Biology subjects

Kundra, R.

Publications and source records attributed to Kundra, R..

7 recordsLinked to original sources

bioRxiv2024

Tumor break load quantitates structural variant-associated genomic instability with biological and clinical relevance across cancers

While structural variants (SVs) are a clear sign of genomic instability, they have not been systematically quantified per patient. Therefore, the biological and clinical impact of high numbers of SVs in patients is unknown. We introduce tumor break load (TBL), defined as the sum of unbalanced SVs, as a measure for SV-associated genomic instability. Using pan-cancer data from TCGA, PCAWG, and CCLE, we show that a high TBL is associated with significant changes in gene expression in 26/31 cancer types that consistently involve upregulation of DNA damage repair and downregulation of immune response pathways. Patients with a high TBL show a higher risk of recurrence and shorter median survival times for 5/15 cancer types. Our data demonstrate that TBL is a biologically and clinically relevant feature of genomic instability that may aid patient prognostication and treatment stratification. For the datasets analyzed in this study, TBL has been made available in cBioPortal.

cancer biology↗

bioRxiv2024

Multimodal Spatial Profiling Reveals Immune Suppression and Microenvironment Remodeling in Fallopian Tube Precursors to High-Grade Serous Ovarian Carcinoma

High-Grade Serous Ovarian Cancer (HGSOC) originates from fallopian tube (FT) precursors. However, the molecular changes that occur as precancerous lesions progress to HGSOC are not well understood. To address this, we integrated high-plex imaging and spatial transcriptomics to analyze human tissue samples at different stages of HGSOC development, including p53 signatures, serous tubal intraepithelial carcinomas (STIC), and invasive HGSOC. Our findings reveal immune modulating mechanisms within precursor epithelium, characterized by chromosomal instability, persistent interferon (IFN) signaling, and dysregulated innate and adaptive immunity. FT precursors display elevated expression of MHC-class I, including HLA-E, and IFN-stimulated genes, typically linked to later-stage tumorigenesis. These molecular alterations coincide with progressive shifts in the tumor microenvironment, transitioning from immune surveillance in early STICs to immune suppression in advanced STICs and cancer. These insights identify potential biomarkers and therapeutic targets for HGSOC interception and clarify the molecular transitions from precancer to cancer. STATEMENT OF SIGNIFICANCEThis study maps the immune response in fallopian tube precursors of high-grade serous ovarian cancer, highlighting localized interferon signaling, CIN, and competing immune surveillance and suppression along the progression axis. It provides an explorable public spatial profiling atlas for investigating precancer mechanisms, biomarkers, and early detection and interception strategies.

cancer biology↗

bioRxiv2024

Ongoing genome doubling promotes evolvability and immune dysregulation in ovarian cancer

Whole-genome doubling (WGD) is a critical driver of tumor development and is linked to drug resistance and metastasis in solid malignancies. Here, we demonstrate that WGD is an ongoing mutational process in tumor evolution. Using single-cell whole-genome sequencing, we measured and modeled how WGD events are distributed across cellular populations within tumors and associated WGD dynamics with properties of genome diversification and phenotypic consequences of innate immunity. We studied WGD evolution in 65 high-grade serous ovarian cancer (HGSOC) tissue samples from 40 patients, yielding 29,481 tumor cell genomes. We found near-ubiquitous evidence of WGD as an ongoing mutational process promoting cell-cell diversity, high rates of chromosomal missegregation, and consequent micronucleation. Using a novel mutation-based WGD timing method, doubleTime, we delineated specific modes by which WGD can drive tumor evolution: (i) unitary evolutionary origin followed by significant diversification, (ii) independent WGD events on a pre-existing background of copy number diversity, and (iii) evolutionarily late clonal expansions of WGD populations. Additionally, through integrated single-cell RNA sequencing and high-resolution immunofluorescence microscopy, we found that inflammatory signaling and cGAS-STING pathway activation result from ongoing chromosomal instability and are restricted to tumors that remain predominantly diploid. This contrasted with predominantly WGD tumors, which exhibited significant quiescent and immunosuppressive phenotypic states. Together, these findings establish WGD as an evolutionarily active mutational process that promotes evolvability and dysregulated immunity in late stage ovarian cancer.

cancer biology↗

bioRxiv2022

Integrative analysis of the MD Anderson Prostate Cancer Patient-Derived Xenograft Series (MDA PCa PDX)

Progress in understanding prostate cancer (PCa) metastasis and therapy resistance has been hampered by the lack of models, representative of the clinical spectrum and biologic complexity of the disease. Our laboratory is home to one of the largest worldwide repositories of PCa patient-derived xenografts (PDXs), the MDA PCa PDX series, a collection of clinically annotated PDXs reflecting the full spectrum of potentially lethal disease, that includes tumors that are not end stage and not castration-resistant PCa. We performed whole genome sequencing, targeted sequencing and RNA sequencing of 46 MDA PCa PDX models derived from biopsy and surgical specimens from 39 patients, selected in order to reflect the clinicopathological PCa subtypes (data available in cBioPortal). MDA PCa PDXs genomic characterization shows that the cohort recapitulates the mutational landscape found in PCa, highlighting the clinical relevance of these models. Interestingly and consistently with the clinic, certain models lack the typical PCa driver alterations, thus providing a suitable tool for discovery of novel drivers. Our cohort also includes PDXs derived from different areas of the same tumor and longitudinal samples, allowing to study disease heterogeneity and progression. Finally, we have developed a procedure to grow organoids from PDXs, thus providing a powerful in vitro platform that supports hypothesis generation, and testing of clinically relevant observations. Genomic and transcriptomic characterization of MDA PCa PDXs together with the ability to grow them as organoids for in vitro experimentation, provides a unique resource to address the existing clinical gap in PCa, helping to better understand mechanisms of response and resistance. One Sentence SummaryMDA PCa PDX series is a dynamic resource capturing the molecular landscape of prostate cancer; a platform for discovery and personalized medicine

cancer biology↗

bioRxiv2021

Immune and malignant cell phenotypes of ovarian cancer are determined by distinct mutational processes

High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability patterned by distinct mutational processes, intratumoral heterogeneity and intraperitoneal spread. We investigated determinants of immune recognition and evasion in HGSOC to elucidate co- evolutionary processes underlying malignant progression and tumor immunity. Mutational processes and anatomic sites of tumor foci were key determinants of tumor microenvironment cellular phenotypes, inferred from whole genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumor sites from 42 treatment-naive HGSOC patients. Homologous recombination-deficient (HRD)-Dup (BRCA1 mutant-like) and HRD- Del (BRCA2 mutant-like) tumors harbored increased neoantigen burden, inflammatory signaling and ongoing immunoediting, reflected in loss of HLA diversity and tumor infiltration with highly- differentiated dysfunctional CD8+ T cells. Foldback inversion (FBI, non-HRD) tumors exhibited elevated TGF{beta} signaling and immune exclusion, with predominantly naive/stem-like and memory T cells. Our findings implicate distinct immune resistance mechanisms across HGSOC subtypes which can inform future immunotherapeutic strategies. HIGHLIGHTSO_LIMulti-region, multi-modal profiling of malignant and immune cell phenotypes in ovarian cancer C_LIO_LIAnatomic site specificity is a determinant of cancer cell and intratumoral immune phenotypes C_LIO_LITumor mutational processes impact mechanisms of immune control and immune evasion C_LIO_LISpatial topology of HR-deficient tumors is defined by immune interactions absent from immune inert HR-proficient subtypes C_LI

cancer biology↗

bioRxiv2021

Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients

Progression to metastatic disease remains the main cause of cancer death. Yet, the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we present MSK-MET, an integrated pan-cancer cohort of tumor genomic and clinical outcome data from more than 25,000 patients. We analyzed this dataset to identify associations between tumor genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma and HR-positive breast ductal carcinoma, but not in others, such as colorectal adenocarcinoma, pancreatic adenocarcinoma and high-grade serous ovarian cancer. We also identified specific somatic alterations associated with increased metastatic burden and specific routes of metastatic spread. Our data offer a unique resource for the investigation of the biological basis for metastatic spread and highlight the crucial role of chromosomal instability in cancer progression.

cancer biology↗

bioRxiv2021

Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating other proteins aggregation

Mitochondria are organelles with their own genomes, but they rely on the import of nuclear-encoded proteins that are translated by cytosolic ribosomes. Therefore, it is important to understand whether failures in the mitochondrial uptake of these nuclear-encoded proteins can cause proteotoxic stress and identify response mechanisms that may counteract it. Here, we report that upon impairments in mitochondrial protein import, high-risk precursor and immature forms of mitochondrial proteins form aberrant deposits in the cytosol. These deposits then cause further cytosolic accumulation and consequently aggregation of other mitochondrial proteins and disease-related proteins, including -synuclein and amyloid {beta}. This aggregation triggers a cytosolic protein homeostasis imbalance that is accompanied by specific molecular chaperone responses at both the transcriptomic and protein levels. Altogether, our results provide evidence that mitochondrial dysfunction, specifically protein import defects, contributes to impairments in protein homeostasis, thus revealing a possible molecular mechanism by which mitochondria are involved in neurodegenerative diseases.

molecular biology↗