R01CA304441

Investigating extrachromosomal DNA (ECDNA) segregation and repair in cancer - Project summary

Extrachromosomal DNA (ECDNA) plays a critical role in cancer biology, contributing to tumor progression and resistance to treatment by enabling rapid genetic adaptation through oncogene amplification.

Unlike chromosomal DNA, ECDNA exists as circular molecules that replicate independently and segregate randomly during cell division, leading to significant genetic diversity within tumors.

This unique non-Mendelian inheritance pattern allows cancer cells to quickly adapt to environmental pressures, including therapeutic interventions, by altering oncogene copy numbers.

Recent studies have identified ECDNA across various cancer types, where it is associated with aggressive tumor growth, increased genetic diversity, and shorter patient survival.

This collaborative project investigates the mechanisms underlying ECDNA segregation and repair, focusing on how their circular topology affects ECDNA function and maintenance.

We propose that proper ECDNA segregation is facilitated by RNA-dependent physical tethering to mitotic chromosomes, thus protecting against cytosolic mis-segregation and chromosomal integration (Aim 1).

Using innovative genetic tools and advanced imaging techniques, we will explore how ECDNA-encoded RNA contributes to its tethering and segregation during mitosis.

We will also explore the pathways that promote ECDNA re-integration into the chromosome following cytosolic mis-segregation.

In Aim 2, we uncover that ECDNA uniquely depends on the mutagenic pathway of microhomology-mediated end-joining (MMEJ) for its repair, distinguishing ECDNA from chromosomal DNA repair.

We hypothesize that rampant ECDNA transcription, which leads to transcription-replication conflicts, generates DNA lesions that create a dependency on MMEJ activity for ECDNA maintenance.

We will test the hypothesis that blocking MMEJ activity will prevent ECDNA accumulation and block drug resistance.

Last, we will design ECDNA to incorporate a palindromic sequence, facilitating its linearization while safeguarding it from degradation (Aim 3).

This will enable us to investigate the functional importance of ECDNA circular topology, which has been proposed to allow increased transcription of embedded oncogenes and test its impact on ECDNA segregation and repair processes.

By revealing the mechanisms behind ECDNA segregation, maintenance, and integration, we aim to discover novel therapeutic strategies to combat drug resistance resulting from ECDNA amplification.

Sloan-Kettering Institute For Cancer Research

TO IDENTIFY CANCER RISKS AND RISK REDUCTION STRATEGIES, TO IDENTIFY FACTORS THAT CAUSE CANCER IN HUMANS, AND TO DISCOVER AND DEVELOP MECHANISMS FOR CANCER PREVENTION AND PREVENTIVE INTERVENTIONS IN HUMANS. RESEARCH PROGRAMS INCLUDE: (1) CHEMICAL, PHYSICAL AND MOLECULAR CARCINOGENESIS, (2) SCREENING, EARLY DETECTION AND RISK ASSESSMENT, INCLUDING BIOMARKER DISCOVERY, DEVELOPMENT AND VALIDATION, (3) EPIDEMIOLOGY, (4) NUTRITION AND BIOACTIVE FOOD COMPONENTS, (5) IMMUNOLOGY AND VACCINES, (6) FIELD STUDIES AND STATISTICS, (7) CANCER CHEMOPREVENTION AND INTERCEPTION, (8) PRE-CLINICAL AND CLINICAL AGENT DEVELOPMENT, (9) ORGAN SITE STUDIES AND CLINICAL TRIALS, (10) HEALTH-RELATED QUALITY OF LIFE AND PATIENT-CENTERED OUTCOMES, AND (11) SUPPORTIVE CARE AND MANAGEMENT OF SYMPTOMS AND TOXICITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO STIMULATE TECHNICAL INNOVATION, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, AND FOSTER PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS.

93.393 - Cancer Cause and Prevention Research

National Cancer Institute (NCI) [HHS - NIH]

New York United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)