. Kshitiz

Our lab's objective is to understand a cell's interaction with its neighbors and the microenvironment. With a particular focus on tumor microenvironment, we aim to unravel the language cells employ to converse with each other, how the grammar and the content of the language adapt to the environment, and how cells behave in response. We use a gamut of of techniques, including live microscopy, bioinformatics, tissue engineering, nanofabrication, cell patterning, evolutionary biology, and genetics to answer fundamental questions in biology and medicine. Our current physiological focus involves understanding how new phenotypes emerge within cancer populations by their neighborly interactions; the evolutionary basis of metastatic tolerance; as well as cardiac maturation for disease modeling. Cancer-Stroma Interaction When we think of cancer, we mostly think of cells constituting the neoplastic part of cancer. But a cancerous lesion consists of many other cell types, which could resist, or help in its progression. These “stromal cells” consist of activated fibroblasts, macrophages, endothelial cells, as well as the specialized environment modulated by these cells. In our lab, we attempt to systematically understand how cancer and stromal cells interact with each other using a variety of approaches, including microfluidics, nanotechnology, live cell imaging, and genetic screens. We aim to elucidate the mechanisms through which stroma facilitates cancer to grow, become invasive, and resistant to chemotherapeutic drugs. Hypoxia and Metabolism Tumors are frequently hypoxic, and glycolytic. Their metabolic pathways are rerouted to help tumor cells continue to divide rapidly under lack of oxygen, and unavailability of certain nutrients. We study how lactate, a byproduct of anaerobic glycolysis, and accompanied acidosis in the microenvironment influences cancer phenotypes. We have found that lactate can increase ROS production in the cells, and increase autophagy. Using in vitro and in silico models of cancer combined with live cell microscop, we aim to explore the role of lactate in regulating cancer growth and metastasis. Systems Cell Biology Mammals exhibit different rates of metastasis, which interestingly correlates with the subtype of placentation during pregnancy. Based on these, and many other evidence, we are advancing a new paradigm of cancer metastasis called: Evolved Levels of Invasability (ELI) suggesting that stromal resistance (or assistance) to cancer invasion is evolutionarily derived. This paradigm presents a roadmap to observe the stromal compartment in cancer as a crucial player in regulating cancer phenotypes, as well as providing new avenues to understand and target cancer dissemination and metastasis. Mechanobiology and Cardiac Maturation Cells, like all of us, live in a matrix. And the nature of the matrix could determine important functions of the cells, including their shape, migration speeds, fate, proliferative state, as well as metabolism. We focus on understanding how matrix rigidity and topography regulates cell signaling, and metabolism, as well as utilize mechanobiology for cardiac maturation. In our lab, we use a variety of tools to both elucidate the signaling machinery involved in mechanotransduction, as well as utilize the gained knowledge for specific therapeutic purposes by bioengineering. A dedicated effort in our lab focuses on creating mature, adult-like cardiac tissues from human pluripotent cell sources as a surrogate for drug screening.

Hif-1 responsive IFFLs to explain specific transcriptional responses to cycling hypoxia in cancers. Evidence for coopetition at the maternal-fetal interface shaping placental invasion. Identifying genes underlying parallel evolution of stromal resistance to placental and cancer invasion. Extravillous trophoblasts reverse the decidualization induced increase in matrix production by secreting TGFβ antagonists Emilin-1 and Gremlin-1. Scar matrix drives Piezo1 mediated stromal inflammation leading to placenta accreta spectrum. Oscillatory hypoxia induced gene expression predicts low survival in human breast cancer patients. Lightsheet microscopy integrates single-cell optical visco-elastography and fluorescence cytometry of 3D live tissues. Lactate in breast cancer cells is associated with eva