1 research outputs found
Identifying and targeting vulnerabilities in cancers that metastasize to the bone and bone marrow
Evolving technologies enable scientist to ask and seek answers to advanced questions,
above and beyond. During the past decade single-cell RNA sequencing (scRNA-seq) has
revolutionized our understanding of biology, in particular within cancer research.
Contributing with its high-resolution has unraveled complicated biological circuits, along
with a profound understanding of heterogeneity, cellular and molecular processes,
including gene expression profiles and transcriptional states. Especially in the quest of
understanding cancer metastasis, aggressive disease phenotype and treatment
resistance.
In Paper I we utilize scRNA-seq on tissue material from untreated human primary clear
cell renal cell carcinoma (ccRCC) patients. We dissect the tumor microenvironment
(TME) and discover a metastatic gene signature that is upregulated in bone metastatic
ccRCC patients that could serve as a predictive tool. We describe an
immunosuppressive microenvironment with tumor associated macrophages (TAMs)
with a M2 phenotype overexpressing TREM2, further associated with low survival
outcome. Computational interactive receptor-ligand analysis reveals CD70 (on tumor)
and CD27 (on cytotoxic T cells and regulatory T cells) as a potential pharmaceutical
target.
In Paper II, a continuation of Paper I, we aimed to understand genetic alterations
involved in metastatic disease from the primary site, namely bone metastatic ccRCC,
including comparison of a normal bone marrow to malignant. Scrutinizing the complex
TME we detect, as well here, an immunosuppressive microenvironment with
transcriptionally different TAMs, exhausted T cell phenotype and a tumor associated
mesenchymal stem/stromal cell (TA-MSC) population that upregulates bone remodeling
genes. Concluding that the relevance of TA-MSC subset causes excessive bone
resorption via RANK/RANKL/OPG signaling pathway.
Finally, in Paper III, we evaluate brequinar, a DHODH inhibitor, as a therapeutic agent in
high-risk neuroblastoma (NB). We find DHODH as an independent risk factor in high-risk
NB demonstrating prolonged survival in preclinical models when inhibited. In
combination with temozolomide, already in clinical use for these children, a synergistic
effect is achieved in vivo, proposing a promising approach to validate clinically.
Taken together, the presented thesis has provided comprehensive insights in the
progression of ccRCC in a primary and a metastatic setting, including the identification
of potential vulnerable targets. Additionally, a potential combination treatment in vitro
and in vivo is presented as a promising treatment option in high-risk NB by inhibiting
DHODH together with standard care of treatment agent temozolomide