Biology subjects

Silver, D. J.

Publications and source records attributed to Silver, D. J..

21 records · Page 2Linked to original sources

bioRxiv2019

Malignant liver cancers have distinct myeloid-derived suppressor cell signatures

Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells that are increased in patients with numerous malignancies including viral-derived hepatocellular carcinoma (HCC). Here, we report an elevation of MDSC in other hepatobiliary malignancies including non-viral HCC, neuroendocrine tumors (NET), colorectal carcinoma with liver metastases (CRLM), but not cholangiocarcinoma (CCA). Investigation of myeloid cell infiltration in HCC, NET and intrahepatic CCA tumors further established that the frequency of antigen-presenting cells was limited compared to benign lesions suggesting that primary and metastatic hepatobiliary cancers have distinct peripheral and tumoral myeloid signatures. Bioinformatics analysis of the Cancer Genome Atlas demonstrated that a high MDSC score in HCC patients predicted poor disease outcome. Mechanistic studies indicated that the oncometabolite D-2-hydroxyglutarate resulting from isocitrate dehydrogenase 1 mutation could be a limiting factor of MDSC accumulation in CCA patients. Given our observation that MDSCs are increased in non-CCA malignant liver cancers, they may comprise suitable targets for effective immunotherapy approaches.

pathology↗

bioRxiv2019

ADAMDEC1 maintains a novel growth factor signaling loop in cancer stem cells

Glioblastomas (GBM) are lethal brain tumors where poor outcome is attributed to cellular heterogeneity, therapeutic resistance, and a highly infiltrative nature. These characteristics are preferentially linked to GBM cancer stem cells (GSCs), but how GSCs maintain their stemness is incompletely understood and the subject of intense investigation. Here, we identify a novel signaling loop that induces and maintains GSCs. This loop consists of an atypical metalloproteinase, a disintegrin and metalloproteinase domain-like protein decysin 1 (ADAMDEC1), secreted by GSCs. ADAMDEC1 rapidly solubilizes fibroblast growth factor-2 (FGF2) to stimulate FGF receptor 1 (FGFR1) expressed on GSCs. This signaling axis induces upregulation of Zinc finger E-box-binding homeobox 1 (ZEB1) that regulates ADAMDEC1 expression, creating a positive feedback loop. Genetic or pharmacological targeting of components of this axis attenuates self-renewal and tumor growth. These findings reveal a new signaling axis for GSC maintenance and highlight ADAMDEC1 and FGFR1 as potential therapeutic targets in GBM. Statement of SignificanceCancer stem cells (CSC) drive tumor growth in many cancers including glioblastoma. We identified a novel sheddase, a disintegrin and metalloproteinase domain-like protein decysin 1, that initiates a fibroblast growth factor autocrine loop to promote stemness in CSCs. This loop can be targeted to reduce glioblastoma growth.

cancer biology↗

bioRxiv2018

Development of a Cx46 targeting strategy for cancer stem cells

Gap junction-mediated cell-cell communication enables tumor cells to synchronize the execution of complex processes. Despite the connexin family of gap junction proteins being considered tumor suppressors, we previously found that glioblastoma cancer stem cells (CSCs) express higher levels of Cx46 compared to non-stem tumor cells, and this was necessary and sufficient for CSC maintenance. To develop a Cx46 targeting strategy, we utilized point mutants to disrupt specific functions of Cx46 and found that gap junction coupling was the critical function of Cx46 for CSCs. Based on this finding, we screened a clinically relevant library of small molecules and identified clofazimine as an inhibitor of Cx46-specific cell-cell communication. Clofazimine attenuated proliferation, self-renewal, and tumor growth and synergized with temozolomide to induce apoptosis. These data suggest that combining clofazimine with standard-of-care therapies may target glioblastoma CSCs. Furthermore, these results demonstrate the importance of targeting cell-cell communication as an anti-cancer therapy.

cancer biology↗