Biology subjects

Christgen, M.

Publications and source records attributed to Christgen, M..

2 recordsLinked to original sources

bioRxiv2024

Deficient cell-cell cohesion is linked with lobular localization in simplified models of lobular carcinoma in situ (LCIS)

Lobular carcinoma in situ (LCIS) is a precursor of invasive lobular carcinoma of the breast. LCIS cells lack cell-cell cohesion due to the loss of E-cadherin. LCIS cells grow in mammary lobules rather than in ducts. The etiology of this pattern, especially its dependence on cellular cohesion, is incompletely understood. We simulated passive intra-glandular scattering of carcinoma in situ (CIS) cells in an ultra-simplified hollow mold tissue replica (HMTR) and a discrete-time mathematical model featuring particles of variable sizes representing single cells (LCIS-like particles) or groups of cohesive carcinoma cells (DCIS-like particles). The HMTR features structures reminiscent of a mammary duct with associated lobules. The discrete mathematical model characterizes spatial redistribution over time and includes transition probabilities between ductal or lobular localizations. Redistribution of particles converged toward an equilibrium depending on particle size. Strikingly, equilibrium proportions depended on particle properties, which we also confirm in a continuous-time mathematical model that considers controlling lobular properties such as crowding. Particles of increasing size, representing CIS cells with proficient cohesion, showed increasingly higher equilibrium ductal proportions. Our investigations represent two conceptual abstractions implying a link between loss of cell-cell cohesion and lobular localization of LCIS, which provide a much-needed logical foundation for studying the connections between collective cell behavior and cancer development in breast tissues. In light of the findings from our simplified modeling approach, we discuss multiple avenues for near-future research that can address and evaluate the redistribution hypothesis mathematically and empirically.

cancer biology↗

bioRxiv2023

Somatic mutation of Afadin leads to anchorage independent survival and metastatic growth of breast cancer through alpha E-catenin dependent destabilization of the adherens junction

Loss of E-cadherin (CDH1) and the adherens junction (AJ) drive development and progression of invasive lobular breast cancer (ILC). However, approximately 40% retain wild type CDH1 alleles, indicating that modulation of other genes attenuates the AJ during ILC etiology. To identify alternative drivers, we performed targeted sequencing in CDH1 wild type samples, based on a defined set of 100 AJ, tight junction, and desmosome genes we designated as the Adhesome. In 146 ILC samples, we identified 62 cases (43%) with wild type CDH1 alleles in which we detected a total of 284 mutations in 36 Adhesome genes. After selection based on occurrence and potential loss of function, we identified an inactivating frameshift mutation in Afadin (AFDN; p.Lys630fs). Functional studies in E-cadherin-expressing breast cancer cells showed that Afadin knockout leads to immature AJs, and a non-cohesive phenotype accompanied by actomyosin dependent anoikis resistance, which are classical ILC hallmarks. Afadin reconstitutions show that F-actin organization critically depends on the E-catenin binding CC domain. Afadin loss in intraductal xenograft mouse breast cancer models leads to ILC-type morphologies and overt lung metastases. AFDN truncate reconstitutions revealed that deletion of the C-terminal E-catenin binding CC domain is sufficient to drive metastatic ILC. In conclusion, we identified and functionally coupled a somatic frameshift AFDN mutation in breast cancer to destabilization the epithelial AJ and the development of ILC hallmarks such as actomyosin-dependent anoikis resistance and single cell invasion. As such, Afadin represents a candidate tumor suppressor for E-cadherin-positive ILC development and progression.

cancer biology↗