Biology subjects

Amant, F.

Publications and source records attributed to Amant, F..

4 recordsLinked to original sources

bioRxiv2021

Wnt/β-catenin inhibition disrupts drug-tolerance in isogenic carboplatin-resistant models of Triple-Negative Breast Cancer.

Triple-Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype, characterized by both limited treatment options and higher relapse rates than hormone-receptor-positive breast cancers. Chemotherapy remains the mainstay treatment for TNBC, and platinum salts have been explored as a therapeutic alternative in neo-adjuvant and metastatic settings. However, primary and acquired resistance to chemotherapy in general and platinum-based regimens specifically strongly hampers TNBC management. In this study, we used carboplatin-resistant in vivo patient-derived xenograft and isogenic TNBC cell-line models and detected enhanced Wnt/{beta}-catenin activity correlating with an induced expression of stem cell markers in both resistant models. In accordance, the activation of canonical Wnt signaling in parental TNBC cell lines increases stem cell markers expression, formation of tumorspheres, and promotes carboplatin resistance. Finally, we prove that Wnt signaling inhibition resensitizes resistant models to carboplatin both in vitro and in vivo, suggesting the synergistic use of Wnt inhibitors and carboplatin as a therapeutic option in TNBC. Here we provide evidence for a prominent role of Wnt signaling in mediating resistance to carboplatin, and we establish that combinatorial targeting of Wnt signaling overcomes carboplatin resistance enhancing chemotherapeutic drug efficacy.

cancer biology↗

bioRxiv2020

The tumor suppressor protein PTEN undergoes amyloid-like aggregation in tumor cells.

Protein aggregation is an underappreciated mechanism that may contribute to the loss- and oncogenic-gain-of-function of mutant tumor suppressors such as p53 and axin. In the present study, we describe amyloid-like aggregation behaviour of the second most frequently mutated tumor suppressor in human cancer, PTEN. In silico analysis revealed a particularly high aggregation vulnerability for this protein, which was corroborated by in vitro aggregation assays. In cultured tumor cells, we found that under stress conditions, PTEN readily undergoes amyloid-like aggregation as a result of mutation. However, we also show that severe dysregulation of protein homeostasis may lead to aggregation of wild-type PTEN. These observations were supported by a small survey of patient-derived uterine tumor tissues, which found that more than 25% of tumors analyzed displayed wild-type PTEN aggregation. Finally, in an exploratory clinical study we found that PTEN aggregation status was correlated with a decline in clinical outcome. Our findings establish that the tumor suppressor PTEN is highly aggregation-prone and our work suggests that protein aggregation might be an underestimated but prevalent component of cancer cell biology.

cancer biology↗

bioRxiv2020

The pleiotropic effects of the MNK1/2-eIF4E axis support immune suppression and metastasis in a model of postpartum breast cancer.

PurposeBreast cancer diagnosed within 10 years following childbirth is defined as postpartum breast cancer (PPBC) and is highly metastatic. Interactions between immune cells and other stromal cells within the involuting mammary gland are fundamental in facilitating an aggressive tumor phenotype. The MNK1/2-eIF4E axis promotes the translation of pro-metastatic mRNAs in tumor cells, but its role in modulating the function of non-tumor cells in the PPBC microenvironment, and in particular its activity in human PPBC, has not been explored. Experimental designWe used a combination of in vivo PPBC models and in vitro assays to study the effects of phospho-eIF4E deficiency on the pro-tumor function of select cells of the TME. Furthermore, we employed Imaging Mass Cytometry on PPBC and non-PPBC patient samples, to chart the expression of the MNK1/2-eIF4E axis components in the TME. ResultsHere, we show that phospho-eIF4E deficient (eIF4ES209A) PPBC mice are protected against lung metastasis and reveal differences in the lung immune microenvironment of the WT and eIF4ES209A mice. Moreover, we show that the expression of fibroblast-derived IL-33, an alarmin known to induce invasion, was repressed upon MNK1/2-eIF4E axis inhibition. Imaging Mass Cytometry results indicated that human PPBC contain phospho-eIF4E high-expressing tumor cells and CD8+ T cells displaying an activated dysfunctional phenotype. Finally, we block lung metastasis in PPBC mice, using combined MNK1/2 inhibition and anti-PD-1 therapy. ConclusionsThese findings implicate the involvement of the MNK1/2-eIF4E axis during PPBC metastasis and suggest a promising immunomodulatory route to enhance the efficacy of immunotherapy by blocking phospho-eIF4E. Translational relevancePostpartum breast cancer (PPBC) is highly aggressive. It is hypothesized that involution-induced changes in the postpartum breast microenvironment, which include an influx of inflammatory immune cells and activation of resident fibroblasts, facilitate the invasiveness of an existing neoplasm. We used imaging mass cytometry to do an in-depth profiling of the MNK1-eIF4E axis in the TME of a unique cohort of PPBC and non-PPBC patients. We observed patterns of phospho-eIF4E in non-tumor cells that were specific to the TME of PPBC. We also noted that the CD8+ T cells present in PPBC express an activated dysfunctional phenotype characterized by the co-expression of HLA-DR and PD-1. This study represents a first look at the expression of the MNK1-eIF4E axis in the stromal cells of metastatic breast cancer and has therapeutic implications as we show, in an animal model of PPBC, that MNK1/2 inhibition can be used to sensitize tumors to anti-PD1 immunotherapy.

cancer biology↗

bioRxiv2019

Sensorimotor functional connectivity in unilateral cerebral palsy: influence of corticospinal tract wiring pattern and clinical correlates

In children with unilateral cerebral palsy (uCP), the corticospinal tract (CST) wiring patterns may differ (contralateral, ipsilateral or bilateral), partially determining motor deficits. However, the impact of such CST wiring on functional connectivity remains unknown. Here, we explored differences in functional connectivity of the resting-state sensorimotor network in 26 uCP with periventricular white matter lesions (mean age (SD): 12.87m (4.5), CST wiring: 9 contralateral, 9 ipsilateral, 6 bilateral) compared to 60 healthy controls (mean age (SD): 14.54 (4.8)), and between CST wiring patterns. Functional connectivity from each M1 to three bilateral sensorimotor regions of interest (primary sensory cortex, dorsal and ventral premotor cortex) and the supplementary motor area was compared between groups (healthy controls vs. uCP; and healthy controls vs. each CST wiring group). Results from the seed-to-voxel analyses from bilateral M1 were compared between groups. Additionally, relations with upper limb motor deficits were explored. Aberrant sensorimotor functional connectivity seemed to be CST-dependent rather than specific from all the uCP population: in the dominant hemisphere, the contralateral CST group showed increased connectivity between M1 and premotor cortices, whereas the bilateral CST group showed higher connectivity between M1 and somatosensory association areas. These results suggest that functional connectivity of the sensorimotor network is CST wiring-dependent, although the impact on upper limb function remains unclear.

neuroscience↗