Wnt/ß-Catenin Inhibition Disrupts Carboplatin Resistance in Isogenic Models of Triple-Negative Breast Cancer.

Triple-Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype, characterized by 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/ß-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.

PPP2R4 dysfunction promotes KRAS-mutant lung adenocarcinoma development and mediates opposite responses to MEK and mTOR inhibition.

KRAS-mutant lung adenocarcinomas represent the largest molecular subgroup of non-small cell lung cancers (NSCLC) and are notorious for their dismal survival perspectives. To gain more insights in etiology and therapeutic response, we focused on the tumor suppressor Protein Phosphatase 2A (PP2A) as a player in KRAS oncogenic signaling. We report that the PP2A activator PTPA (encoded by PPP2R4) is commonly affected in NSCLC by heterozygous loss and low-frequent loss-of-function mutation, and this is specifically associated with poorer overall survival of KRAS-mutant lung adenocarcinoma patients. Reduced or mutant PPP2R4 expression in A549 cells increased anchorage-independent growth in vitro and xenograft growth in vivo, correlating with increased Ki67 and c-MYC expression. Moreover, KrasG12D-induced lung tumorigenesis was significantly accelerated in Ppp2r4 gene trapped mice as compared to Ppp2r4 wild-type. A confined kinase inhibitor screen revealed that PPP2R4-depletion induced resistance against selumetinib (MEK inhibitor), but unexpectedly sensitized cells for temsirolimus (mTOR inhibitor), in vitro and in vivo. Our findings underscore a clinically relevant role for PTPA loss-of-function in KRAS-mutant NSCLC etiology and kinase inhibitor response.

Ether-Oxygen Containing Electrospun Microfibrous and Sub-Microfibrous Scaffolds Based on Poly(butylene 1,4-cyclohexanedicarboxylate) for Skeletal Muscle Tissue Engineering.

We report the study of novel biodegradable electrospun scaffolds from poly(butylene 1,4-cyclohexandicarboxylate-co-triethylene cyclohexanedicarboxylate) (P(BCE-co-TECE)) as support for in vitro and in vivo muscle tissue regeneration. We demonstrate that chemical composition, i.e., the amount of TECE co-units (constituted of polyethylene glycol-like moieties), and fibre morphology, i.e., aligned microfibrous or sub-microfibrous scaffolds, are crucial in determining the material biocompatibility. Indeed, the presence of ether linkages influences surface wettability, mechanical properties, hydrolytic degradation rate, and density of cell anchoring points of the studied materials. On the other hand, electrospun scaffolds improve cell adhesion, proliferation, and differentiation by favouring cell alignment along fibre direction (fibre morphology), also allowing for better cell infiltration and oxygen and nutrient diffusion (fibre size). Overall, C2C12 myogenic cells highly differentiated into mature myotubes when cultured on microfibres realised with the copolymer richest in TECE co-units (micro-P73 mat). Lastly, when transplanted in the tibialis anterior muscles of healthy, injured, or dystrophic mice, micro-P73 mat appeared highly vascularised, colonised by murine cells and perfectly integrated with host muscles, thus confirming the suitability of P(BCE-co-TECE) scaffolds as substrates for skeletal muscle tissue engineering.