Functional heterogeneity in cancers


Cells within a cancer are highly heterogeneous with respect to their phenotype and can manifest distinct morphological, molecular and functional features. As a consequence, it is challenging to design treatment therapies that target all cancer cells as effectively. 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.

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.



Shapeshifting cancer cells during liver metastasis formation

Ever wondered what the cellular trajectory is of a cancer cell metastasizing to the liver? Maria finished a tour de force @Cancer Research, mapping shapeshifting cancer stem cell phenotypes with high precision during metastasis formation.

Ooh…, regarding epithelial self-organization in organoids: it is conserved between mice, human, normal and cancer organoids. Its clinical relevance: the exact same processes take place during liver metastasis formation in patients.

Press release

Snippertlab PLOS BIOL

CRISPR with ease

Super happy with this technology, foremost as we now can make (complex) knock-ins in human organoids on weekly basis. Major advantages are no off-targets. As a consequence, you can pool all knock-in cells to expedite culture expansion and/or maintenance of polyclonality (in case of tumors). Targeting vectors enable one-step cloning (and all are available @Addgene).

Overall result, amazing looking knock-in organoids within 2wks! @PLOS BIOLOGY

Snippertlab-NG 3D Live-Seq

Tumor evolution in real-time

Proud on this fantastic publication in Nat Genet. We established 3D Live-Seq: the integration of live-cell imaging of tumor organoids and whole-genome sequencing of each imaged cell. Combined, these super powerful technologies enable the exact reconstruction how evolving tumor genomes change and mutate over consecutive cell generations. Mapping the tempo and rate of genome alterations identified punctuated and gradual patterns.

Press release

Dr. Hugo Snippert  is Group Leader at the department of Molecular Cancer Research within the Center of Molecular Medicine at the University Medical Center Utrecht. In 2017 he became an Oncode Investigator.
Hugo received his PhD (cum laude) in the lab of Hans Clevers (Hubrecht Institute) where he used advanced mouse genetics and microscopy to characterize (new) stem cell populations in the mouse intestine, skin and intestinal cancer.

His main interests relate to cell fate specifications and how multiple individual cells act in concert to secure tissue functioning. He is always looking for concepts and principles, with a strong emphasis on developing new technology.

He received an HFSP young investigators grant and ERC starting grant in 2018. NWO VIDI in 2021.