Project description:Integrative analysis of primary estrogen receptor-positive (ER+) breast cancer, triple-negative breast cancer (TNBC), and metaplastic breast cancer (MBC) tumors using Starfysh.
Project description:Deciphering breast cancer treatment resistance remains hindered by the lack of models that can successfully capture the four-dimensional dynamics of the tumor microenvironment. Here, we show that microextrusion bioprinting can reproducibly produce distinct cancer and stromal compartments integrating cells relevant to human pathology. Our findings unveil the functional maturation of this millimeter-sized model, showcasing the development of a hypoxic cancer core and an increased surface proliferation. Maturation was also driven by the presence of cancer-associated fibroblasts (CAF) that induced elevated microvascular-like structures complexity. Such modulation was concomitant to extracellular matrix remodeling, with high levels of collagen and matricellular proteins deposition by CAF, simultaneously increasing tumor stiffness and recapitulating breast cancer fibrotic development. Importantly, our bioprinted model faithfully reproduced response to treatment, further modulated by CAF. Notably, CAF played a protective role for cancer cells against radiotherapy, facilitating increased paracrine communications. This model holds promise as a platform to evaluate microenvironment targeting drugs in a human pathology relevant context, that could lead to significant improvements for patient care.
Project description:Intratumor heterogeneity is one of the hallmarks of cancers, including breast cancers. We performed spatial transcriptomics to profile heterogeneous cell populations within ER+ breast cancers as well as to determine their importance for estrogen-dependent tumor growth. Our analysis has revealed the key functional compartments for developing targeted therapeutic strategies against ER+ breast cancers.
Project description:The fibrotic kidney microenvironment is shaped by cellular crosstalk, extracellular matrix (ECM) remodeling, metabolic reprogramming, and spatial heterogeneity. While late-stage ECM changes dominate fibrosis, the role of early-activated matrix proteins remains unclear. Here, we identified Ecm1 as an early regulator of kidney remodeling. Global Ecm1 knockout mice develop spontaneous fibrosis and early death, whereas Ecm1 levels markedly increase in biofluids during CKD. Targeting Ecm1 by AAV9-mediated knockdown or fibroblast-specific deletion substantially reduces renal fibrosis. Mechanistically, Ecm1 deletion disrupts the integrin α2β1-RhoC axis, suppressing Yap activity. Reduced Yap nuclear translocation and diminished Yap-Tead4 complex formation relieve Tead4-mediated repression of Pgc1α, enhancing mitochondrial OXPHOS and promoting repair. Spatial transcriptomics and proteomics confirm this mechano-metabolic pathway, revealing mitochondrial reprogramming in tubules that counteracts fibrotic progression. Notably, fibroblast Yap inactivation limits aberrant activation without impairing their OXPHOS. This selective ECM-mitochondrial crosstalk uncovers a mechano-metabolic pathway where mitochondrial shifts drive defense against kidney fibrosis.
Project description:The mouse uterine microenvironment at pregnancy D7.5 was investigated by Visium spatial transcriptome. Ten distinct uterine microenvironments were identified with diverse biological functions, different endocrine regulations and intensive interactions. The single cell RNA-seq of D7.5 mouse uterus has been intergrated with the spatial visium results and predicted the presence of mutiple types of cells in each microenvironment.