Pathways Involved in Formation of Mammary Organoid Architecture Have Keys to Understanding Drug Resistance and to Discovery of Druggable Targets

Abstract

Signals from the extracellular matrix (ECM) are received at the cell surface receptor, transmitted to the cytoskeletons, and transferred to the nucleus and chromatin for tissue-and context-specific gene expression. Cells, in return, modulate the cell shape and ECM, allowing for the maintenance of tissue homeostasis as well as for coevolution and adaptation to the environmental signals. We postulated the existence of dynamic and reciprocal interactions between the ECM and the nucleus more than three decades ago, but now these pathways have been proven experimentally thanks to the advances in imaging and cell/molecular biology techniques. In this review, we will introduce some of our recent work that has validated the critical roles of the three-dimensional (3D) tissue architecture in determining mammary biology, therapeutic response, and druggable targets. We describe a novel screen based on reversion of the malignant phenotype in 3D assays. We will also summarize our recent discoveries of the integration of feedback signaling for mammary acinar formation and phenotypic reversion of tumor cells in the LrECM. Lastly, we will introduce our exciting discovery of the physical linkages between the cell surface and cytofibers within a tunnel deep inside of the nucleus, enabling interaction with nuclear lamin and SUN proteins.

Melflufen, a peptide‐conjugated alkylator, is an efficient anti‐neo‐plastic drug in breast cancer cell lines

“…This is in agreement with previous studies that have shown that cellular behavior and drug sensitivity is different between 2D and 3D conditions. [8][9][10][11] Cells cultured in 2D have lost their polarity and their differentiation profile is different from the one seen in vivo resulting in altered cell signaling and gene expression, which eventually may affect drug sensitivity. 12,13 In contrast, cells cultured in 3D microenvironment in vitro can capture phenotypes as evidenced by the generation of structures akin to the condition in tissues and organs in the human body.…”

“…9 These isogenic cell lines have been used to study the molecular mechanism of branching morphogenesis and cancer progression in the breast gland. 2,[9][10][11][12] Melphalan is a well-known cancer drug used for decades for the treatment of various cancer types, and it is still widely used for hematological cancers today. 13 It is an alkylating agent that works by adding an alkyl group to the guanine base of the DNA, resulting in an aberrant linkage between DNA strands, DNA breakage, and inhibition of DNA synthesis.…”

Radial Profile Analysis of Epithelial Polarity in Breast Acini: A Tool for Primary (Breast) Cancer Prevention

“…Acini cultures recapitulate important characteristics of the normal mammary gland, namely single cell-layered structures, proliferation arrest (90-95% Ki67negative cells) and apical-basal polarity (37,38). Signaling pathways are dramatically rewired in 3D acini cultures (39). Moreover, nuclear organization features, such as gene positioning and nucleoskeletal arrangement are strikingly different in acini cultures compared to 2D monolayer cultures (40,41).…”

Integrating Biophysics in Toxicology

“…For example, several studies underline an intimate relationship between cancer and ECM [61][62][63][64]. ECM stiffness was related to crucial parameters in cell resistance such as i) chemotherapeutics availability, ii) epithelial mesenchymal transition (EMT), and iii) regulation of oncogenic signaling pathways [65], thus highlighting ECM as an essential player in determining tumor progression [66,67]. Moreover, high-density tumor-specific ECM can hinder the T-cells proliferation and infiltration, without affecting cancer cells [68].…”