Biology subjects

Chakravarty, P.

Publications and source records attributed to Chakravarty, P..

5 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

EphB6 regulates TFEB-lysosomal pathway and survival of disseminated indolent breast cancer cells

Late relapse of disseminated cancer cells is a common feature of some types of tumors. Several intrinsic and extrinsic factors have been shown to affect reawakening of disseminated dormant cancer cells (DDCCs); however, the signals and processes sustaining survival of DDCCs in a foreign environment are still poorly understood. We have recently shown that crosstalk with lung epithelial cells promotes persistence of DDCCs from estrogen receptor positive (ER+) breast tumors. Here we show that TFEB-lysosomal axis is activated in DDCCs and that it is modulated by the pro-survival ephrin receptor EphB6. TFEB lysosomal direct targets are enriched in DDCCs in vivo and correlate with relapse in ER+ breast cancer patients. Direct contact of DDCCs with alveolar type I-like lung epithelial cells drives lysosomal accumulation and EphB6 induction. EphB6 contributes to TFEB transcriptional activity and lysosome formation in DDCCs in vitro and in vivo, and supports survival of DDCCs in coculture and in vivo. Furthermore, signaling from EphB6 promotes the proliferative response of surrounding lung parenchymal cells in vivo.

cancer biology↗

bioRxiv2020

Critical role of WNK1 in MYC-dependent early thymocyte development

WNK1, a kinase that controls kidney salt homeostasis, also regulates adhesion and migration in CD4+ T cells. Wnk1 is highly expressed in thymocytes, and since migration is important for thymocyte maturation, we investigated a role for WNK1 in thymocyte development. We find that WNK1 is required for the transition of double negative (DN) thymocytes through the {beta}-selection checkpoint and subsequent proliferation and differentiation into double positive (DP) thymocytes. Furthermore, we show that WNK1 negatively regulates LFA1-mediated adhesion and positively regulates CXCL12-induced migration in DN thymocytes. Despite this, migration defects of WNK1-deficient thymocytes do not account for the developmental arrest. Instead, we show that in DN thymocytes WNK1 transduces pre-TCR signals via OXSR1 and STK39 kinases and the SLC12A2 ion co-transporter that are required for post-transcriptional upregulation of MYC and subsequent proliferation and differentiation into DP thymocytes. Thus, a pathway regulating ion homeostasis is a critical regulator of thymocyte development.

immunology↗

bioRxiv2020

SOX2 is required independently in both stem and differentiated cells for pituitary tumour genesis in p27 null mice.

Loss of P27 predominantly results in development of murine pituitary intermediate lobe (IL) tumours. We previously showed that the pleiotropic protein P27 can drive repression of the transcription factor Sox2. This interaction plays an important role during development of p27-/- IL tumours because loss of one copy of Sox2 diminishes tumorigenesis. Here, we have explored the cellular origin and mechanisms underlying melanotroph tumorigenesis in p27-/- IL. We show that IL hyperplasia is associated with reduced cellular differentiation, while levels of SOX2 increase in both stem cells (SC) and melanotrophs. Using loss-of-function and lineage tracing approaches, we demonstrate that SOX2 is required cell-autonomously in p27-/- melanotrophs and SCs for tumorigenesis. This is supported by studies deleting the Sox2 regulatory region 2 (Srr2), which is the target of P27 repressive action. Single cell transcriptomic analysis reveals that activation of a SOX2-dependent MAPK pathway in SCs is important for p27-/- tumorigenesis. Our data highlight different roles of SOX2 following loss of p27, according to the cellular context. Furthermore, we uncover a tumor-promoting function for SCs, which is SOX2-dependant. In conclusion, our results imply that targeting SCs, in addition to tumour cells themselves, may represent an efficient anti-tumoral strategy in certain contexts.

cancer biology↗

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↗