Biology subjects

Subhash, S.

Publications and source records attributed to Subhash, S..

4 recordsLinked to original sources

bioRxiv2026

Microbial induction of MHC-II expression in colon cancer cells overcomes immunotherapy resistance and limits metastasis

Colorectal cancer remains a major cause of cancer mortality, and most microsatellite stable tumors derive little benefit from immune checkpoint blockade. Here, we identify a microbiome-dependent mechanism that converts immune-refractory colorectal cancer into a more immunologically responsive state. Using orthotopic mouse models spanning distinct genetic and immunologic contexts, we show that a Helicobacter-containing microbiome suppresses primary tumor growth and limits metastasis. This protective state is associated with increased intratumoral lymphocyte infiltration and stronger effector programs. Mechanistically, microbial exposure induces MHC class II expression in colon cancer cells to promote anti-tumor immunity. Tumor-intrinsic loss of CIITA abrogates microbial protection, whereas enforced CIITA expression is sufficient to increase intratumoral T cell accumulation, restrict progression and metastasis, and sensitize microsatellite-stable tumors to PD-1 and CTLA-4 blockade. In human microsatellite-stable patient-derived organoids, increased cancer-cell MHC-II enhanced interactions with autologous immune cells and increased tumor cell apoptosis. Together, these findings define a microbiome-cancer cell antigen presentation axis that restrains metastasis and overcomes immunotherapy resistance in colorectal cancer.

immunology↗

bioRxiv2026

A Single-Cell Atlas of Uterine Carcinosarcoma from Diverse Ancestries

Uterine carcinosarcoma (UCS) is an aggressive endometrial cancer defined by coexisting malignant epithelial and mesenchymal components, rapid metastatic dissemination, and poor therapeutic response. However, its cellular ecosystem remains poorly resolved, particularly in patients of African ancestry who are underrepresented in genomic datasets despite a disproportionate disease burden. Here, we generated a single-cell atlas of 15 primary and metastatic UCS specimens from a diverse cohort of 13 patients enriched for African ancestry, integrated with whole-genome sequencing. Malignant cells exhibited epithelial-like, mesenchymal-like, transitional, and stem/progenitor-like states within individual tumors that mapped to patient-specific copy number-defined subclones and RNA-velocity trajectories, supporting metaplastic state transitions. Compared to normal endometrium, primary tumors were enriched for epithelial-mesenchymal-transition (EMT), mTORC1, and glycolytic programs, whereas matched metastases show enhanced TNF-NF{kappa}B-associated invasive programs. The tumor microenvironment contained immunosuppressive myeloid states and diverse cancer-associated fibroblast (CAF) subsets, including pericyte-like and matrix-remodeling subsets that act as predicted communication hubs through chemokine and immune-checkpoint circuits. We found a CAF-centered CCL2-CXCL1/2-IL10 module linked to CD8 T-cell dysfunction and a TIGIT-CD96-PVR checkpoint module. These data define the UCS cellular ecosystem in which malignant plasticity is coupled to stromal-immune cell remodeling in a patient cohort of enriched ancestries and nominate stromal-immune axes for further therapeutic investigation.

cancer biology↗

bioRxiv2026

A Patient-derived Organoid Platform for Uterine Carcinosarcoma that Emulates Disease Characteristics

Uterine carcinosarcoma (UCS) is a rare but extremely lethal endometrial cancer that metastasizes early and resists current treatment modalities. It is biphasic, built from malignant epithelial and mesenchymal cells. Genomic studies indicate that these tumors are clonal, and that the mesenchymal cells arise from the epithelial cells through cancer cell plasticity. This biology has been hard to study, because faithful patient-derived models are scarce. The gap is widened by inequity. Women of African ancestry carry the greatest burden of UCS, yet are underrepresented in existing models. To address this, we established patient-derived organoids (PDOs) from an ancestrally inclusive UCS cohort, alongside matched normal endometrial PDOs. The organoids reproduced the biphasic histology of the original tumors. Across four sequencing platforms, they retained the tumor mutation and copy-number landscape, remained stable across passages, and expanded for up to 28 months. At single-cell resolution, UCS PDOs captured both malignant compartments and traced continuous transcriptional trajectories along the epithelial-to-mesenchymal axis, capturing patient-specific cancer cell plasticity. The models also nominated candidate vulnerabilities in proof-of-concept therapeutic testing. UCS PDOs were enriched for CREB-family transcriptional programs, and CREB inhibition reduced their viability. Combined FGFR and YAP inhibition outperformed either agent alone. Together, this work delivers a histologically, genomically, and transcriptionally faithful, ancestrally inclusive, and lineage-resolved UCS organoid platform for studying cancer cell plasticity and its vulnerabilities in an aggressive and inequitably burdened cancer.

cancer biology↗

bioRxiv2026

Diverse high-fat diets drive multi-omic reprogramming that persists after dietary reversal

Dietary fat composition modulates host physiology and the gut microbiome, but the long-term effects of specific fat sources and the extent to which these changes resolve after dietary reversal remain incompletely defined. Here, we present a longitudinal multi-omic resource of mice maintained for one year on a purified control diet, seven high-fat diets differing in predominant fat source, or reversal regimens in which animals were switched from high-fat to control diet after 4 or 9 months. We further incorporated two cohorts with distinct pre-existing microbiome configurations to determine how baseline community structure shapes diet-induced remodeling of the gut microbiome ecosystem. By integrating longitudinal phenotyping, fecal metagenomics, fecal metabolomics, plasma metabolomics and lipidomics, and intestinal single-cell RNA sequencing, we defined the shared and dietary fat-specific responses across host and microbiome compartments. Baseline microbiome composition strongly influenced microbial responses to diet, indicating that pre-existing community structure is a major determinant of dietary ecosystem remodeling. Although many altered features shifted toward baseline after dietary reversal, only approximately half of diet-associated microbial changes recovered within the study window. A subset of taxa exhibited persistent alterations, including sustained depletion of Lactobacillus johnsonii and Bifidobacterium pseudolongum and sustained enrichment of Alistipes finegoldii, consistent with a "microbiome memory" of prior high-fat diet exposure. This memory effect is mirrored in the host, by sustained suppression of major histocompatibility complex class II (MHC-II) gene expression in intestinal epithelial cells after dietary reversal. These findings indicate that dietary fats leave a lasting imprint on the host-microbiome interactome that survives dietary intervention. Together, these data establish a resource for defining how dietary fat source, baseline microbiome composition, and dietary history shape host-microbiome states. The entire resource is available online as an RShiny app.

systems biology↗