Yasir Suhail

Among eutherian (placental) mammals, placental embedding into the maternal endometrium exhibits great differences, from being deeply invasive (e.g., humans) to noninvasive (e.g., cattle). The degree of invasion of placental trophoblasts is positively correlated with the rate of cancer malignancy. Previously, we have shown that fibroblasts from different species offer different levels of resistance to the invading trophoblasts as well as to cancer cell invasion. Here we present a comparative genomic investigation revealing cis-regulatory elements underlying these interspecies differences in invasibility. We identify transcription factors that regulate proinvasibility and antiinvasibility genes in stromal cells. Using an in vitro invasibility assay combined with CRISPR-Cas9 gene knockout, we found that the transcription factors GATA2 and TFDP1 strongly influence the invasibility of endometrial and skin fibroblasts. This work identifies genomic mechanisms explaining species differences in stromal invasibility, paving the way to therapies targeting stromal characteristics to regulate placental invasion, wound healing, and cancer dissemination.

Cancer metastasis is no longer viewed as a linear cascade of events but rather as a series of concurrent, partially overlapping processes, as successfully metastasizing cells assume new phenotypes while jettisoning older behaviors. The lack of a systemic understanding of this complex phenomenon has limited progress in developing treatments for metastatic disease. Because metastasis has traditionally been investigated in distinct physiological compartments, the integration of these complex and interlinked aspects remains a challenge for both systems-level experimental and computational modeling of metastasis. Here, we present some of the current perspectives on the complexity of cancer metastasis, the multiscale nature of its progression, and a systems-level view of the processes underlying the invasive spread of cancer cells. We also highlight the gaps in our current understanding of cancer metastasis as well as insights emerging from interdisciplinary systems biology approaches to understand this complex phenomenon. Cancer metastasis is a complex disease, arising from a growing tumor from which cells escape to other parts of the body. For long, cancer metastasis was considered as a combination of steps, which were studied separately, limiting our understanding of this complex disease. Here, we present the new developments and our perspective on how the new systems biology approach is changing our view of cancer metastasis as an integrated multiscale phenomenon comprising interlinked parts that allow tumors to metastasize.