Cells within a cancer are highly heterogeneous with respect to their phenotype and can manifest distinct morphological, molecular and functional features. The main aspects that drive functional diversity are 1) genetic heterogeneity as a result of genetic instability, as well as 2) phenotypic heterogeneity as a result of cellular differentiation status. As a consequence, it is challenging to design treatment therapies that target all cancer cells as effectively.

The Snippert group has a long-lasting interest in heterogeneity of cellular behavior during homeostasis, cancer growth and therapy resistance (Snippert et al., Cell 2010; Schepers et al., Science 2012; Snippert et al., EMBO rep 2014; Vermeulen & Snippert, Nat Rev Cancer 2014).

Currently, the Snippert group main interest is to use patient-derived cancer organoids and advanced imaging to study cellular phenomena that have a large impact on human cancer treatment. Among others, we use cutting-edge imaging technology to monitor and quantify chromosomal instability in relation to karyotype evolution in tumors, as well as drug responses of cancer organoids at the cellular level and in real-time. In addition, we study the developmental processes that underlie clonal outgrowth of tumor tissue like metastases. In general, we apply molecular genetics to engineer cancer organoids to our own interest, which includes CRISPR/Cas9-mediated homologous recombination to introduce or correct cancer mutations, as well as introduction of cell fate reporters and signaling sensors to monitor and/or manipulate cellular processes in real-time.

Genetic heterogeneity

The vast majority of tumors is genetically heterogeneous, meaning that cancers are composed of many different genetic subclones. In recent years, continuous innovation in sequencing techniques has been the main driver to advance our knowledge about genetic heterogeneity in cancers. Unfortunately, little is known about tumor evolution at cell cycle resolution.

Phenotypic heterogeneity

Phenotypic heterogeneity in tumors includes non-genetic processes, such as different cell fates and phenotypes due to variable expression patterns. These are either established by tumor intrinsic cues, e.g. cellular differentiation hierarchy, or upon interaction with the tumor microenvironment.
The exact interplay between genetic and non-genetic factors remains elusive with respect to tumor growth, progression and therapy resistance.

(Single-cell) drug response

Regularly, anti-cancer therapies are effective against the majority of tumor cells. Unfortunately, there is frequently a small population of cells that shows resistance against the applied therapy. Little is known about the nature and origin of these resistant cells.