Unraveling cellular crosstalk in liver metastases of gastrointestinal cancer: Multimodal analysis of metastatic invasion.
Hematology, Oncology
Final Report Abstract
The liver is a common site for cancer metastasis, which can severely limit treatment options and worsen patient outcomes. To date, no metastasis-tailored targeted therapy options are available for patients with pancreatic or colorectal cancer that has spread to the liver. Understanding how the hepatic microenvironment with its highly specified cell types influences the growth of metastases is essential for developing novel therapeutic options. In this project, we focused on investigating the role of tumor-hepatocyte interactions and the composition of the stromal microenvironment in liver metastases. We used single cell RNA sequencing and cellular interaction mapping of liver metastases mouse models to discover that the metastasis-surrounding liver activates a multistep injury response when encountering metastasis growth. In an area surrounding the tumor, hepatocytes initiate the expression of acute phase proteins. In the tumor periphery, we found re-activation of hepatocyte developmental programs and could show by CRISPR/Cas9 genetic modifications that the Jagged 1/Notch/Sox9 signaling pathway is involved in hepatocyte de-differentiation. We successfully validated our findings in human colorectal and pancreatic cancer liver metastases. We used metastases sections, serum protein levels and survival data of a large cohort comprising approximately 700 patients to show that acute phase proteins, activated upon live injury, can serve as indicators for aggressive tumor invasion into the liver. In a second line of investigation, we performed a systematic characterization of the tumor-liver interface in encapsulated metastases where the tumor resides in the liver without engaging in direct contact with the liver epithelial cells. Instead, encapsulated metastases are surrounded by a stromal rim separating it from the liver plates. Combining large-scale histopathological and clinical data from colorectal cancer liver metastases patients, we uncover that a higher degree of encapsulation is associated with prolonged survival. With the help of liver metastases mouse models, we were then able to validate that metastases encapsulation is a result of failed tumor cell invasion, occuring preferentially in areas of tumor regression after chemotherapy. Multimodal spatial profiling enabled a comprehensive characterization of the stromal capsule, providing a valuable starting point for future investigations into the molecular regulation of the clinically highly relevant phenomenon of metastasis encapsulation. Overall, our findings highlight the importance of tumor-liver interactions and their clinical relevance for the progression and treatment response of liver metastases.
Publications
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Histopathological growth patterns of liver metastasis: updated consensus guidelines for pattern scoring, perspectives and recent mechanistic insights. British Journal of Cancer, 127(6), 988-1013.
Latacz, Emily; Höppener, Diederik; Bohlok, Ali; Leduc, Sophia; Tabariès, Sébastien; Fernández Moro, Carlos; Lugassy, Claire; Nyström, Hanna; Bozóky, Béla; Floris, Giuseppe; Geyer, Natalie; Brodt, Pnina; Llado, Laura; Van Mileghem, Laura; De Schepper, Maxim; Majeed, Ali W.; Lazaris, Anthoula; Dirix, Piet; Zhang, Qianni ... & Vermeulen, Peter B.
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An idiosyncratic zonated stroma encapsulates desmoplastic liver metastases and originates from injured liver. Nature Communications, 14(1).
Fernández Moro, Carlos; Geyer, Natalie; Harrizi, Sara; Hamidi, Yousra; Söderqvist, Sara; Kuznyecov, Danyil; Tidholm Qvist, Evelina; Salmonson Schaad, Media; Hermann, Laura; Lindberg, Amanda; Heuchel, Rainer L.; Martín-Bernabé, Alfonso; Dhanjal, Soniya; Navis, Anna C.; Villard, Christina; del Valle, Andrea C.; Bozóky, Lorand; Sparrelid, Ernesto; Dirix, Luc ... & Gerling, Marco
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What’s in a name? Refining the nomenclature of liver metastases growth patterns by changing “desmoplastic” to “encapsulated”. BJC Reports, 1(1).
Fernández Moro, Carlos; Bozóky, Béla; Geyer, Natalie; Engstrand, Jennie; Dirix, Luc; Vermeulen, Peter & Gerling, Marco
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A distinctive tumor compartment in pancreatic lobules defined by nascent stroma and classical tumor cell phenotype. openRxiv.
Söderqvist, Sara; Viljamaa, Annika; Geyer, Natalie; Strell, Carina; Hekmati, Neda; Engstrand, Jennie; Sparrelid, Ernesto; Salmén, Caroline; Heuchel, Rainer L.; Zacharouli, Argyro; Ghorbani, Poya; Harrizi, Sara; Hamidi, Yousra; Khorosjutina, Olga; Milanova, Stefina; Schmierer, Bernhard; Bozóky, Béla; Moro, Carlos Fernández & Gerling, Marco
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Cellular spartans at the pass: Emerging intricacies of cell competition in early and late tumorigenesis. Current Opinion in Cell Biology, 86, 102315.
Fernández Moro, Carlos; Geyer, Natalie & Gerling, Marco
