Cutting The Trunk Is Not Enough!
If cancer is the tree trunk, then metastasis was postulated to be its branches, thereby the idea of treating metastasis by cutting the trunk of the tree, i.e. successful surgery, was born (1). However, even after that, the tumors would return in different places, sometimes in months and sometimes in years. Medical oncologists had no clue as to the why and when.
Size Does Not Matter !
Also, it was thought that only when a tumor was significantly large did it become metastatic, which was due to the overwhelming size and additional genetic changes. However, recent data have shown that even when the tumor is very small in size (< 103 cells), some cells would disseminate into the blood and there were not much genetic differences between these primary and secondary tumor cells (2,3). Given that PET scan could detect only around 109 cells and liquid biopsy sensitivity was no less than 105 cells, for most patients, the inevitable have had happened even before the tumor was diagnosed. This early dissemination also explains why all targeted therapeutics around metastasis, starting from matrix metallo-proteases to integrin inhibitors had failed in the clinic. It was too late!!
“To-EMT or Not To EMT”
The biggest challenge, or controversy, that have marred the metastasis field was “to EMT or not to EMT” (4). Many scientists believed that epithelial to mesenchymal transition (EMT) was key to metastasis, whereas others pointed out that mesenchymal cells were not enough to induce metastasis. Recently, some pioneering work has suggested that EM plasticity is the key and not only the ability to change to mesenchymal cells was important, but the ability to change back to epithelial form was equally important (5).
Key unanswered questions
The question is how much of epithelial to mesenchymal transition is required? How much of the reverse mesenchymal to epithelial form is necessary and sufficient? What properties of metastasis are complimented by the epithelial forms and what would require the mesenchymal forms? How much of the complex metastasis biology is cancer agnostic? Is there any pattern across different carcinomas? Can we help the medical oncologist in understanding which of the patients have a higher probability of metastasis in the future, based on the functional properties of their primary tumors? Can we exploit the unique properties of mesenchymal cells for robust anti-metastasis drug discovery?
Mestastop is creating epithelial mesenchymal hybrids of different cancers and monitoring them in multiple cell based functional assays. Each of these assays compliment a single metastatic step, and the cumulative summation of them represents the holistic biology of metastasis. The idea is to evaluate the significance of each steps vis-à-vis understanding the critical M:E ratio required for its successful completion. This will enable us to create an algorithm-based platform that will not only help us to identify the key cell types required for successful metastasis but also assign weightage to each step, thereby underlining the most significant ones, that can be later targeted for drug discovery. We intend to validate this platform, with respect to real patient sample, in a retrospective analysis that will help us design a prospective study for prediction of metastasis based on functional characteristics of a patients primary tumor.
1. Nature, 2016, 532, 166
2. Nature Genetics, 2019, 51, 1113
3. Nature, 2016, 540, 588
4. Nature Reviews Cancer, 2016, 16, 199
5. Nature, 2018, 556, 463
- Arnab Roy Chowdhury, Debabani Roy Chowdhury, Manoj Pandre, Samrat Roy, Sundarajan Kannan, John W. Ellingboe. Abstract 2868: A cell based phenotypic assay platform for cancer metastasis drug discovery and diagnostics, Mestastop Solutions Pvt. Ltd, Bangalore, India. https://cancerres.aacrjournals.org/content/81/13_Supplement/2868
- Samrat Roy, Debabani Roy Chowdhury, Manoj Pandre, Sundarajan Kannan, Rajesh Kumar RK, Amit K. Sharma, John W. Ellingboe, Arnab Roy Chowdhury. Abstract 2841: Dissecting tumorigenesis and metastatic properties of cell lines by phenotypic functional assays and plasticity ratio (PR), Mestastop Solutions Private Limited, Bangalore, India. https://cancerres.aacrjournals.org/content/81/13_Supplement/2841