Exploration of the Transcriptional Landscape of ALPPS Reveals the Pathways of Accelerated Liver Regeneration

Pieter Borger; Marcel Schneider; Lukas Frick; Magda Langiewicz; Maksim Sorokin; Anton Buzdin; Ekaterina Kachaylo; Rolf Graf; Bostjan Humar; Pierre-Alain Clavien

doi:10.3389/fonc.2019.01206

Exploration of the Transcriptional Landscape of ALPPS Reveals the Pathways of Accelerated Liver Regeneration

Front Oncol. 2019 Nov 19:9:1206. doi: 10.3389/fonc.2019.01206. eCollection 2019.

Authors

Pieter Borger¹, Marcel Schneider¹, Lukas Frick¹, Magda Langiewicz¹, Maksim Sorokin^{2

3

4}, Anton Buzdin^{2

3

4

5}, Ekaterina Kachaylo¹, Rolf Graf¹, Bostjan Humar¹, Pierre-Alain Clavien¹

Affiliations

¹ Laboratory of the Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, Department of Surgery, University Hospital Zürich, Zurich, Switzerland.
² OmicsWay Corp., Walnut, CA, United States.
³ I.M. Sechenov First Moscow State Medical University, Moscow, Russia.
⁴ Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
⁵ Oncobox Ltd., Moscow, Russia.

Abstract

Background and Aims: ALPPS (associating liver partition and portal vein ligation for staged hepatectomy), a novel 2-staged hepatectomy, dramatically accelerates liver regeneration and thus enables extensive liver tumor resection. The signaling networks underlying the ALPPS-induced accelerated regeneration process are largely unknown. Methods: We performed transcriptome profiling (TP) of liver tissue obtained from a mouse model of ALPPS, standard hepatectomy (68% model), and additional control surgeries (sham, PVL and Tx). We also performed TP using human liver biopsies (n = 5) taken from the occluded lobe and the future liver remnant (FLR) during the first step of ALPPS surgery (4-5 h apart). We used Oncofinder computational tools, which covers 378 ISPs, for unsupervised, unbiased quantification of ISP activity. Results: Gene expression cluster analysis revealed an ALPPS specific signature: the IGF1R Signaling Pathway (Cell survival), the ILK Pathway (Induced cell proliferation), and the IL-10 Pathway (Stability determination) were significantly enriched, whereas the activity of the Interferon Pathway (Transcription) was reduced (p < 0.05). Further, the PAK- and ILK-associated ISPs were activated at an earlier time point, reflecting significant acceleration of liver regeneration (p < 0.001). These pathways, which were also recovered in human liver biopsies, control cell growth and proliferation, inflammatory response, and hypoxia-related processes. Conclusions: ALPPS is not a straightforward addition of portal vein ligation (PVL) plus transection-it is more. The early stages of normal and accelerated liver regeneration are clearly discernible by a significantly increased and earlier activation of a small number of signaling pathways. Compounds mimicking these responses may help to improve the ALPPS method and further reduce the hospitalization time of the patient.

Keywords: ALPPS; oncofinder; signaling pathways; transcriptome profiling; two-staged hepatectomy.