he is investigating the effect of physiologically relevant mechanical forces on cancer cell growth using microfluidic and ultrasound devices. Interestingly, he found that mechanical stretching promotes cancer cell killing without damaging normal cells. To enable clinical mechanical therapy, Dr. Tijore, Prof. Sheetz and colleagues have developed a non-invasive ultrasound-based technology, in which ultrasound generated mechanical forces induce cancer cell killing. Based on the encouraging results, they have recently established the company Mechanobiologics, Inc to systematically develop the ultrasound technology for cancer treatment. Here, Dr. Tijore talks about his findings that has been recently published as a research article entitled “Selective killing of transformed cells by mechanical stretch” in the journal ‘Biomaterials’ in 2021.

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How would you explain your paper’s key results to the non-scientific community?

For decades, biologists have focused on understanding the effect of genes and growth factors on cell and tissue growth. However, the mechanical forces have largely remained ignored. In the last two decades, the field has particularly learnt that the mechanical forces play a crucial role in regulating physiological and pathological conditions- right from embryo development to cancer development. Moreover, recent studies observed a stark difference between the mechanical properties of cancer cells and normal cells due to cancer cell’s altered mechanosensing function. Mechanosensing is the process by which cells sense the mechanical signals from their surroundings. Along the same line, we found that altered mechanosensing causes different cancer cells to be killed by the application of physiologically relevant mechanical forces. Interestingly, a similar magnitude of mechanical forces promoted normal cell growth. In support of our findings, we noticed that the National Cancer Institute (NIH USA) lists seven types of cancer that are suppressed by exercise and another eight cancer types where data is indicative.

Figure 1: The schematic illustrating the selective killing (apoptosis) of tumor cells by mechanical forces. Interestingly, similar mechanical forces promote normal cell survival and growth.

What are the possible consequences of these findings for your research area?

As our findings highlighted that the mechanical forces selectively kill cancer cells without damaging normal cells, we sensed a great possibility of developing a mechanical force-based therapy to selectively kill metastatic cancer cells present in a patient’s body. It has been shown that the ultrasound can provide a non-invasive way to kill cancer cells located inside the body as ultrasound can easily penetrate tissues. In the past, different modes of ultrasound have been used for cancer treatment e.g. high-intensity focused ultrasound (HIFU) and sonodynamic therapy. However, these treatments often caused healthy tissue damage surrounding cancer due to thermal heating associated with ultrasound. Thus, these methods found limited clinical use.

To enable clinical mechanical therapy, we have developed a non-invasive ultrasound-based technology in which ultrasound generated-mechanical forces (and not the thermal heating) induce cancer cell killing. Not only does ultrasound treatment promote cancer cell apoptosis in cell-based assays, but also it kills tumors grown in chick embryo- and mouse-model as well as patient-derived tumor organoids without damaging normal cells/tissues. Mechanistically, the ultrasound mediated-cancer cell killing pathway mimics the mechanical stretch-mediated cancer cell killing pathway. Based on the encouraging results, we have recently established the company Mechanobiologics, Inc to systematically develop the ultrasound technology for cancer treatment. Please refer to our bioRxiv preprint on the ultrasound technology (preprint link).

What was the exciting moment (eureka moment) during your research?

In the early days of the project, we had no idea that mechanical stretching can kill cancer cells. The initial experiments involving prolonged cell stretching suggested that breast cancer cells showed high levels of apoptosis. We further validated our findings using different cancer cell types and our findings remained true. The moment of observing apoptotic cells in stretched cancer cell samples was a eureka moment for me.

What do you hope to do next?

After spending nearly four exciting years in the cancer mechanobiology area, I plan to establish my lab in India in the near future. My immediate goal will be to study the basic and clinical aspects of cancer mechanobiology to effectively develop the mechanical force-based technology (including ultrasound) for the treatment of most prevalent cancer types in the Indian population. Currently, I have been interviewing for faculty positions in India.

Where do you seek scientific inspiration?

Since my school days, I have always been fascinated by science and the scientific discoveries and engineering marvels that revolutionized human civilization. My inclination towards Biology and Chemistry pushed me to do my doctoral studies in the field of stem cell engineering. The support and training I got from my PhD supervisor, Prof. Tan Lay Poh helped me in many ways to develop the critical thinking of a researcher. My postdoctoral supervisor and mentor Prof. Michael Sheetz has been a role model for me even before joining his group. He has contributed immensely to establish the ‘Mechanobiology’ field. It is like a ‘scientific feast’ to discuss the research problem with him that we are interested to address.

How do you intend to help Indian science improve?

I always believe in giving back to society. I think I can serve Indian science and society well though my research expertise. In India, the Mechanobiology field is still in its early phase. Also, there is a need for collective efforts to explore the translational approach of the mechanobiological findings. Hence I would like to build a platform for all Mechanobiologist working in India to foster collaboration, develop greater awareness in students about the field and communicate the findings to a wider research audience.

Reference

  1. Tijore A, Yao M, Wang Y-H, Hariharan A, Nematbakhsh Y, Doss BL, Lim CT, Sheetz Michael*, Selective killing of transformed cells by mechanical stretch, Biomaterials, 2021, 275, 120866.
  2. Tijore A, Margadant F, Yao M, Hariharan A, Chew CAZ, Powell S, Bonney GK, Michael Sheetz*, Ultrasound-mediated mechanical forces activate selective tumor cell apoptosis, Biomaterials, in revision. Available on bioRxiv.
  3. Singh A, Tijore A*, Margadant F, Simpson C, Chitkara D, Low BC, Michael Sheetz*, Enhanced tumor cell killing by ultrasound with microtubule depolymerization, Bioengineering and Translational Medicine, 2021.

Edited by: Pragya Gupta

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