Document text
Principal Investigator: JOHN BLENIS
Organization: WEILL MEDICAL COLL OF CORNELL UNIV
Fiscal Year: 2024
Award: $681,905
Funding agency: National Cancer Institute
PROJECT SUMMARY
The goal of this proposal is to discover how ongoing chromosome missegregation events in cancer cells (a
process called chromosomal instability, or CIN) alters the tumor ecosystem to promote cancer progression.
Chromosome copy number alterations (also referred to as aneuploidy) have long been associated with immune
suppressive phenotypes, drug resistance, and metastasis. Beyond aneuploidy, however, it remains unknown
whether the ongoing process of chromosome missegregation gives rise to tumor progression. Harnessing ex-
perimental tools that enable us to dial-up or dial-down chromosome missegregation rates in otherwise isogenic
backgrounds, we have previously found that ongoing chromosome missegregation generates rupture-prone mi-
cronuclei, which expose genomic double-stranded DNA (dsDNA) to the cytosol, leading to persistent activation
of the cGAS-STING innate immune pathway (1). Yet, instead of promoting a robust type I interferon (IFN) re-
sponse, STING activation in cancer cells with CIN promotes noncanonical NF-kB (nc-NF-kB) signaling – through
an unknown mechanism – to drive metastasis. The extent to which CIN-driven metastasis is dependent on the
immune system remains unknown. We made the surprising observation that CIN drives tumor progression in a
cancer cell non-autonomous manner by shaping the interaction between cancer cells and the tumor microenvi-
ronment (TME). This finding motivated the development of a fundamentally new, systems-level approach to
evaluate the nature and conditional-dependence of cell-cell interactions in the TME called ContactTracing. This
method exploits intrinsic biological variance captured by single cell RNA sequencing technologies, to infer cellu-
lar responses to ligand-receptor mediated interactions without prior knowledge of downstream target genes.
Combining this innovative computational tool with genetic perturbation of CIN and STING we found that CIN
engenders a pro-metastatic TME by inducing a cancer cell-intrinsic ER-stress response. In Aim 1, we propose
to mechanistically dissect the epistatic relationship between CIN, STING, and ER-stress in the progression of
triple negative breast cancer (TNBC) to determine whether ER-stress can represent a therapeutic target in chro-
mosomally unstable tumors. We will also test whether an ER-stress response underlies nc-NF-kB activation.
Under Aim 2, we will improve causal inference of tumor-derived ligand effects and explore their molecular basis
using gene regulatory networks to ask whether CIN-dependent cell-cell interaction networks are conserved
across cancer types using both human data and mouse models of breast, pancreatic, and lung cancers. The
amalgamation of these approaches, combined with our deep understanding of CIN in cancer, is poised to eluci-
date the complex roles of CIN-induced STING signaling on tumor-immune crosstalk during disease progression.
Importantly, this work is poised to reveal novel strategies aimed at targeting chromosomally unstable tumors,
which are otherwise difficult to treat.
Terms: <ATF6><ATF6 gene><Aberrant Chromosome><Activating Transcription Factor 6><Aneuploid><Aneuploidy><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Apo-E><ApoE><ApoE protein><Apolipoprotein E><Benchmarking><Best Practice Analysis><Biological><Biological Response Modifiers><Biomodulators><Blood granulocytic cell><Breast Cancer><Breast Cancer Model><Breast tumor model><Bypass><Cancers><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Signaling><Cell-to-Cell Interaction><Cells><Chromosomal Aberrations><Chromosomal Abnormalities><Chromosomal Alterations><Chromosomal Instability><Chromosomal Loss><Chromosome Aberrations><Chromosome Alterations><Chromosome Anomalies><Chromosome Instability><Chromosome Segregation><Chromosome abnormality><Chromosomes><Chronic><Colorectal Cancer><Complex><Computational toolkit><Computing Methodologies><Coupling><Cytogenetic Aberrations><Cytogenetic Abnormalities><Cytosol><Data><Data Set><Dependence><Development><Disease Progression><Double-Stranded DNA><Drug resistance><ER stress><Ecologic Systems><Ecological Systems><Ecosystem><Epistasis><Epistatic Deviation><Equilibrium><Event><Exhibits><Experimental Models><Gene Transcription><Genes><Genetic><Genetic Epistasis><Genetic Transcription><Genomics><Goals><Granular Leukocytes><Granulocytic cell><Heterogeneity><Human><IFN><Immune><Immune Evasion><Immune Mediators><Immune Mediators/Modulators><Immune Regulators><Immune system><Immunes><Immunocompetent><Immunoglobulin Enhancer-Binding Protein><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Infiltration><Interaction Deviation><Interferon Type I><Interferons><Intracellular Communication and Signaling><KRAS(G12D)><KRASG12D><Knowledge><Ligands><LoxP-flanked allele><Lung><Lung Respiratory System><Macrophage><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Malignant neoplasm of pancreas><Mediating><Mediator><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methods><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Mφ><NF-kB><NF-kappa B><NF-kappaB><NFKB><Nature><Neoplasm Metastasis><Nuclear Envelope><Nuclear Factor kappa B><Nuclear Membrane><Nuclear Transcription Factor NF-kB><Pancreas><Pancreas Cancer><Pancreatic><Pancreatic Cancer><Peptide Domain><Phenotype><Physiologic><Physiological><Process><Protein Domains><Pulmonary Cancer><Pulmonary malignant Neoplasm><RNA Expression><Receptor Protein><Recurrence><Recurrent><Role><Rupture><Sampling><Secondary Neoplasm><Secondary Tumor><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Source><Stimulator of Interferon Genes><Stress Tests><System><T-Cells><T-Lymphocyte><TNBC><Tachyphylaxis><Technology><Tertiary Protein Structure><Testing><Therapeutic><Transcription><Transcription Factor NF-kB><Tumor Cell><Tumor Immunity><Tumor-Derived><Work><anti-tumor immunity><antitumor immunity><balance><balance function><benchmark><biologic><biological adaptation to stress><biological signal transduction><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><cancer cell><cancer immunity><cancer metastasis><cancer microenvironment><cancer progression><cancer type><case control><case-controlled><cell type><chromosomal defect><chromosomal missegregation><chromosome defect><chromosome division><chromosome missegregation><computational methodology><computational methods><computational toolbox><computational tools><computational toolset><computer based method><computer methods><computerized tools><computing method><cyclic GMP-AMP synthase/STING><cytokine><data modeling><desensitization><detection method><detection procedure><detection technique><developmental><drug resistant><ds-DNA><dsDNA><endoplasmic reticulum stress><epistatic relationship><floxed><floxed allele><gene manipulation><gene regulatory network><gene x gene interaction><genetic epistases><genetic manipulation><genetically manipulate><genetically perturb><granulocyte><human data><immune competent><immune evasive><immune suppression><immune suppressive activity><immune suppressive function><immunomodulatory biologics><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><in silico><innate immune pathways><innovate><innovation><innovative><kappa B Enhancer Binding Protein><lung cancer><malignancy><malignant breast tumor><mammary cancer model><mammary tumor model><micronucleus><model of data><model the data><modeling of the data><mouse model><murine model><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><new approaches><novel approaches><novel strategies><novel strategy><nuclear factor kappa beta><pancreatic malignancy><paracrine><programs><pulmonary><reaction; crisis><receptor><resistance to Drug><resistance to therapy><resistant to Drug><resistant to therapy><response><scRNA-seq><sensor><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stress response><stress; reaction><therapeutic resistance><therapeutic target><therapy resistant><thymus derived lymphocyte><tool><treatment resistance><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor cell metastasis><tumor microenvironment><tumor progression>