Biology subjects

Rahhal, R.

Publications and source records attributed to Rahhal, R..

4 recordsLinked to original sources

bioRxiv2026

Impact of Trastuzumab and Pertuzumab on HER2 Localization and the Estrogen Receptor Cistrome in ER+/HER2+ Breast Cancer

Background: Although anti-HER2 monoclonal antibody therapy with trastuzumab and pertuzumab is highly effective for HER2-positive breast cancer, co-expression of estrogen receptor (ER) significantly reduces pathologic complete response rates. Objective: We investigated how HER2-targeted inhibition affects HER2 cellular localization and ER genomic binding in ER-positive, HER2-positive breast cancer. Methods: We evaluated HER2 localization in a tissue microarray of treatment-naive patients. Using cellular fractionation, immunofluorescence, chromatin immunoprecipitation, and genome-wide profiling (CUT&RUN), we evaluated HER2 localization and ER genomic binding following acute anti-HER2 treatment and in models of treatment resistance. The treatment-induced ER-bound gene signature was assessed for associations with pathologic complete response and survival in breast cancer clinical cohorts. Results: In treatment-naive primary breast tumors, nuclear HER2 inversely correlated with ER levels. In cell models, treatment with trastuzumab and pertuzumab induced nuclear and chromatin accumulation of HER2. Concurrently, acute anti-HER2 treatment displaced ER from canonical estrogen response elements at classical target genes, yet genome-wide profiling revealed redistribution of ER binding toward non-canonical zinc finger motifs adjacent to pro-survival Wnt and RAGE pathway genes (FZD8, RELA). Expression of a drug-induced ER-bound gene signature was significantly higher in tumors of individuals who did not achieve pathologic complete response following neoadjuvant anti-HER2 therapy and significantly correlated with reduced distant metastasis-free survival in clinical cohorts. Conclusions: Anti-HER2 targeted therapy causes dynamic cistromic reprogramming of ER from classical estrogen pathways toward alternative pro-survival networks. These findings implicate ER redistribution as a possible mediator of resistance and highlight novel therapeutic targets in ER-positive, HER2-positive breast cancer.

cancer biology↗

bioRxiv2025

TEAD inhibition alters the lung immune microenvironment and attenuates metastasis.

The Hippo pathway signaling mediated through YAP/TAZ, and the transcription factor TEAD is known to be involved in primary tumor progression. Here we report that novel TEAD inhibitors (iTEAD) cause a significant reduction in the outgrowth of lung metastases from triple negative breast cancer (TNBC) models mediated predominantly through changes in stromal immune signaling. TEAD inhibition did not affect the proliferation of TNBC cancer cells in vitro or the growth of the primary tumor in vivo. In normal mice that were treated with iTEAD in the absence of tumors, the lungs showed a decrease in pro-tumor inflammatory pathways. However, the IL12 signaling pathway was enhanced and its production from isolated lung tissue resident macrophages, but not bone marrow derived macrophages, was elevated. In syngeneic TNBC mouse models, inhibition of TEAD suppressed pro-tumor inflammation and the M2-like macrophage phenotype in lung tissues, and increased the infiltration of CD8+ T cells into the lung as well as Th1 CD4+ T cells, restoring an immune responsive microenvironment. iTEAD-treated T cells showed enhanced cytotoxicity and degranulation when co-cultured with cancer cells via increased IL-2 activity. Furthermore, TEAD inhibition or knockdown, enhanced T-cell macrophage crosstalk and anti-tumor activity in 3D tumorspheres which was reversed by IL12 neutralizing antibodies. Our data supports a multifaceted model of TEAD inhibition on the innate and adaptive immune cells as they respond to tumor cell signals and reveals an important stromal phenotype by which TEAD inhibitors could reverse immune suppression and eliminate seeded metastases in the lungs.

cancer biology↗

bioRxiv2023

Loss of the mitochondrial citrate carrier, SLC25A1/CIC disrupts embryogenesis via 2-Hydroxyglutarate

Germline inactivating mutations of the SLC25A1 gene contribute to various human developmental disorders, including combined D/L-2-hydroxyglutaric aciduria (D/L-2HGA), a severe systemic syndrome characterized by the accumulation of both enantiomers of 2-hydroxyglutaric acid (2HG). The mechanisms by which SLC25A1 deficiency leads to this disease and the role of 2HG are unclear and no therapies exist. We now show that mice lacking both Slc25a1 alleles display a spectrum of alterations that resemble human D/L-2HGA. Mechanistically, SLC25A1 loss results in a proliferation defect and activates two distinct senescence pathways, oncogene-induced senescence (OIS) and mitochondrial dysfunction-induced senescence (MiDAS), both involving the p53 tumor suppressor and driven by two discernible signals: the accumulation of 2HG, inducing OIS, and mitochondrial dysfunction, triggering MiDAS. Inhibiting these senescence programs or blocking p53 activity reverses the growth defect caused by SLC25A1 dysfunction and restores proliferation. These findings reveal novel pathogenic roles of senescence in human disorders and suggest potential strategies to correct the molecular alterations caused by SLC25A1 loss.

developmental biology↗

bioRxiv2020

Fra1 is required for TGFβ1 induced collective invasion

Phenotypic heterogeneity promotes tumor evolution and confounds treatment. Minority subpopulations of trailblazer cells enhance the heterogeneity of invading populations by creating paths in extracellular matrix (ECM) that permit the invasion of phenotypically diverse siblings. The regulatory programs that induce a trailblazer state are poorly understood. Here, we define a new Tgf{beta} induced trailblazer population that is more aggressive than previously characterized Keratin 14 expressing trailblazer cells. Rather than triggering a binary switch to a single trailblazer state, Tgf{beta} induced multiple unique states that were distinguished by their expression of regulatory transcription factors, genes involved in ECM reorganization and capacity to initiate collective invasion. The integration of a parallel Egfr signaling program was necessary to induce pro-motility genes and could be targeted with clinically approved drugs to prevent trailblazer invasion. Surprisingly, Egfr pathway activity also had the collateral consequence of antagonizing the expression of a cohort of Tgf{beta} induced genes, including a subset involved in ECM remodeling. Together, our results reveal a new compromise mode of signal integration that promotes a trailblazer state and can be therapeutically targeted to prevent collective invasion.

cancer biology↗