Spatiotemporal regulation of clonogenicity in colorectal cancer xenografts

Abstract

Cancer evolution is predominantly studied by focusing on differences in the genetic characteristics of malignant cells within tumors. However, the spatiotemporal dynamics of clonal outgrowth that underlie evolutionary trajectories remain largely unresolved. Here, we sought to unravel the clonal dynamics of colorectal cancer (CRC) expansion in space and time by using a color-based clonal tracing method. This method involves lentiviral red-green-blue (RGB) marking of cell populations, which enabled us to track individual cells and their clonal outgrowth during tumor initiation and growth in a xenograft model. We found that clonal expansion largely depends on the location of a clone, as small clones reside in the center and large clones mostly drive tumor growth at the border. These dynamics are recapitulated in a computational model, which confirms that the clone position within a tumor rather than cell-intrinsic features, is crucial for clonal outgrowth. We also found that no significant clonal loss occurs during tumor growth and clonal dispersal is limited in most models. Our results imply that, in addition to molecular features of clones such as (epi-)genetic differences between cells, clone location and the geometry of tumor growth are crucial for clonal expansion. Our findings suggest that either microenvironmental signals on the tumor border or differences in physical properties within the tumor, are major contributors to explain heterogeneous clonal expansion. Thus, this study provides further insights into the dynamics of solid tumor growth and progression, as well as the origins of tumor cell heterogeneity in a relevant model system.

Spatially constrained tumour growth affects the patterns of clonal selection and neutral drift in cancer genomic data

“…Other cells may remain ‘imprisoned’ in the centre of the tumour unable to proliferate because of the lack of empty space around them. Boundary-driven growth has been observed experimentally [27–29] as well as in model systems [30]. The magnitude of this effect is controlled in our simulation with the parameter a , which considers cell location and defines the probability that a cell will push neighbouring cells to create empty spots depending on how far is the cell from the boundary (see Materials and Methods).…”

Stem Cell Plasticity and Dormancy in the Development of Cancer Therapy Resistance

“…For example, microvesicles produced by breast cancer-associated fibroblasts transfer miR-221 to cancer cells thus increasing the drug resistant CD133 hi stem cell population (26). In addition to soluble factors, other microenvironmental features such as clone location have been recently shown to determine the self-renewal capacity of colorectal cancer cells (27). In light of these evidences, stemness in cancer can be defined as a transient state of enhanced plasticity and robustness crucially influenced by microenvironmental signals, including interactions with niche elements, tumor, and non-tumoral cells, soluble factors, and anticancer therapies.…”

Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

“…However, a large body of data has shown that most tumors grow in their interaction with a highly heterogeneous microenvironment with different densities of blood and lymph vessels, amount and types of infiltrating cells, extracellular matrix composition, and content of signaling molecules, among others [15] Moreover, many tumors are not monoclonal despite originating from a single cell; instead, they are composed of multiple distinct clones that can be differentiated by morphological and phenotypic features, and can vary depending on cancer type, cancer stage, and treatment regimes, among other factors [16][17][18]. This phenomenon denoted as tumor heterogeneity implies that a heterogeneous population of various cell types with distinct gene expression and metabolic profiles, as well as proliferative, angiogenic, and metastatic potential, co-exist within a definite tumor.…”