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Abstract Solid tumors develop within a complex environment called the tumor microenvironment (TME), which is sculpted by the presence of other cells, such as cancer‐associated fibroblasts (CAFs) and immune cells like macrophages (Mφs). Despite the presence of immune cells, tumor cells orchestrate a tumor‐supportive environment through intricate interaction with the components of the TME. However, the specific mechanism by which this intercellular dialogue is regulated is not fully understood. To that end, the development of an organotypic 3D breast TME‐on‐a‐chip (TMEC) model, integrated with single‐cell RNA sequencing analysis, is reported to mechanistically evaluate the progression of triple‐negative breast cancer (TNBC) cells in the presence of patient‐derived CAFs and Mφs. Extensive functional assays, including invasion and morphometric characterization, reveal the synergistic influence of CAFs and Mφs on tumor cells. Furthermore, gene expression and pathway enrichment analyses identify the involvement of theKYNUgene, suggesting a potential immune evasion mechanism through the kynurenine pathway. Lastly, the pharmacological targeting of the identified pathway is investigated. 

Abstract Mutations in theTP53tumor suppressor gene occur in >80% of the triple-negative or basal-like breast cancer. To test whether neomorphic functions of specificTP53missense mutations contribute to phenotypic heterogeneity, we characterized phenotypes of non-transformed MCF10A-derived cell lines expressing the ten most common missense mutant p53 proteins and observed a wide spectrum of phenotypic changes in cell survival, resistance to apoptosis and anoikis, cell migration, invasion and 3D mammosphere architecture. The p53 mutants R248W, R273C, R248Q, and Y220C are the most aggressive while G245S and Y234C are the least, which correlates with survival rates of basal-like breast cancer patients. Interestingly, a crucial amino acid difference at one position—R273C vs. R273H—has drastic changes on cellular phenotype. RNA-Seq and ChIP-Seq analyses show distinct DNA binding properties of different p53 mutants, yielding heterogeneous transcriptomics profiles, and MD simulation provided structural basis of differential DNA binding of different p53 mutants. Integrative statistical and machine-learning-based pathway analysis on gene expression profiles with phenotype vectors across the mutant cell lines identifies quantitative association of multiple pathways including the Hippo/YAP/TAZ pathway with phenotypic aggressiveness. Further, comparative analyses of large transcriptomics datasets on breast cancer cell lines and tumors suggest that dysregulation of the Hippo/YAP/TAZ pathway plays a key role in driving the cellular phenotypes towards basal-like in the presence of more aggressive p53 mutants. Overall, our study describes distinct gain-of-function impacts on protein functions, transcriptional profiles, and cellular behaviors of different p53 missense mutants, which contribute to clinical phenotypic heterogeneity of triple-negative breast tumors. 

Abstract Let X be a simply connected closed oriented manifold of rationally elliptic homotopy type. We prove that the string topology bracket on the $S^1$ -equivariant homology $$ {\overline {\text {H}}}_\ast ^{S^1}({\mathcal {L}} X,{\mathbb {Q}}) $$ of the free loop space of X preserves the Hodge decomposition of $$ {\overline {\text {H}}}_\ast ^{S^1}({\mathcal {L}} X,{\mathbb {Q}}) $$ , making it a bigraded Lie algebra. We deduce this result from a general theorem on derived Poisson structures on the universal enveloping algebras of homologically nilpotent finite-dimensional DG Lie algebras. Our theorem settles a conjecture of [7]. 

By a fundamental theorem of D. Quillen, there is a natural duality - an instance of general Koszul duality - between differential graded (DG) Lie algebras and DG cocommutative coalgebras defined over a field k of characteristic 0. A cyclic pairing (i.e., an inner product satisfying a natural cyclicity condition) on the cocommutative coalgebra gives rise to an interesting structure on the universal enveloping algebra Ua of the Koszul dual Lie algebra a called the derived Poisson bracket. Interesting special cases of the derived Poisson bracket include the Chas-Sullivan bracket on string topology. We study the derived Poisson brackets on universal enveloping algebras Ua, and their relation to the classical Poisson brackets on the derived moduli spaces DRep_g(a) of representations of a in a finite dimensional reductive Lie algebra g. More specifically, we show that certain derived character maps of a intertwine the derived Poisson bracket with the classical Poisson structure on the representation homology HR(a, g) related to DRep_g(a).