Biology subjects

Chan, S. M.

Publications and source records attributed to Chan, S. M..

3 recordsLinked to original sources

bioRxiv2025

Blood-based Epigenetic Instability Linked to Human Aging and Disease

The abundance, dynamics, and context-dependent heterogeneity of DNA methylation--where a pattern considered abnormal in one cell type may be normal in another--poses challenges in identifying methylation abnormalities linked to disease risk. Through genome-wide analyses, we identified CpG sites with remarkably consistent methylation profiles in healthy whole blood, predominantly existing in an unmethylated state. We examined alterations at these epigenetically stable loci in diverse cohorts, including those with cardiovascular disease and hematological cancers. Our findings reveal methylation pattern disruption in myeloid and lymphoid malignancies, correlating with clonal burden fluctuations during leukemia treatment. In non-cancer cohorts, we observed that normally stable CpG sites exhibited progressive instability with advancing age, which was also associated with the onset of cardiovascular disease and decreased survival rates. This study links DNA methylation instability with the expansion of risk-prone blood cells and highlights its role as a biomarker for both cancer and cardiovascular disease.

genetics↗

bioRxiv2024

Hematopoietic Tet2 inactivation enhances the response to checkpoint blockade immunotherapy

Somatic mutations inactivating TET2 are among the most common drivers of clonal hematopoiesis (CH). While TET2 inactivation is associated with monocyte-derived inflammation and improved chimeric antigen-receptor-T cell function, its impact on immunotherapy response is unknown. In our mouse model, hematopoietic Tet2 mutation enhanced immune checkpoint blockade (ICB) response. Enhanced ICB response with Tet2 mutation required phagocytes, CD4 and CD8 T cells. Mechanistically, in Tet2-mutant tumor-infiltrating leukocytes (TILs), ICB preferentially induced anti-tumor states and restricted cell states linked to tumor progression. Tet2-mutant monocytes activated costimulatory programs, while Tet2-mutant T cells showed enhanced T cell memory signatures, lesser exhaustion and decreased regulatory phenotype. Our murine data was clinically relevant, since we found that melanomas from patients with TET2 driver mutation-CH (TET2-CH) showed enhanced immune infiltration, T cell activation, and T cell memory programs. In melanoma patients treated with ICB, TET2-CH was associated with 6-fold greater odds of clinical benefit. Collectively, our data establishes that hematopoietic Tet2 inactivation primes leukocytes for anti-tumor states associated with immunotherapy response and provides a potential biomarker for personalized therapy.

cancer biology↗

bioRxiv2024

A molecularly engineered lectin destroys EGFR and inhibits the growth of non-small cell lung cancer

Survival rates for non-small cell lung cancer (NSCLC) remain low despite the advent of novel therapeutics. Tyrosine kinase inhibitors (TKIs) targeting mutant epidermal growth factor receptor (EGFR) in NSCLC have significantly improved mortality but are plagued with challenges--they can only be used in the small fraction of patients who have susceptible driver mutations, and resistance inevitably develops. Aberrant glycosylation on the surface of cancer cells is an attractive therapeutic target as these abnormal glycosylation patterns are typically specific to cancer cells and are not present on healthy cells. H84T BanLec (H84T), a lectin previously engineered by our group to separate its antiviral activity from its mitogenicity, exhibits precision binding of high mannose, an abnormal glycan present on the surface of many cancer cells, including NSCLC. Here, we show that H84T binds to and inhibits the growth of diverse NSCLC cell lines by inducing lysosomal degradation of EGFR and leading to cancer cell death through autophagy. This is a mechanism distinct from EGFR TKIs and is independent of EGFR mutation status; H84T inhibited proliferation of both cell lines expressing wild type EGFR and those expressing mutant EGFR that is resistant to all TKIs. Further, H84T binds strongly to multiple and diverse clinical samples of both pulmonary adenocarcinoma and squamous cell carcinoma. H84T is thus a promising potential therapeutic in NSCLC, with the ability to circumvent the challenges currently faced by EGFR TKIs.

cancer biology↗