Biology subjects

Yui, A.

Publications and source records attributed to Yui, A..

5 recordsLinked to original sources

bioRxiv2026

Targeting fibroblast activation suppresses chemotherapy-induced pro-invasive remodeling of the extracellular matrix

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that accounts for nearly 20% of breast cancer diagnoses. Despite recent approvals of novel therapeutic agents for TNBC, neoadjuvant chemotherapy remains part of standard of care treatment for TNBC patients. However, approximately 60% of TNBC patients who received neoadjuvant chemotherapy fail to achieve pathological complete response and face significantly elevated risks of recurrence and distant metastasis. We have shown that chemotherapy can induce significant changes in TNBC tumor extracellular matrix (ECM) that drive tumor cell invasion and may contribute to recurrence. Here, we investigate how chemotherapy drugs can impact resident fibroblasts, the major generators of ECM in the breast tissue. We find that chemotherapy activates fibroblasts and that doxorubicin specifically induces the production of pro-invasive ECM by fibroblasts via TGF-{beta}/Smad3 signaling. An FDA-approved tyrosine kinase inhibitor nintedanib suppressed doxorubicin-induced fibroblast activation and pro-invasive ECM production by fibroblasts in vitro. Additionally, in a TNBC mouse model, nintedanib reduced fibroblast activation markers in tumors, suppressed tumor cell motility in the tumor ECM, and reduced lung metastasis. These findings demonstrate a novel mechanism by which chemotherapy can induce fibroblast activation and imply that targeting fibroblast activation reduces chemotherapy-induced metastasis in TNBC.

cancer biology↗

bioRxiv2025

Cell-line specific role of Cathepsin B in triple-negative breast cancer growth, invasion and response to chemotherapy

Cathepsins are papain-family cysteine proteases known to play a cell-intrinsic role in protein degradation in the lysosome, as well as in digesting ECM and surface proteins after being secreted. Both of these functions are known to mediate pro-tumorigenic effects of CTSB in a range of cancers. Here, we specifically investigate the role of CTSB in TNBC, an aggressive subtype of breast cancer, where we find that high expression of CTSB in TNBC is associated with better outcomes. We used CRISPR to knockout CTSB in two highly metastatic TNBC cell lines, MDA-MB-231 and MDA-MB-468, and find different effects. In MDA-MB-231 cells, knockout of CTSB has no effect on cell viability, increases tumor cell 3D invasion in an ECM-independent manner, and increases sensitivity to many standard of care chemotherapy drugs. However, in MDA-MB-468 cells, knockout of CTSB increases cell viability, decreases tumor cell 3D invasion, in an ECM-independent manner, and drives resistance to certain chemotherapy drugs without affecting response to others. We find that in these cells, CTSB is not secreted, and that differential downstream mTOR and Akt activation can explain the differences seen in these phenotypes. Overall, our studies demonstrate that CTSB can regulate TNBC cell phenotypes via its lysosomal cell-intrinsic role, but that effects are cell-line specific, suggesting potential heterogeneity in the role of CTSB in TNBC.

cancer biology↗

bioRxiv2023

Cell morphology best predicts tumorigenicity and metastasis in vivo across multiple TNBC cell lines of different metastatic potential

BackgroundMetastasis is the leading cause of death in breast cancer patients. For metastasis to occur, tumor cells must invade locally, intravasate, and colonize distant tissues and organs, all steps that require tumor cell migration. The majority of studies on invasion and metastasis rely on human breast cancer cell lines. While it is known that these cells have different properties and abilities for growth and metastasis, the in vitro morphological, proliferative, migratory, and invasive behavior of these cell lines and their correlation to in vivo behavior is poorly understood. Thus, we sought to classify each cell line as poorly or highly metastatic by characterizing tumor growth and metastasis in a murine model of six commonly used human triple-negative breast cancer xenografts, as well as determine which in vitro assays commonly used to study cell motility best predict in vivo metastasis. MethodsWe evaluated the liver and lung metastasis of human TNBC cell lines MDA-MB-231, MDA-MB-468, BT549, Hs578T, BT20, and SUM159 in immunocompromised mice. We characterized each cell lines cell morphology, proliferation, and motility in 2D and 3D to determine the variation in these parameters between cell lines. ResultsWe identified MDA-MB-231, MDA-MB-468, and BT549 cells as highly tumorigenic and metastatic, Hs578T as poorly tumorigenic and metastatic, BT20 as intermediate tumorigenic with poor metastasis to the lungs but highly metastatic to the livers, and SUM159 as intermediate tumorigenic but poorly metastatic to the lungs and livers. We showed that metrics that characterize cell morphology are the most predictive of tumor growth and metastatic potential to the lungs and liver. Further, we found that no single in vitro motility assay in 2D or 3D significantly correlated with metastasis in vivo. ConclusionsOur results provide an important resource for the TNBC research community, identifying the metastatic potential of 6 commonly used cell lines. Our findings also support the use of cell morphological analysis to investigate the metastatic potential and emphasize the need for multiple in vitro motility metrics using multiple cell lines to represent the heterogeneity of metastasis in vivo.

cancer biology↗

bioRxiv2022

Molecular mechanism underlying the increased risk of colorectal cancer metastasis caused by single nucleotide polymorphisms in LI-cadherin gene

LI-cadherin is a member of the cadherin superfamily. LI-cadherin mediates Ca2+-dependent cell-cell adhesion by forming a homodimer. A previous study reported two single nucleotide polymorphisms (SNPs) in the LI-cadherin-coding gene (CDH17). These SNPs correspond to the amino acid changes of Lys115 to Glu and Glu739 to Ala. Patients with colorectal cancer carrying these SNPs are reported to have a higher risk of lymph node metastasis than patients without the SNPs. Although proteins associated with metastasis have been identified, the molecular mechanisms underlying the functions of these proteins remain unclear, making it difficult to develop effective strategies to prevent metastasis. In this study, we employed biochemical assays and molecular dynamics (MD) simulations to elucidate the molecular mechanisms by which the amino acid changes caused by SNPs in the LI-cadherin-coding gene increase the risk of cancer metastasis. Cell aggregation assays showed that the amino acid changes weakened the LI-cadherin-dependent cell-cell adhesion. In vitro assays demonstrated a decrease in homodimerization tendency due to the mutation of Lys115, and MD simulations suggested an alteration in the intramolecular hydrogen bond network due to the amino acid change. Taken together, our results indicate that the increased risk of lymph node metastasis is due to weakened cell-cell adhesion caused by the decrease in homodimerization tendency.

biochemistry↗

bioRxiv2020

Dimerization mechanism and structural features of human LI-cadherin

LI-cadherin is a member of the cadherin superfamily, which encompasses a group of Ca2+-dependent cell adhesion proteins. The expression of LI-cadherin is observed on various types of cells in the human body, such as normal small intestine and colon cells, and gastric cancer cells. Because its expression is not observed on normal gastric cells, LI-cadherin is a promising target for gastric cancer imaging. However, since the cell adhesion mechanism of LI-cadherin has remained unknown, rational design of therapeutic molecules targeting this cadherin has been hampered. Here, we have studied the homodimerization mechanism of LI-cadherin. We report the crystal structure of the LI-cadherin EC1-4 homodimer. The EC1-4 homodimer exhibited a unique architecture different from that of other cadherins reported so far. The crystal structure also revealed that LI-cadherin possesses a noncanonical calcium ion-free linker between EC2 and EC3. Various biochemical techniques and molecular dynamics (MD) simulations were employed to elucidate the mechanism of homodimerization. We also showed that the formation of the homodimer observed by the crystal structure is necessary for LI-cadherin-dependent cell adhesion by performing cell aggregation assay.

biochemistry↗