Biology subjects

Saladi, S. V.

Publications and source records attributed to Saladi, S. V..

5 recordsLinked to original sources

bioRxiv2025

YAP1 drives aggressive and therapy resistant state in melanoma through reprogramming the chromatin and regulating immune evasive programs

Despite promising initial results in targeting the RAF-MEK-ERK cascade, resistance to BRAF/MEK inhibitors remains a critical challenge in nearly 50% of melanoma patients. Our study demonstrates that robust YAP1 activation in metastatic melanoma correlates with poor survival and drives transcriptional programs linked to therapeutic resistance. Mechanistically, YAP1 predominantly remodels the chromatin landscape in resistant tumors by partnering with BRD4 and TEAD, creating a permissive transcriptional state that sustains oncogenic signaling. Clinical validation in biopsies from resistant melanoma confirms elevated expression of YAP1 target genes. Furthermore, pharmacological inhibition of BRD4 or TEAD reduces YAP1-driven transcription and reactivates antitumor immunity programs. TEAD specific inhibitors (and not verteporfin which is a highly non-specific inhibitor) synergize with immune checkpoint blockade in in vivo model system by promoting increased CD8 T cell infiltration and prolonged survival in the melanoma mouse model. Collectively, these findings reveal a chromatin-centric vulnerability in BRAF/MEK inhibitor-resistant melanoma and propose TEAD specific inhibitors as a promising dual strategy to overcome resistance and reinvigorate the immune response, offering a novel therapeutic avenue for patients. Resistance to BRAF and MEK inhibitors remains a major obstacle in the treatment of melanoma. Here, we show that elevated YAP1 activity in metastatic melanoma is associated with poor patient survival and drives transcriptional programs that promote therapeutic resistance. Mechanistically, YAP1 cooperates with BRD4 and TEAD to reprogram the chromatin landscape, establishing an oncogenic transcriptional state that sustains resistance. Analysis of patient-derived melanoma biopsies confirms increased expression of YAP1 target genes in resistant tumors. Targeting this epigenetic circuitry using pharmacological inhibitors of BRD4 or TEAD effectively suppresses YAP1-driven transcriptional output and restores antitumor immune activity, as evidenced by enhanced CD8 T cell infiltration and prolonged survival in resistant melanoma models. These effects are further supported by transcriptomic and chromatin accessibility analyses, which reveal reduced expression of immune-suppressive and proliferation-associated gene networks upon TEAD inhibition. Collectively, our findings identify a chromatin-centric mechanism underlying resistance to MAPK-targeted therapy and nominate TEAD inhibition as a promising dual-action strategy to both overcome resistance and re-engage antitumor immunity. This work offers a compelling therapeutic avenue for patients with drug-resistant melanoma.

cancer biology↗

bioRxiv2024

Impact of PI3K pathway alterations on response to immune checkpoint inhibitors in HPV-negative head and neck squamous cell carcinoma

Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway (PI3K pathway) is a major intracellular regulatory pathway commonly involved in cancer survival, proliferation, migration, and metabolism. Activating mutations and amplifications of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) are frequent genomic features of head and neck squamous cell carcinoma (HNSCC). A growing body of evidence suggests that dysregulation of the PI3K pathway suppresses the anti-tumor immune response, thereby enabling tumor immune evasion. We retrospectively analyzed clinicopathologic and genomic data of patients with recurrent or metastatic (R/M) HNSCC treated with immune checkpoint inhibitors (ICI). PI3K pathway alterations were found in 44% and were associated with poor clinical outcomes in the human papillomavirus-negative (HPV-ve) HNSCC patients. PIK3CA expression was found to be inversely correlated with immune gene expression, decreased T-cell infiltration, and reduced CD8 T-cell cytotoxic activity. The pharmacologic inhibition of the PI3K pathway induced an increase in key immune-responsive gene expression in PIK3CA-mutant HPV-ve HNSCC cells. These findings suggest that the PI3K pathway activation promotes immune suppressive phenotype, and playing a role in conferring resistance to immune checkpoint inhibitors in HPV-ve subset of HNSCC patients. HighlightsAlterations in PI3K pathway are associated with poor clinical outcomes in HPV-negative HNSCC patients treated with immune checkpoint therapy. PI3K pathway activation correlates to immune suppressive tumor microenvironment in HNSCC. Pharmacologic inhibition of PI3K induces the expression of interferon-gamma responsive and antigen presentation machinery genes in HNSCC.

cancer biology↗

bioRxiv2023

A deep lung cell atlas reveals cytokine-mediated lineage switching of a rare cell progenitor of the human airway epithelium

The human airway contains specialized rare epithelial cells whose roles in respiratory disease are not well understood. Ionocytes express the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), while chemosensory tuft cells express asthma-associated alarmins. However, surprisingly, exceedingly few mature tuft cells have been identified in human lung cell atlases despite the ready identification of rare ionocytes and neuroendocrine cells. To identify human rare cell progenitors and define their lineage relationship to mature tuft cells, we generated a deep lung cell atlas containing 311,748 single cell RNA-Seq (scRNA-seq) profiles from discrete anatomic sites along the large and small airways and lung lobes of explanted donor lungs that could not be used for organ transplantation. Of 154,222 airway epithelial cells, we identified 687 ionocytes (0.45%) that are present in similar proportions in both large and small airways, suggesting that they may contribute to both large and small airways pathologies in CF. In stark contrast, we recovered only 3 mature tuft cells (0.002%). Instead, we identified rare bipotent progenitor cells that can give rise to both ionocytes and tuft cells, which we termed tuft-ionocyte progenitor cells (TIP cells). Remarkably, the cycling fraction of these TIP cells was comparable to that of basal stem cells. We used scRNA-seq and scATAC-seq to predict transcription factors that mark this novel rare cell progenitor population and define intermediate states during TIP cell lineage transitions en route to the differentiation of mature ionocytes and tuft cells. The default lineage of TIP cell descendants is skewed towards ionocytes, explaining the paucity of mature tuft cells in the human airway. However, Type 2 and Type 17 cytokines, associated with asthma and CF, diverted the lineage of TIP cell descendants in vitro, resulting in the differentiation of mature tuft cells at the expense of ionocytes. Consistent with this model of mature tuft cell differentiation, we identify mature tuft cells in a patient who died from an asthma flare. Overall, our findings suggest that the immune signaling pathways active in asthma and CF may skew the composition of disease-relevant rare cells and illustrate how deep atlases are required for identifying physiologically-relevant scarce cell populations.

cell biology↗

bioRxiv2022

Nuclear autophagy interactome unveils WSTF as a constitutive nuclear inhibitor of inflammation

Macroautophagy (hereafter referred to as autophagy) degrades a variety of cellular components. A poorly understood area is autophagic degradation of nuclear substrates, or "nuclear autophagy". It remains unclear what can be degraded by autophagy from the mammalian nuclei. We began our study by investigating the nuclear binding partners of ATG8 family proteins that play important roles in recognizing autophagy substrates. We systematically evaluated the ATG8 nuclear interactome in primary human cells and in mouse brain, identifying hundreds of novel interactions. We continued our study by evaluating the nuclear proteomes of cellular senescence, a stable form of cell cycle arrest program associated with inflammation, in which nuclear autophagy is involved. Combined with the ATG8 nuclear interactome data, we identified WSTF, a component of the ISWI chromatin remodeling complex, as a novel substrate of nuclear autophagy. The degradation of WSTF, mediated by a direct interaction with the GABARAP isoform of ATG8, promotes chromatin accessibility of inflammatory genes and induces senescence-associated inflammation. Furthermore, WSTF directly binds the p65 subunit of NF-{kappa}B and inhibits its acetylation, thus blocking inflammatory gene expression in the setting of senescence, cancer, and pathogen infection. In addition, we show that loss of WSTF is required for the immuno-surveillance of oncogenic Ras in mouse liver; forced expression of WSTF inhibited tumor-suppressive inflammation and led to the development of liver tumors. Taken together, our study provides a global view of mammalian nuclear autophagy and reveals a novel nuclear inhibitor of inflammation implicated in diverse pathological contexts. Targeting WSTF may be broadly valuable as therapeutic intervention of inflammatory diseases.

cell biology↗

bioRxiv2019

Aneuploidy and deregulated DNA damage response define haploinsufficiency in breast tissues of BRCA2 mutation carriers

Women harboring heterozygous germline mutations of BRCA2 have a 50-80% risk of developing breast cancer, yet the early pathogenesis of these cancers is poorly understood. We sought to reveal early steps in BRCA2-associated carcinogenesis through analysis of sorted cell populations from freshly-isolated, non-cancerous breast tissues among a cohort of BRCA2 mutation carriers and matched controls. Single-cell whole-genome sequencing demonstrates that >25% of BRCA2 carrier (BRCA2mut/+) luminal progenitor (LP) cells exhibit sub-chromosomal copy number variations (CNVs), which are rarely observed in non-carriers. Correspondingly, primary BRCA2mut/+ breast epithelia exhibit spontaneous and replication stress-induced DNA damage together with attenuated replication checkpoint and apoptotic responses, associated with an age-associated expansion of the LP compartment in human carrier tissues. These phenotypes are not associated with loss of wild-type BRCA2. Collectively, these findings provide evidence for BRCA2 haploinsufficiency and associated DNA damage in vivo that precede histologic abnormalities. These results provide unanticipated opportunities for new cancer risk assessment and prevention strategies in high-risk patients.

cancer biology↗