8 research outputs found
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Abstract 827: A journey to deconvolute the multifaceted functions and context-dependency of cancer driver genes
Abstract
Lung cancer is a lethal and genomically-complex disease. Structural genomics has largely advanced our knowledge of genomic alterations, yet the function of a majority of altered genes remains less clear. Previous in silico and in vitro functional genomics data often lead to contradictory conclusions on gene functions. Genetically-engineered mouse models are reliable approaches for in vivo functional analyses, but development of these models are lagging behind due to the throughput limit. To overcome this throughput limit, we developed tumor barcoding and ultradeep barcode sequencing (Tuba-seq) that precisely quantifies the growth metrics of hundreds of tumor genotypes, which is a huge leap forward. Through this approach, we have begun a journey to create a quantitative functional taxonomy of tumor suppression in oncogenic KRAS-driven lung cancer. For example, STAG2 and CDKN2C emerged as novel functional tumor suppressor genes in the lung, when they were often overlooked by computational analyses due to relatively low mutation prevalence. Interestingly, STK11 and PTEN, both playing an important role in tumor growth, exhibit distinct roles in tumor initiation. These findings suggest that structural genomics is not sufficient to predict cancer driver genes, and calls for closer investigation of tumor suppressor functions in specific tumorigenesis stages. Furthermore, the quantitative nature of our data has enabled systematic characterization of interactions between tumor suppressor genes. For instance, RNF43 exhibits different tumor suppression modes in the presence or absence of STK11 or TRP53, while TRP53 can play opposite roles in PTEN- and RB1-deficient tumors. In addition, Foggetti et al. (2021) reported that tumor suppressors can play opposite roles in the contexts of different oncogenes. Collectively, these findings suggest that cooccurring mutations shift the functional landscape of tumor suppressors even in the same pathological subtype of cancer. Given the genomic diversity of lung cancer patients, driver genes may change case by case. We are now investigating the molecular mechanisms underlying these tumor suppressors and their genetic interactions. Our findings underscore the necessity of determining the consequences of enormous combinations of genomic alterations in their natural environment, which is challenging but critical for understanding cancer evolution, interpreting clinical cancer genome sequencing data, and directing approaches to limit tumor initiation and progression.
Citation Format: Hongchen Cai, Su Kit Chew, Chuan Li, Christopher W. Murray, Laura Andrejka, Jess D. Hebert, Min K. Tsai, Rui Tang, Nicholas W. Hughes, Emily G. Shuldiner, Emily L. Ashkin, Shi Ya C. Lee, Maryam Yousefi, Dmitri A. Petrov, Charles Swanton, Monte W. Winslow. A journey to deconvolute the multifaceted functions and context-dependency of cancer driver genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 827
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A Functional Taxonomy of Tumor Suppression in Oncogenic KRAS-Driven Lung Cancer.
Cancer genotyping has identified a large number of putative tumor suppressor genes. Carcinogenesis is a multistep process, but the importance and specific roles of many of these genes during tumor initiation, growth, and progression remain unknown. Here we use a multiplexed mouse model of oncogenic KRAS-driven lung cancer to quantify the impact of 48 known and putative tumor suppressor genes on diverse aspects of carcinogenesis at an unprecedented scale and resolution. We uncover many previously understudied functional tumor suppressors that constrain cancer in vivo. Inactivation of some genes substantially increased growth, whereas the inactivation of others increases tumor initiation and/or the emergence of exceptionally large tumors. These functional in vivo analyses revealed an unexpectedly complex landscape of tumor suppression that has implications for understanding cancer evolution, interpreting clinical cancer genome sequencing data, and directing approaches to limit tumor initiation and progression. SIGNIFICANCE: Our high-throughput and high-resolution analysis of tumor suppression uncovered novel genetic determinants of oncogenic KRAS-driven lung cancer initiation, overall growth, and exceptional growth. This taxonomy is consistent with changing constraints during the life history of cancer and highlights the value of quantitative in vivo genetic analyses in autochthonous cancer models.This article is highlighted in the In This Issue feature, p. 1601
The Transitions Clinic Network: Post Incarceration Addiction Treatment, Healthcare, and Social Support (TCN-PATHS): A hybrid type-1 effectiveness trial of enhanced primary care to improve opioid use disorder treatment outcomes following release from jail
In 2016, at least 20% of people with opioid use disorder (OUD) were involved in the criminal justice system, with the majority of individuals cycling through jails. Opioid overdose is the leading cause of death and a common cause of morbidity after release from incarceration. Medications for OUD (MOUD) are effective at reducing overdoses, but few interventions have successfully engaged and retained individuals after release from incarceration in treatment.
To assess whether follow-up care in the Transitions Clinic Network (TCN), which provides OUD treatment and enhanced primary care for people released from incarceration, improves key measures in the opioid treatment cascade after release from jail. In TCN programs, primary care teams include a community health worker with a history of incarceration, and they attend to social needs, such as housing, food insecurity, and criminal legal system contact, along with patients' medical needs.
We will bring together six correctional systems and community health centers with TCN programs to conduct a hybrid type-1 effectiveness/implementation study among individuals who were released from jail on MOUD. We will randomize 800 individuals on MOUD released from seven local jails (Bridgeport, CT; Niantic, CT; Bronx, NY; Caguas, PR; Durham, NC; Minneapolis, MN; Ontario County, NY) to compare the effectiveness of a TCN intervention versus referral to standard primary care to improve measures within the opioid treatment cascade. We will also determine what social determinants of health are mediating any observed associations between assignment to the TCN program and opioid treatment cascade measures. Last, we will study the cost effectiveness of the approach, as well as individual, organizational, and policy-level barriers and facilitators to successfully transitioning individuals on MOUD from jail to the TCN.
Investigation Review Board the University of North Carolina (IRB Study # 19-1713), the Office of Human Research Protections, and the NIDA JCOIN Data Safety Monitoring Board approved the study. We will disseminate study findings through peer-reviewed publications and academic and community presentations. We will disseminate study data through a web-based platform designed to share data with TCN PATHS participants and other TCN stakeholders. Clinical trials.gov registration: NCT04309565.
•Few interventions have engaged and retained people with OUD in evidence-based addiction treatment after release from jail.•This will be the first multi-site study to evaluate enhanced primary care program for individuals released from jail on MOUD.•No trial has tested enhanced primary care as an effective model of longitudinal care for this high-risk population with OUD.•This trial will test whether addressing social determinants of health after release from jail impacts the OUD treatment
Combinatorial Inactivation of Tumor Suppressors Efficiently Initiates Lung Adenocarcinoma with Therapeutic Vulnerabilities
Lung cancer is the leading cause of cancer death worldwide, with lung adenocarcinoma being the most common subtype. Many oncogenes and tumor suppressor genes are altered in this cancer type, and the discovery of oncogene mutations has led to the development of targeted therapies that have improved clinical outcomes. However, a large fraction of lung adenocarcinomas lacks mutations in known oncogenes, and the genesis and treatment of these oncogene-negative tumors remain enigmatic. Here, we perform iterative in vivo functional screens using quantitative autochthonous mouse model systems to uncover the genetic and biochemical changes that enable efficient lung tumor initiation in the absence of oncogene alterations. Generation of hundreds of diverse combinations of tumor suppressor alterations demonstrates that inactivation of suppressors of the RAS and PI3K pathways drives the development of oncogene-negative lung adenocarcinoma. Human genomic data and histology identified RAS/MAPK and PI3K pathway activation as a common feature of an event in oncogene-negative human lung adenocarcinomas. These Onc-negativeRAS/PI3K tumors and related cell lines are vulnerable to pharmacologic inhibition of these signaling axes. These results transform our understanding of this prevalent yet understudied subtype of lung adenocarcinoma. SIGNIFICANCE: To address the large fraction of lung adenocarcinomas lacking mutations in proto-oncogenes for which targeted therapies are unavailable, this work uncovers driver pathways of oncogene-negative lung adenocarcinomas and demonstrates their therapeutic vulnerabilities