Stark, M. S. | Search bioRxiv

bioRxiv2023

Benchmarking robust spatial transcriptomics approaches to capture the molecular landscape and pathological architecture of archived cancer tissues

AbtractsApplying spatial transcriptomics (ST) to explore a vast amount of formalin-fixed paraffin-embedded (FFPE) archival cancer tissues has been highly challenging due to several critical technical issues. In this work, we optimised ST protocols to generate unprecedented spatial gene expression data for FFPE skin cancer. Skin is among the most challenging tissue types for ST due to its fibrous structure and a high risk of RNAse contamination. We evaluated tissues collected from ten years to two years ago, spanning a range of tissue qualities and complexity. Technical replicates and multiple patient samples were assessed. Further, we integrated gene expression profiles with pathological information, revealing a new layer of molecular information. Such integration is powerful in cancer research and clinical applications. The data allowed us to detect the spatial expression of non-coding RNAs. Together, this work provides important technical perspectives to enable the applications of ST on archived cancer tissues.

pathology↗

bioRxiv2020

The deacylase SIRT5 supports melanoma viability by regulating chromatin dynamics

Cutaneous melanoma remains the most lethal skin cancer, and ranks third among all malignancies in terms of years of life lost. Despite the advent of immune checkpoint and targeted therapies, only roughly half of patients with advanced melanoma achieves a durable remission. SIRT5 is a member of the sirtuin family of protein deacylases that regulate metabolism and other biological processes. Germline Sirt5 deficiency is associated with mild phenotypes in mice. Here we show that SIRT5 is required for proliferation and survival across all cutaneous melanoma genotypes tested, as well as uveal melanoma, a genetically distinct melanoma subtype that arises in the eye and is incurable once metastatic. Likewise, SIRT5 is required for efficient tumor formation by melanoma xenografts and in an autochthonous mouse Braf;Pten-driven melanoma model. Via metabolite and transcriptomic analyses, we find that SIRT5 is required to maintain histone acetylation and methylation levels in melanoma cells, thereby promoting proper gene expression. SIRT5-dependent genes notably include MITF, a key lineage-specific survival oncogene in melanoma, and the c-MYC proto-oncogene. SIRT5 may represent a novel, druggable genotype-independent addiction in melanoma.

cancer biology↗