Histopathological Image Analysis for Necroptosis Biomarkers Research

摘要

Necroptosis is a caspase independent programmed cell death similar to necrosis. It also exhibits cell swelling and rupture of the cellular membrane and hence it can promote an inflammatory response. Recent studies have linked necroptosis to immune inflammatory diseases such as psoriasis and IBD and several 'necroptosis inhibitors' are currently being studied in clinical trials for their potential to treat these diseases. Among the most studied necroptosis key players are Caspase-8, RIP1, RIP3 and MLKL. During Caspase-8 inactivation, RIPK1 recruits RIPK3 forming the necrosome which autophosphorylates and then recruits and activates MLKL. Finally MLKL translocates to the cell membrane increasing its permeability and ultimately causing cell death. In this work, we present our current approaches to study necroptosis biomarkers through digital pathology. We tuned image analysis algorithms to study total or activated forms of Caspase-8, RIP1, RIP3 and MLKL in skin and colon biopsies. We will also discuss some image analysis validation guidelines followed in the GSK Histo Hub. Because necroptosis has also been implicated in neurodegenerative diseases such as ALS, Alzheimer, Parkinson and immunotherapy resistance in cancer, we will introduce the early development of multiplexing and algorithm calibration studies to identify necroptotic and immune cell populations in nervous tissue and tumors.