This National Cancer Institute (CFDA 93.396 Cancer Biology Research) Project Grant award of $560,297 to the Icahn School of Medicine at Mount Sinai supports research to functionally characterize oncofetal stem cells (ONFSCs) in colorectal cancer (CRC). The key objectives are to: Generate phenotypic transcriptional reporters to track the dynamics of LGR5+ cancer stem cells (CSCs) and ONFSCs, and use these to dissect the functional interplay between these stem cell populations. Employ a multi-omic...
This federal Project Grant award from the National Cancer Institute (NCI), under the Cancer Cause and Prevention Research program (CFDA 93.393), provides $551,848 to the Dana-Farber Cancer Institute, Inc. (DFCI) in Boston, MA to investigate the molecular mechanisms by which the transcription factor SOX9 impairs cell differentiation and drives developmental reprogramming in colorectal cancer (CRC). The research aims to: 1) Use single-cell sequencing analyses to identify regulators of fetal gene...
This $460,985 Project Grant award was provided by the National Cancer Institute (NCI) under the Cancer Treatment Research program (CFDA 93.395) to The Ohio State University. The grant funds a 5-year research project to develop a novel therapeutic approach targeting liver metastasis in colon cancer patients. The key objectives are to: 1) Determine the therapeutic efficacy of selective dopamine D4 receptor (DRD4) agonists, alone or in combination with anti-cancer drugs, to prevent or reduce...
This $230,010 project grant awarded by the National Cancer Institute (NCI) under the Cancer Detection and Diagnosis Research program (CFDA 93.394) aims to unravel the drivers of metastasis in small cell lung cancer (SCLC) using human pluripotent stem cell-based models. The research strategy integrates stem cell-derived SCLC models, clinical samples, patient-derived xenografts, and advanced technologies like single-cell sequencing to examine cell behavior in primary tumors and metastatic sites....
This Project Grant award from the National Cancer Institute (CFDA 93.396 - Cancer Biology Research) to Cedars-Sinai Medical Center will investigate the molecular mechanisms by which metabolic dysfunction-associated steatotic liver disease (MASLD) promotes liver metastasis in gastrointestinal cancers. The $646,739 award, effective from April 1, 2025 to March 31, 2030, will focus on the roles of hepatic stellate cells (HSCs) - both intra-tumoral and extra-tumoral - and the effect of...
The National Cancer Institute (NCI) awarded a $151,000 Project Grant under the Cancer Cause and Prevention Research (CFDA 93.393) program to The Medical University of South Carolina (MUSC) to investigate the role of polyploid cancer cells in high-grade serous ovarian carcinoma (HGSOC). The project aims to: 1) Define essential genes for the polyploid cancer cell lifecycle and its critical transition stages using CRISPR-Cas9 screening, and 2) Determine the expression of putative polyploid cancer...
This federal Project Grant award from the National Cancer Institute (CFDA 93.395 Cancer Treatment Research) provides $205,700.00 to the Sloan-Kettering Institute for Cancer Research in New York to support research aimed at addressing the problem of rapid resistance to targeted therapies in colorectal cancer. The key objectives are to: 1) evaluate how intrinsic tumor features modulate the development of targeted therapy resistance, and 2) test a novel combination approach of DNA repair inhibition...
This Project Grant award from the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) provides $406,611 to the University of Texas Health Science Center at Houston (UTHealth) to investigate the role and therapeutic targeting of the GPR56 receptor in colorectal cancer. The key objectives are to: 1) characterize how GPR56 signaling impacts colorectal cancer stem cell plasticity and metastasis using patient-derived organoid models; 2) develop and evaluate highly potent...
This $181,640 federal Project Grant award from the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) supports research led by a clinical scientist at The University of Texas MD Anderson Cancer Center. The primary objectives are to: Expand on the role of liquid biopsy biomarkers, specifically circulating tumor DNA (ctDNA) and extravesicle RNA (evRNA), to generate novel combination immunotherapy trials for colorectal and anal cancers. This includes analyzing samples from...
This Project Grant award from the National Cancer Institute (CFDA 93.396 - Cancer Biology Research) provides $164,500 to The Trustees of Columbia University in the City of New York to investigate the mechanisms by which the protein S100A9 mediates brain metastasis in epidermal growth factor receptor (EGFR)-mutant lung cancer. The key goals are to: Examine how S100A9 expression is epigenetically regulated by histone methylation and the MEIS1 transcription factor in brain metastasis-prone cells....
DEFINING THE ROLE OF SEED AND SOIL IN PERITONEAL METASTASIS EVOLUTION - THE PERITONEUM IS THE THIRD MOST COMMON SITE OF METASTASIS IN COLON CANCER. DESPITE THE COMMON OCCURRENCE OF PERITONEAL METASTASIS AND ITS DIRE PROGNOSIS, VERY LITTLE IS KNOWN ABOUT ITS ORIGINS AND CHARACTERISTICS. THE LACK OF BASIC RESEARCH INTO PERITONEAL METASTASIS HAS STYMIED TREATMENT ADVANCES. WE HAVE SPENT THE LAST 4 YEARS STUDYING THE GENETICS OF COLORECTAL CANCER PERITONEAL METASTASIS IN A LARGE INTERNATIONAL COLLABORATION. BUILDING ON THE FINDINGS FROM THIS EFFORT, WE HERE PROPOSE THREE AIMS TO ADVANCE BASIC SCIENCE AND CLINICAL CARE IN THIS CRUCIAL AREA. ALL AIMS WILL TAKE ADVANTAGE OF A LARGE, RETROSPECTIVE COHORT OF PERITONEAL METASTASIS PATIENTS (N=103) THAT WILL UNDERGO MULTI-REGION GENOMIC ANALYSIS. THE GOAL OF THE PROJECT IS TO RIGOROUSLY DEFINE THE EVOLUTIONARY HISTORY AND GENETIC CHARACTERISTICS OF PERITONEAL METASTASES AND TO TIE THESE FEATURES TO CLINICAL OUTCOMES. IN SPECIFIC AIM 1, WE WILL DETERMINE HOW CANCER CELLS REACH THE PERITONEAL CAVITY AND HOW THEIR SEEDING ROUTES IMPACT THE GENETIC DIVERSITY OF PERITONEAL METASTASES. OUR PRELIMINARY DATA SHOW PROFOUND DIFFERENCES IN GENETIC DIVERSITY BETWEEN SYNCHRONOUS AND METACHRONOUS PERITONEAL METASTASES. THE FORMER ARE GENETICALLY HOMOGENEOUS AND CLOSELY RELATED TO THE DEEP INVADING EDGE OF THE PRIMARY TUMOR, WHILE THE LATTER ARE HETEROGENEOUS AND DO NOT APPEAR TO ORIGINATE AT THE INVASIVE FRONT, INDICATING THAT THEIR SEEDING ROUTES MAY BE DISTINCT (DIRECT GROWTH THROUGH THE SEROSA VS. CANCER CELL RELEASE DURING PRIMARY TUMOR SURGERY). IN THIS AIM, WE WILL MAP THE ROUTES BY WHICH PERITONEAL METASTASES ARE SEEDED AND STUDY HOW THEIR ORIGINS SHAPE GENETIC DIVERSITY, USING A COMBINATION OF HIGH-EFFICIENCY PHYLOGENETIC RECONSTRUCTION AND DEEP EXOME SEQUENCING. IN SPECIFIC AIM 2, WE WILL DETERMINE THE GENETIC CHARACTERISTICS OF CANCER CELLS THAT SUCCEED IN COLONIZING THE PERITONEUM. WE HAVE PREVIOUSLY FOUND THAT CANCER CELLS DISSEMINATING TO DIFFERENT HOST ORGANS ARE EXPOSED TO ENVIRONMENT-SPECIFIC SELECTIVE PRESSURES. OUR PRELIMINARY DATA INDICATE THAT GENOMICALLY RELATIVELY INTACT CANCER CELLS MAY BE AT AN ADVANTAGE OVER HIGHLY MUTATED OR ANEUPLOID CELLS DURING PERITONEAL COLONIZATION. WE WILL USE OUR EXTENSIVELY SAMPLED COHORT OF PERITONEAL METASTASIS CASES TO COMPARE DRIVER MUTATIONS, SOMATIC COPY NUMBER ALTERATIONS (SCNAS), AS WELL AS GLOBAL MEASURES OF GENETIC STABILITY (TUMOR MUTATION BURDEN, SCNA BURDEN) BETWEEN PRIMARY TUMORS, LOCOREGIONAL, DISTANT AND PERITONEAL METASTASES. IN SPECIFIC AIM 3, WE WILL STUDY HOW THE CHARACTERISTICS OF PERITONEAL METASTASES RELATE TO SURVIVAL OUTCOMES. PROGNOSTIC FACTORS TO HELP CLINICIANS ESTIMATE THE LIKELIHOOD OF DIFFERENT SURVIVAL OUTCOMES ARE URGENTLY NEEDED. WE WILL COLLECT DETAILED FOLLOW-UP DATA ON OUR PERITONEAL METASTASIS PATIENT COHORT. IN AIM 3A, WE WILL STUDY THE ASSOCIATION BETWEEN SURVIVAL AND THE GENETIC CHARACTERISTICS INVESTIGATED IN AIMS 1 AND 2. IN AIM 3B, WE WILL BROADEN OUR INQUIRY TO THE MICROENVIRONMENT AND EXAMINE VIA SINGLE-NUCLEUS RNA SEQUENCING (SNRNASEQ) AND MULTI-COLOR IMMUNOFLUORESCENCE WHETHER THE COMPOSITION AND TRANSCRIPTOME OF STROMAL AND IMMUNE CELLS PRESENT IN PERITONEAL METASTASES CORRELATE WITH SURVIVAL.