Cancer Cell Invasion

Cancer cells are highly susceptible to influences from their microenvironment.
We study tumor-microenvironment interactions to understand how cellular crosstalk enables tumor cell invasion.

CIM-seq illustration
Illustration of Cellular Interaction by Multiplet sequencing (CIM-seq) Photo: Martin Enge

Publication in Nature Methods with Martin Enge's group, July 12th, 2021.

An unsupervised method for physical cell interaction profiling of complex tissues, Andrews, Serviss et al. 
 

Single cell sequencing generates detailed maps of cells in a given tissue. However, spatial information is lost. In CIM-seq, developed by Martin Enge's group at KI, we sequence multiplets of physically connected cells and deconvolute their composition based on single cell blueprints. The result is an atlas of tightly interacting cells.

We hope that this method will greatly help us understand the cellular crosstalk of invading cancer cells and their non-malignant neighbours. 

Colorectal and Pancreatic Cancer

Colorectal and pancreatic cancers account for more than 5000 new cancer cases every year in Sweden alone.

The aggressiveness of both tumors is tightly controlled by their microenvironment, such that direct cell-cell interactions and stromal signaling processes regulate differentiation and proliferation of the tumor cells.

We use genetic mouse models, ex vivo cell culture with live cell 2-photon imaging, and single cell RNA sequencing to chart and to experimentally modify cell-cell interactions in these cancer types. We are building large clinical cohorts of liver metastases patients and pancreatic cancer patients at Karolinska University Hospital to validate our findings. 

Our goal is to bridge clinical and basic research in order to uncover ways of exploiting cellular interactions for cancer therapy.

Multiplex immunohistochemistry of pancreatic cancer cells invading into the small intestine.
Multiplex immunohistochemistry of pancreatic cancer cells invading into the small intestine. Cells with brown nuclei have integrated into the intestinal epithelium and replace the normal enterocytes. Photo: Carlos F Moro

Preprint, February 2nd 2021: 

When pancreatic cancer cells invade into the small intestine, they change their phenotype and start expressing markers of intestinal cells. Thanks to persistent efforts by the collaborating pathology team and a wealth of immunostainings, we could map this phenotypic switch that occurs upon integration of cancer cells into the small intestinal epithelium, demonstrating the remarkable plasticity of human pancreatic cancer cells in vivo. 

Histology of a liver metastasis
Histologic image of a liver metastasis, stained with antibodies for different cytokeratins. Tumor cells in brown, hepatocytes in red. Photo: Carlos F Moro

Liver Metastases

When tumor cells metastasise to distant organs, they encounter entirely new interaction partners.

Most metastases of gastrointestinal cancers are found in the liver, where tumor cells meet novel cell types, such as hepatocytes, hepatic stellate cells, liver sinusoid cells, and Kupffer cells. 

Little is known about tumor-microenvironment interactions in metastases, despite their clinical importance. Therefore, we have developed models to alter the metastatic microenvironment in the liver, and we analyse clinical samples from patients with liver metastases. Our aim is to understand how cancer cells progress in the liver parenchyma, in order to find ways to slow down or even revert this process.

Who we are

Group members

  • Marco Gerling, group leader & resident in oncology at Karolinska University Hospital, Tema Cancer.
  • Natalie Geyer, postdoc, supported by The German Research Foundation
  • Andrea del Valle, postdoc
  • Sara Harrizi, MD, Research Assistant
  • Media Salmonsson Schaad, Research Assistant

Affiliated PhD students

Previous members

  • Iva Šutevski, visiting student. Iva did her Master's project in Molecular Biology with us and was visiting from the University of Zagreb, Croatia. She established an ex vivo model of liver metastases that can be imaged live with 2-photon confocal microscopy.
  • Ewa Dzwonkowska, MSc; Ewa has completed an internship with us and finished her Master’s thesis on pancreatic cancer liver metastases in close collaboration with Martin Enge’s group at KI campus Solna.
  • Rosan Heijboer, MSc: Rosan was a visiting student from Utrecht University in The Netherlands from March to December 2018 and set up a pancreas cancer metastases model in genetically modified mice.
  • Anna Privitera, MSc: Anna joined as a visiting PhD student from Sicily from April to July 2019, working on bioinformatics analysis of stromal signaling modules in colorectal cancer.
  • Xiaoze Li-Wangsenior lab manager
  • Lorand Bozoky, medical student
  • Linnéa Longhi, Biomedical Sciences student

Main collaboration partners in Stockholm:

Key publications relevant for ongoing projects:

An unsupervised method for physical cell interaction profiling of complex tissues. Nathanael Andrews, Jason T. Serviss et al. Nature Methods, 12th of July 2021. https://doi.org/10.1038/s41592-021-01196-2

Hedgehog Signaling in Colorectal Cancer: All in the Stroma?
Geyer N, Gerling M
Int J Mol Sci 2021 Jan;22(3):

Pathological features of vessel co-option versus sprouting angiogenesis.
Latacz E, Caspani E, Barnhill R, et al. Angiogenesis. 2020 Feb;23(1):43-54. doi: 10.1007/s10456-019-09690-0.

Growth patterns of colorectal cancer liver metastases and their impact on prognosis: a systematic review.
Fernández Moro C, Bozóky B, Gerling M, BMJ Open Gastroenterol 2018 ;5(1):e000217

Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth.
Gerling M, Büller NV, Kirn LM, et al. Nature Communications 2016 08;7():12321

Lgr6 labels a rare population of mammary gland progenitor cells that are able to originate luminal mammary tumours.
Blaas L, Pucci F,  et al. Nature Cell Biology. 2016 Dec;18(12):1346-1356

Preprint, together with the Pathology Team at Karolinska University Hospital:

Basal-to-classical phenotypic switch of pancreatic cancer cells upon integration into the duodenal epithelium. Benedek Bozoky, Carlos Fernández Moro et al., doi: https://doi.org/10.1101/2021.02.01.429212bioRxiv, February 02, 2021.

 

Grateful for Support from:

Marco Gerling

group leader
H2 Department of Biosciences and Nutrition