Spatial Heterogeneity in Cancer

TUMOR HETEROGENEITY:

Cancer evolves under a strong evolutionary and selection pressure resulting from differential availability of oxygen, nutrients, and immunological factors. This unequal distribution of factors results in ‘Tumor Heterogeneity’ which is a major hurdle against effective therapeutic response. Generation of intratumoral heterogeneity is promoted by both cell-intrinsic and cell-extrinsic factors. Major extrinsic signals are determined by proximity to blood vessels (BVs) due to differential availability of oxygen, nutrients, and blood-borne trophic factors, as well as by exposure to vascular cues such as angiocrine factors. The relative influence of these factors changes over space and time, resulting in a very heterogeneous tumor with a different response to therapy within the same tumor.

Spatial Zonation in Cancer will be explored...

Perivascular vs Hypoxic Niches:

We have developed a unique methodology to identify tumor cells solely based on their proximity to BVs (See figure on the right). Using this approach, we would like to explore the cellular rewiring that occurs in different tumor microenvironments both spatially and temporally with the goal of identifying novel vulnerabilities that could be potential targets for cancer therapy. Our goal is to investigate the epigenetic, transcriptional, and metabolic rewiring in tumors resulting from differential vascular inputs.

PFDLC Technique - Perfusion based Fluorescent Dye Labeling of Cells - Tool developed to study perfusion in glioblastoma (GFP - Green) tumor, Red - Blood vessels, Blue - Perfusion Dye labeling perivascular cells)

Reference : Kumar S et al, Cell Metabolism (2019); Kumar S et al, Bio-protocol (2020)

CSCs in perivascular niche (CSC - white, Blood vessels - Red)

We have also developed a new strategy to isolate quiescent tumor-initiating cells (also referred to as Cancer Stem Cells - CSCs) from xenografted tumors (See figure above). Using this approach, we would like to isolate, characterize the CSCs in different cancers, study what are the cell surface markers, ligands, and other markers that are unique to them, and if we could target them as a potential avenue for improving therapeutics.

Reference: Kumar S et al, Angiogenesis (2022)

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