Biology subjects

Behbod, F.

Publications and source records attributed to Behbod, F..

3 recordsLinked to original sources

bioRxiv2026

Cellular stemness identifies high-risk ductal carcinoma in situ and offers a therapeutic interception opportunity

Ductal carcinoma in situ (DCIS) exhibits substantial heterogeneity in its risk of progression to invasive breast cancer, yet the cellular and molecular determinants of high-risk lesions remain incompletely defined. Using spatially resolved single-cell transcriptomic and epigenomic profiling of 43 patient-derived DCIS and DCIS/invasive ductal carcinoma (IDC) samples, we delineate cellular programs, spatial organization, and epigenetic regulatory mechanisms associated with invasive potential. We identify an epithelial population with stemness features within luminal hormone-responsive (LumHR) cells that progressively expands from benign tissue to DCIS and IDC, and is strongly associated with invasive progression and recurrence-linked transcriptional programs. Spatial mapping reveals discrete DCIS niches enriched for stem-like LumHR cells, characterized by elevated CEACAM6 expression and enhanced ligand-receptor interactions, including CEACAM6-EGFR signaling between epithelial and stromal compartments, including cancer-associated fibroblasts, macrophages (APOC1-positive) and perivascular cells. These niches define a microenvironmental context that supports stemness and invasive potential. Epigenomic analyses implicate FOXA1 as a key regulator of these stem-like transcriptional states. Pharmacologic disruption of FOXA1-regulatory network using LSD1 inhibition suppresses stemness-associated transcriptional programs in vitro and significantly restrains tumor growth in vivo. Collectively, these findings define high-risk DCIS as a stemness-driven disease embedded within specialized microenvironments, and identify associated regulatory networks as candidate biomarkers and therapeutic vulnerabilities.

cancer biology↗

bioRxiv2024

Preferential Release of microRNAs via Extracellular Vesicles is Associated with Ductal Carcinoma In Situ to Invasive Breast Cancer Progression

Ductal carcinoma in situ (DCIS) is a benign "pre-cancer" that increases the risk of invasive breast cancer (IBC). Not all DCIS progress to IBC, and the primary factors driving progression remain unclear. Small extracellular vesicles (sEVs) or exosomes are known to play a role in advanced cancers, but their involvement in DCIS is poorly understood. This study examined the role of sEVs and their RNA content in DCIS progression. Rab27A, which regulates exosome release, is elevated in DCIS and IBC tissues compared with normal breast tissues. Inhibition of sEV release via Rab27A knockdown alters pro-invasive pathways and reduces invasion in a DCIS mouse model. Using the isogenic MCF10 breast cancer progression series, we found a significant increase in microRNAs (miRNAs) in sEVs from normal to malignant states, with the highest number of differentially expressed miRNAs in IBC sEVs compared with DCIS sEVs. In vivo, DCIS invasive progression elevated circulating sEV miRNA levels, which decreased upon Rab27A knockdown. Re-expression of miR-205, preferentially loaded into IBC sEVs, reduced proliferation, invasion, and EMT marker expression in DCIS cells. Combined Rab27A knockdown and miR-205 expression repressed TGF-{beta} signaling, activated p38, and induced cell cycle arrest and cell death. These findings illustrate that sEVs and their miRNAs promote DCIS progression, and the reintroduction of miR-205 in DCIS cells can inhibit invasive progression.

cancer biology↗

bioRxiv2019

Semaphorin 7a dependent programs of cell surivival, matrix remodeling, and EMT drive postpartum breast tumor progression

Young women diagnosed with breast cancer (BC) have poor prognosis due to increased rates of metastasis. Additionally, women within 10 years of most recent childbirth at diagnosis are [~]3 times more likely to develop metastasis than age and stage matched nulliparous women. We define these cases as postpartum BC (PPBC) and propose that the unique biology of the postpartum mammary gland drives tumor progression. Our published results revealed roles for SEMA7A in breast tumor cell growth, motility, invasion, and tumor associated-lymphangiogenesis, all of which are also increased in pre-clinical models of PPBC. However, whether SEMA7A drives progression in PPBC remains largely unexplored. Our results presented herein show that silencing of SEMA7A decreases tumor growth in a model of PPBC while overexpression is sufficient to increase growth in nulliparous hosts. Further, we show that SEMA7A promotes multiple known drivers of PPBC progression including tumor associated COX-2 expression and fibroblast-mediated collagen deposition in the tumor microenvironment. Additionally, we show for the first time that SEMA7A expressing cells deposit fibronectin to promote tumor cell survival. Finally, we show that co-expression of SEMA7A/COX-2/FN predicts for poor prognosis in breast cancer patient cohorts. These studies suggest SEMA7A as a key mediator of BC progression and that targeting SEMA7A may open avenues for novel therapeutic strategies.

cancer biology↗