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.

Cancer Cell Invasion

@cancer_invasion on Twitter

The authors: Marcus Skribek, Ulrika Harmenberg, Lisa Liu and Marco Gerling
The authors: Marcus Skribek, Ulrika Harmenberg, Lisa Liu, Marco Gerling

Publication in JITC: Systemic inflammatory syndromes as life-threatening side effects of immune checkpoint inhibitors, March 6th, 2023

Immunotherapy has been shown to greatly improve survival rates for certain types of cancer. However, in some cases, it can lead to an over-activation of the immune system, which can be dangerous. This side effect is rare and was only identified during regular clinical use rather than in clinical trials or animal experiments. To better understand this over-activation, we analysed data from all published international reports on this issue after cancer immunotherapy. Our findings indicate that potentially life-threatening inflammation may occur more frequently than previously thought and can often be treated with existing drugs such as steroids or anti-inflammatory therapies commonly used for rheumatoid arthritis.

Shoutout to Narcisa and Sabina from Karolinska University Library for their professional help finding thousands of articles!

Stay tuned for a link to liver metastases! 

New preprint on medRxiv, August 2022:

An idiosyncratic, zonated stroma encapsulates desmoplastic liver metastases and originates from injured liver

This is close to our heart: Digital pathology, tons of whole-slide-images, meticulous quantification of protein gradients.

To cut a long story short, we show that there are two outcomes of metastases invasion: "Tumor wins" or "liver wins". Our collaborators Béla Bozóky and Carlos Fernández Moro phrased it like this already years ago - now we think we have evidence to prove this concept. 

Tweetorial here!

histological staining of a liver metastasis
Heamatoxylin & eosin stain of a colorectal cancer liver metastasis. Photo: Marco Gerling

Updated clinical guidelines for scoring of liver metastasis growth patterns published, June 1st 2022, British Journal of Cancer:

A major effort coordinated by our collaborator Peter Vermeulen.

New mouse models, a new, clinically applicable cut-off to identify patients with excellent outcome, and new insights into growth pattern biology based on immunohistochemistry:

Latacz et al., Histopathological growth patterns of liver metastasis: updated consensus guidelines for pattern scoring, perspectives, and recent mechanistic insights.

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.

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
  • Carlos Fernández Moro, postoc, supported by SSMF
  • Sara Söderqvist, PhD student
  • Annika Viljamaa, exchange student
  • Laura Hermann, Master student
  • Carlos Fernández Moro, consultant pathologist, postdoc

Affiliated PhD students

Previous members

  • Sara Harrizi, Research Assistant
  • Yousra Hamidi, Research Assistant
  • Andrea del Valle, postdoc
  • 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-Wang, senior lab manager
  • Lorand Bozoky, medical student
  • Linnéa Longhi, Biomedical Sciences student
  • Sarah Rümpeler Calheiros Vera-Cruz, intern, Master student, University of Lübeck, Germany. Sarah worked on quantification and spatial remapping of tumor-hepatocyte interactions in pancreatic cancer liver metastases.
  • Media Salmonsson Schaad, Research Assistant
  • Manuela Cano, BMA student (main supervisor: Carlos Fernández Moro)
  • Christos Vogiatzakis, summer student (stipend)

Main collaboration partners in Stockholm:

Key publications relevant for ongoing projects:

Histopathological growth patterns of liver metastasis: updated consensus guidelines for pattern scoring, perspectives and recent mechanistic insights. Latacz, Höppener, Bohlok et al., British Journal of Cancer, https://doi.org/10.1038/s41416-022-01859-7

Comprehensive clinicopathological guidelines for growth pattern scoring of liver metastases with a dash of novel hypothesis.

Stabilization of the classical phenotype upon integration of pancreatic cancer cells into the duodenal epithelium. Bozóky, Fernández Moro et al., Neoplasia, December 2021, https://doi.org/10.1016/j.neo.2021.11.007 

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

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

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. 

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

Grateful for Support from:

Marco Gerling

group leader
H2 Department of Biosciences and Nutrition
MG
Content reviewer:
Marco Gerling
06-03-2023