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NF1 modulates microtubular repair and dictates sensitivity to maytansinoid antibody-drug conjugates in HER2-positive breast cancer

ABSTRACT: NF1 is a tumor suppressor widely mutated across several cancers. Its best characterized function is the inhibition of RAS signaling through its GTPase-Activating Protein (GAP) domain. Additional functions have been proposed but not deeply investigated, due to its large size and complex domain structure. Here, combining patient data, in vitro/in vivo models and protein biochemistry, we show that NF1 is a novel Microtubule-Associated Protein (MAP) that modulates microtubular dynamics and intra-tubular repair. NF1 loss results in mitotic defects such as prolonged mitosis, supranumerary centrosomes and chromosome missegregation, leading to low-grade aneuploidy in cell lines and patients. Loss of NF1-mediated intratubular repair creates a liability specifically targetable by maytansinoids, a class of microtubule-depolymerizing agents widely used as payloads in Antibody-Drug Conjugates such as Trastuzumab-Emtansine (T-DM1). Our results directly imply loss of intratubular repair as a driver of tumorigenesis, and NF1 as the first ADC payload-associated biomarker.

ORGANISM(S): Homo sapiens

PROVIDER: GSE267855 | GEO | 2024/12/01

REPOSITORIES: GEO

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NF1 modulates microtubular repair and dictates sensitivity to maytansinoid antibody-drug conjugates in HER2-positive breast cancer

Project description:NF1 modulates microtubular repair and dictates sensitivity to maytansinoid antibody-drug conjugates in HER2-positive breast cancer

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Centrosome-mediated microtubule remodeling during axon formation in human iPSC-derived neurons

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2021-02-12 | PXD020221 | Pride

Extra centrosomes induce PIDD1-mediated inflammation and Immunosurveillance

Project description:Unscheduled increases in cellular ploidy underlie defects in tissue function, premature aging, and malignancy. A concomitant event to polyploidization is the amplification of centrosomes, the main microtubule organization center in animal cells. Supernumerary centrosomes are frequent in tumors, correlating with higher aggressiveness and poor prognosis. However, extra centrosomes also exert an onco-protective effect by activating the p53 network and eliciting cell cycle arrest. Here, we report that extra centrosomes, arising during unscheduled polyploidization or aberrant centriole biogenesis, induce activation of NF-κB signaling and sterile inflammation. This signaling requires the NEMO-PIDDOsome, a multi-protein complex composed of PIDD1, RIPK1, and NEMO/IKKγ. Remarkably, the presence of supernumerary centrosomes suffices to induce a paracrine chemokine and cytokine profile, able to polarize macrophages into a pro-inflammatory phenotype. Furthermore, extra centrosomes, accumulating after cytokinesis failure, increase immunogenicity of cancer cells and render them more susceptible to NK-cell attack. Hence, extra centrosomes, the PIDDosome acts as a dual effector, able to engage not only the p53 network for cell cycle control but also NF-κB signaling to instruct innate immunity.

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Project description:Control of the number of centrosomes is critical for cell division, trafficking and cilia. Regulation of centrosome number occurs through the precise duplication of centrioles that reside in the center of centrosomes. Here we explored transcriptional control of centriole assembly by focusing on alternative splicing factors in isolation from other cell cycle processes. Of five splicing factors originally identified as required for centriole assembly, only SON is specifically required. Procentriole assembly is severely disrupted when SON is reduced but early centriole assembly events still occur. Whole genome mRNA sequencing identified thousands of genes whose splicing and expression are affected by the reduction of SON, with an enrichment of genes involved in the microtubule cytoskeleton. SON is required for the proper splicing and expression of the centriolar satellite protein, CEP131. Fluorescence microscopy and electron tomography establish key differences to the trafficking and microtubule network around the centrosomes that contribute to the centriole assembly defects. This establishes SON as required for centriole assembly, partially through its activity in splicing CEP131 and through control of microtubules organized by the centrosome.

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Transcriptome analysis of rigosertib resistant MDA-MB-453 cells, obtained from a CRISPR screen with WNK1 depletion.

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Oncogene-like induction of cellular invasion from centrosome amplification

Project description:Centrosome amplification has long been recognized as a feature of human tumors, however its role in tumorigenesis remains unclear. Centrosome amplification is poorly tolerated by non-transformed cells, and, in the absence of selection, extra centrosomes are spontaneously lost. Thus, the high frequency of centrosome amplification, particularly in more aggressive tumors, raises the possibility that extra centrosomes could, in some contexts, confer advantageous characteristics that promote tumor progression. Using a three-dimensional model system and other approaches to culture human mammary epithelial cells, we find that centrosome amplification triggers cell invasion. This invasive behavior is similar to that induced by overexpression of the breast cancer oncogene ErbB2 and indeed enhances invasiveness triggered by ErbB2. We show that, through increased centrosomal microtubule nucleation, centrosome amplification increases Rac1 activity, which disrupts normal cell-cell adhesion and promotes invasion. These findings demonstrate that centrosome amplification, a structural alteration of the cytoskeleton, can promote features of malignant transformation. genome-wide human SNP 6.0 arrays from Affymetrix was used to determine the copy number changes of MCF10A cells with extra centrosomes or depleted of MCAK after grown 4 days in 3-D cultures

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Gene expression in mitotic tissues of Drosophila larvae without centrosomes or too many centrosomes

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Project description:HCD Triggered UVPD and EThcD files for characterization of trastuzumab-emtansine (T-DM1)

2023-08-03 | MSV000092585 | MassIVE