Biology subjects

Calado, D. P.

Publications and source records attributed to Calado, D. P..

3 recordsLinked to original sources

bioRxiv2021

N-myristoyltransferase inhibition is synthetic lethal in MYC-deregulated cancers

Human N-myristoyltransferases (NMTs) catalyze N-terminal protein myristoylation, a modification regulating membrane trafficking and interactions of >100 proteins. NMT is a promising target in cancer, but a mechanistic rationale for targeted therapy remains poorly defined. Here, large-scale cancer cell line screens against a panel of NMT inhibitors (NMTi) were combined with systems-level analyses to reveal that NMTi is synthetic lethal with deregulated MYC. Synthetic lethality is mediated by post-transcriptional failure in mitochondrial respiratory complex I protein synthesis concurrent with loss of myristoylation and degradation of complex I assembly factor NDUFAF4, followed by mitochondrial dysfunction specifically in MYC-deregulated cancer cells. NMTi eliminated MYC-deregulated tumors in vivo without overt toxicity, providing a new paradigm in which targeting a constitutive co-translational protein modification is synthetically lethal in MYC-deregulated cancers. One-sentence summaryN-myristoyltransferase inhibition leads to post-transcriptional complex I failure and cell death in MYC-deregulated cancers

cancer biology↗

bioRxiv2020

Jchain-driven cre enables specific genetic manipulation and timestamping of plasma cell in their niche.

Plasma cells (PC)s are essential for protection from infection, and at the origin of incurable cancers. Current studies do not circumvent limitations of removing PCs from their microenvironment and confound formation and maintenance. This is in part due to the lack of tools to perform specific genetic manipulation in vivo. Also, studies of PC population dynamics have mostly relied on the use of nucleotide analog incorporation that does not label quiescent cells, a property of most PCs. Here we characterize in detail a genetic tool (JchaincreERT2) that permits first-ever specific genetic manipulation in PC in vivo, across immunoglobulin isotypes. Using this tool we found that PC numbers remained constant over-time and that PC decay was compensated by the emergence of new cells, supporting an homeostatic turnover of the population. The JchaincreERT2 genetic tool paves the way for in-depth mechanistic understanding of PC biology and pathology in vivo, in their microenvironment. HighlightsJchain expression occurs in most plasma cells across immunoglobulin isotypes JchaincreERT2 mediated genetic manipulation is effective only in plasma cells Genetic timestamping of plasma cells reveals homeostatic regulation

immunology↗

bioRxiv2020

Co-activation of NF-κB and MYC renders cancer cells addicted to IL6 for survival and phenotypic stability

NF-{kappa}B and MYC are found co-deregulated in human B and plasma-cell cancers. In physiology, NF-{kappa}B is necessary for terminal B-to-plasma cell differentiation, whereas MYC repression is required. It is thus unclear if NF-{kappa}B/MYC co-deregulation is developmentally compatible in carcinogenesis and/or impacts cancer cell differentiation state, possibly uncovering unique sensitivities. Using a mouse system to trace cell lineage and oncogene activation we found that NF-{kappa}B/MYC co-deregulation originated cancers with a plasmablast-like phenotype, alike human plasmablastic-lymphoma and was linked to t(8;14)[MYC-IGH] multiple myeloma. Notably, in contrast to NF-{kappa}B or MYC activation alone, co-deregulation rendered cells addicted to IL6 for survival and phenotypic stability. We propose that conflicting oncogene-driven differentiation pressures can be accommodated at a cost in poorly-differentiated cancers. SignificanceOur studies improve the understanding of cancer pathogenesis by demonstrating that co-deregulation of NF-{kappa}B and MYC synergize in forming a cancer with a poorly-differentiated state. The cancers in the mouse system share features with human Plasmablastic lymphoma that has a dismal prognosis and no standard of care, and with t(8;14)[MYC-IGH] Multiple myeloma, which is in overall resistant to standard therapy. Notably, we found that NF-{kappa}B and MYC co-deregulation uniquely render cells sensitive to IL6 deprivation, providing a road-map for patient selection. Because of the similarity of the cancers arising in the compound mutant mouse model with that of human Plasmablastic lymphoma and t(8;14)[MYC-IGH] Multiple myeloma, this model could serve in preclinical testing to investigate novel therapies for these hard-to-treat diseases. HighlightsO_LINF-{kappa}B and MYC co-activation originates (pre)plasmablast-like cancer C_LIO_LINF-{kappa}B/MYC+ renders cancer cells addicted to IL6 for survival and phenotypic stability C_LIO_LINF-{kappa}B/MYC+ cancers are alike a fraction of human plasmablastic lymphoma C_LIO_LIt(8;14)[MYC-IGH] multiple myeloma is linked to a NF-{kappa}B/MYC co-activation signature C_LI

cancer biology↗