Inhibition of glucuronidation in pancreatic cancer improves gemcitabine anticancer activity

Pancreatic ductal adenocarcinoma (PDAC) treatmentis focused on two regimens. The polychemotherapy, FOLFIRINOX (folinic acid, fluorouracil, irinotecan, oxali-platin), is used in patients with good health conditions, while gemcitabine, as monotherapy, in patients withpoor health conditions. Gemcitabine resistance-associated pathways have been targeted to sensitize cancercells, but the results were disappointing. Using a transcrip-tomic bioinformatics analysis combined with biologicalvalidation, we showed that glucuronidation was associated with the gemcitabine resistance in PDAC, and its inhibition could switch tumors from resistant to sensitive.To unravel the biological drivers of gemcitabineresponse in PDAC, we determined the transcriptomic dissimilarity between two preclinical models with definedgemcitabine sensitivity.Fil: Fraunhoffer Navarro, Nicolas Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Meilerman Abuelafia, Analía. Inserm; FranciaFil: Chanez, Brice. Inserm; FranciaFil: Bigonnet, Martin. Inserm; FranciaFil: Gayet, Odile. Inserm; FranciaFil: Roques, Julie. Inserm; FranciaFil: Chuluyan, Hector Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Dusetti, Nelson. Inserm; FranciaFil: Iovanna, Juan Lucio. Inserm; Franci

Microtubule associated proteins participates to regulate tumoral migration and matrix degradation by tumoral cells

La migration et l'invasion tumorale sont des étapes clés de la cascade métastatique. Les microtubules (MT) contribuent à la division cellulaire et constitue la cible des agents de chimiothérapie anti-MT (ACM). Ce sont des structures dynamiques qui s'ancrent aux structures cellulaires périphériques. Durant ma thèse, j’ai étudié comment les protéines régulant le bout « + » des MT (+TIP) contribuent à la migration cellulaire et à la dégradation de la matrice extracellulaire. D’abord j’ai étudié l'impact de l'eribuline, un ACM dépolymérisant, sur la migration de cellules mammaires. L'éribuline s'est avérée empêcher l'ancrage des MT, modifier leur dynamique et inhiber la migration dirigée cellulaire, phénomène que nous avons expliqué par son action sur la +TIP EB1 mais surtout par la délocalisation de la tubuline polymérase ch-TOG de l'extrémité + des MT. Puis, nous avons examiné le rôle des +TIP dans la dégradation de la matrice, par les invadopodes, de petites protrusions riches en actine dégradant la matrice. La déplétion de EB1 et ses partenaires, APC et ACF7, régulaient négativement l’action des invadopodes, laissant supposer la présence d'un complexe fonctionnel : EB1, APC et ACF7 régulant négativement les invadopodes. En parallèle, par analyse protéomique systématique des composant des invadopodes, nous avons identifié de nouveaux proches voisins de TKS5, protéines indispensable à la formation des invadopodes, dont une protéine associée aux MT, MAP4. Au total, la régulation de la dynamique des +TIP est importante pour la migration et l'invasion et développer des stratégies ciblées contre ces acteurs pourrait améliorer la prise en charge du cancer du sein métastatique.Migration and invasion are key steps in the metastatic cascade. Microtubules (MT) are involved in cell division and are dammaged by MT tagetting agents(MTA), a widely used chemotherapy drugs. MT are dynamic structures anchored to peripheral cell structures. During this work, I studied how proteins that regulates the "+" end of MT (+ TIP) cell migration and extracellular matrix degradation. First I adressed the impact of eribulin, a new depolymerizing MTA, on mammary cell migration. Eribulin was found to prevent the anchoring of MT to cell cortex, to modify their dynamics and to inhibit cell migration, a phenomenon that we explained by its action on +TIP EB1 but more precisely by the delocalization of tubulin polymerase ch-TOG. Next we investigated the role of TIPs in invadopodia matrix degradation , which are actin-rich protrusion specialized in matrix digestion. The depletion of EB1 and its partners, APC and ACF7, negatively regulated the action of invadopodia, assumed the presence of a complex complex: EB1, APC and ACF7 negatively regulating invadopodia activity. In parallel, by systematic proteomic analysis of the component of the invadopodia, we identified new close neighbors of TKS5, an essential proteins in invadopodia formation, including a MT associated protein MAP4. In conclusion, the regulation of + TIP dynamics is important for migration and invasion and developping targeted strategies against them could improve the management of metastatic breast cancer

EB1 Restricts Breast Cancer Cell Invadopodia Formation and Matrix Proteolysis via FAK

International audienceRegulation of microtubule dynamics by plus-end tracking proteins (+TIPs) plays an essential role in cancer cell migration. However, the role of +TIPs in cancer cell invasion has been poorly addressed. Invadopodia, actin-rich protrusions specialized in extracellular matrix degradation, are essential for cancer cell invasion and metastasis, the leading cause of death in breast cancer. We, therefore, investigated the role of the End Binding protein, EB1, a major hub of the +TIP network, in invadopodia functions. EB1 silencing increased matrix degradation by breast cancer cells. This was recapitulated by depletion of two additional +TIPs and EB1 partners, APC and ACF7, but not by the knockdown of other +TIPs, such as CLASP1/2 or CLIP170. The knockdown of Focal Adhesion Kinase (FAK) was previously proposed to similarly promote invadopodia formation as a consequence of a switch of the Src kinase from focal adhesions to invadopodia. Interestingly, EB1-, APC-, or ACF7-depleted cells had decreased expression/activation of FAK. Remarkably, overexpression of wild type FAK, but not of FAK mutated to prevent Src recruitment, prevented the increased degradative activity induced by EB1 depletion. Overall, we propose that EB1 restricts invadopodia formation through the control of FAK and, consequently, the spatial regulation of Src activity

Medical Treatment of Lung Cancer: Can Immune Cells Predict the Response? A Systematic Review

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Assessment of biological effect of nab-paclitaxel combined with gemcitabine, using contrast enhanced ultrasonography and elastography, in advanced pancreatic ductal carcinoma: A single-center pilot study

International audienceEUS associated with contrast-enhanced harmonic EUS (CH-EUS) and EUS elastography (EUS-E) are used in clinical practice to assess pancreatic tumor at the diagnosis. In case of pancreatic ductal adenocarcinoma (PDAC) with liver metastasis, nab-paclitaxel combined with gemcitabine is a first-line treatment option. We aimed to assess the modification of PDAC microenvironment induced by the combination of nab-paclitaxel with gemcitabine, by endoscopic ultrasonography techinics. This single center phase III study conducted between February 2015 and June 2016 included patients with pancreatic adenocarcinoma with mesurable liver metastasis and no prior cancer treatment fit for two cycles of nab-paclitaxel combined with gemcitabine. We aimed to perform EUS with CH-EUS and EUS-E of the pancreatic tumor, CT scan and contrast enhanced ultrasonogram (CE-US) of a reference liver metastasis, before and after the two cylces of chemotherapy. Primary end point was modification of vascularizaion of primary tumor and a reference liver metastasis. Secondary end points were modification of stromal content, safety profile of drug combination and tumor response rate. Sixteen patients were analyzed, but only 13 received two cycled of chemotherapy (CT) (toxicity [n = 1] or death [n = 2]). There was no statistical modification induced by CT concering vascularity of primary tumor (time to maximum intensity P = 0.24, value of maximum intensity P = 0.71, hypoechogenic aspect generated by injection of contrast enhancing agent), vascularity of a reference liver metastasis (time to maximum intensity P = 0.99, value of maximum intensity P = 0.71) and tumor elasticity (P = 0.22). Eleven patients had tumor response assessement, 6/11 (54%) had measurable disease response 4/11 (36%) with partial responses and 2/11 (18%) with stable disease. All other patients showed disease progression. No serious side effects occurred, 6/11 patients had a dose adjustment. We did not show significant modification of vascularity and elasticity but these results should be taken with caution because of important limitations

Adoptive Cell Therapy in Hepatocellular Carcinoma: Biological Rationale and First Results in Early Phase Clinical Trials

International audienceThe mortality of hepatocellular carcinoma (HCC) is quickly increasing worldwide. In unresectable HCC, the cornerstone of systemic treatments is switching from tyrosine kinase inhibitors to immune checkpoints inhibitors (ICI). Next to ICI, adoptive cell transfer represents another promising field of immunotherapy. Targeting tumor associated antigens such as alpha-fetoprotein (AFP), glypican-3 (GPC3), or New York esophageal squamous cell carcinoma-1 (NY-ESO-1), T cell receptor (TCR) engineered T cells and chimeric antigen receptors (CAR) engineered T cells are emerging as potentially effective therapies, with objective responses reported in early phase trials. In this review, we address the biological rationale of TCR/CAR engineered T cells in advanced HCC, their mechanisms of action, and results from recent clinical trials

Place of anti-EGFR therapy in older patients with metastatic colorectal cancer in 2020

International audienceAlmost half of the new cases of colorectal cancer concern patients aged ≥70 years. However, very few clinical trials have specifically included older patients. As a consequence, the treatment of these patients is controversial because the balance between clinical benefits and toxicities remains uncertain. In patients without comorbidities and with an ECOG performance score of 0-1, treatment indications are similar to those of younger patients. For frail patients, chemotherapy is possible, but a comprehensive geriatric assessment is recommended. Anti-EGFR (epidermal growth factor receptor) therapy is indicated either in combination with chemotherapy in the first-line or second-line setting or as monotherapy in the third-line setting (i.e., after failure of chemotherapy). For fit older patients, clinical trials that compared chemotherapy alone with doublet chemotherapy plus anti-EGFR in either first-line or second-line setting suggested that age is not an absolute contraindication for the use of this regimen. In frail patients, anti-EGFR monotherapy in the first-line, second-line or third-line setting has shown feasibility and antitumor activity and had mainly cutaneous toxicities that were easily managed. In any case, administration of treatment must be very cautious in older patients and the treatment dose needs to be adapted according to comorbidities

A scoring system to guide the decision for a new systemic treatment after at least two lines of palliative chemotherapy for metastatic cancers: a prospective study

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A proximity-labeling proteomic approach to investigate invadopodia molecular landscape in breast cancer cells

International audienceMetastatic progression is the leading cause of mortality in breast cancer. Invasive tumor cells develop invadopodia to travel through basement membranes and the interstitial matrix. Substantial efforts have been made to characterize invadopodia molecular composition. However, their full molecular identity is still missing due to the difficulty in isolating them. To fill this gap, we developed a non-hypothesis driven proteomic approach based on the BioID proximity biotinylation technology, using the invadopodia-specific protein Tks5α fused to the promiscuous biotin ligase BirA* as bait. In invasive breast cancer cells, Tks5α fusion concentrated to invadopodia and selectively biotinylated invadopodia components, in contrast to a fusion which lacked the membrane-targeting PX domain (Tks5β). Biotinylated proteins were isolated by affinity capture and identified by mass spectrometry. We identified known invadopodia components, revealing the pertinence of our strategy. Furthermore, we observed that Tks5 newly identified close neighbors belonged to a biologically relevant network centered on actin cytoskeleton organization. Analysis of Tks5β interactome demonstrated that some partners bound Tks5 before its recruitment to invadopodia. Thus, the present strategy allowed us to identify novel Tks5 partners that were not identified by traditional approaches and could help get a more comprehensive picture of invadopodia molecular landscape

Soluble BTN2A1 Is a Potential Prognosis Biomarker in Pre-Treated Advanced Renal Cell Carcinoma

International audienceThe development of immune checkpoint inhibitors (ICI) has dramatically changed the landscape of therapies for metastatic renal cell carcinoma. However, many patients do not benefit from such therapy and prognostic or predictive validated biomarker validated for ICI are still needed to better select and treat patient. Plasmatic soluble immune checkpoints have been described as potential immune biomarkers in hematological malignancies and solids tumors, then, we would like to explore the prognostic value of different soluble immune checkpoints in patients with mRCC treated with nivolumab after TKI. We prospectively collected plasma samples before nivolumab infusion from 38 patients previously treated for mRCC with TKI at Paoli-Calmettes Institute, from the NIVOREN GETUG-AFU 26 study (NCT03013335). Enzyme-linked immunosorbent assays (ELISA) were performed for soluble forms of PD-1, PD-L1, global BTN3, BTLA, BTN3A1 and BTN2A1. Among the different soluble checkpoints analyzed, only high baseline plasmatic level of BTN2A1 was significantly associated with shorter PFS: median PFS was 3.95 months for sBTN2A1high vs 14.30 months for sBTN2A1low (sBTN2A1 cut-off: 6.7ng/mL; HR = 2.26, 95%CI [0.68 – 4.60], p = 0.0307). There was no statistical difference in OS between sBTN2A1high and sBTN2A1 low . Our results suggest that the baseline level of plasmatic BTN2A1 could be an independent prognosis factor of PFS after nivolumab for pre-treated patient with mRCC. However, these results need to be validated in a larger prospective cohort and the biological role of BTN subfamily and γδ T cell immunity in mRCC must be elucidated