CDI Explores Vast Implications of the Gastrointestinal Tract, from Cancer to Autoimmune Disorders to Infectious Disease

The gastrointestinal (GI) tract, spanning from the mouth through the stomach and intestines, and including partner organs such as the liver and pancreas, is absolutely foundational to biology. But GI dynamics in a wide array of diseases have often been overlooked, because the system is so complex in its countless processes of ingestion and digestion of food, nutrient absorption, secretion of water and enzymes, and ultimate excretion of waste products.

Science in the 21st century is increasingly looking into the role the GI tract plays in the genesis and progression of disease, its function in preventing afflictions, and also consequently how science might modulate its workings to better treat cancer, certain infections, and a host of other conditions.

Laboratories at the Hackensack Meridian Center for Discovery and Innovation (CDI) have brought together a series of projects which explore the fundamental effects and factors of the GI tract - with the promise to discover new molecular tactics to use against cancers of the liver and colon and pancreas, autoimmune disorders, and opportunistic infections.

“This is a fundamental building block to better understand cancer and infectious diseases,” said David Perlin, Ph.D., chief scientific officer and executive vice president of the CDI. “These research projects at the CDI are at the vanguard of our understanding of these complex systems, and many of them are truly collaborative. It’s a testament to the value of the CDI in pushing the envelope forward into the future.”

Tycko Lab: A new NIH grant to tackle Celiac, Crohn’s diseases

The laboratory of Benjamin Tycko, M.D., Ph.D., member of the CDI, has received a new 5-year, $4.4 million grant from the National Institutes of Health focused on celiac disease and Crohn’s disease, two important autoimmune/inflammatory disorders that affect the GI tract. Tycko and colleagues are taking a combined genomic and epigenomic approach to pinpoint and understand the mechanisms of action of common genetic variants that regulate critical genes in intestinal epithelial cells and in cells of the immune system, and which thereby confer increased risk of these difficult-to-treat GI conditions. The research team for this project is co-led by Dr. Tycko at the CDI and Kathryn E. Hamilton, Ph.D., at the Children's Hospital of Philadelphia, and includes investigators with expertise in molecular genetics, intestinal epithelial cell biology, bioinformatics and statistical genetics, and clinical care for these diseases. Using intestinal organoid cultures from biopsies, with and without exposure to disease relevant external stimuli, whole-genome and targeted DNA-methylation sequencing, and CRISPR-Cas9 manipulations in tissue culture, the team is elucidating cell type-specific biological pathways and gene-environment interactions that drive the onset and progression of these diseases, with implications for improved prevention and treatment. This work - and parallel studies by the Tycko lab on human cancers - is being accelerated by a recent grant to the CDI from the National Institute for Standards and Technology (NIST) for state-of-the-art "3rd generation" Nanopore sequencing, which simultaneously reveals both the DNA sequence and the patterns of DNA methylation over long contiguous stretches of human chromosomes.

Shin Lab: Aiming at Liver Diseases

The laboratory of Ji-Yeon Shin, Ph.D., assistant member of the CDI, is establishing a research program in liver disease, specifically focusing on liver lipid metabolism, steatohepatitis and hepatocellular carcinoma.

Abnormalities in hepatic lipid metabolism cause steatotic liver disease (SLD), a growing public health issue in the United States. SLD encompasses a spectrum of liver pathologies, from simple steatosis to steatohepatitis and can progress to hepatocellular carcinoma (HCC). The lab’s previous research has discovered a protein complex localized in the nuclear envelope is a novel regulator of hepatic lipid metabolism, and, when disrupted, a potent driver of steatosis and steatohepatitis. In Shin’s more recent study, the scientists found that the disruption of a nuclear envelope protein from hepatocytes leads to steatohepatitis and liver tumor development. Using unique preclinical models and advanced techniques, the research aims to uncover novel molecular mechanisms underlying the progression from hepatic steatosis to steatohepatitis and ultimately HCC. The ultimate goal is to use this knowledge to develop potential therapies for the disease.

Dalerba Lab: Identifying a potentially-overlooked drug for colon cancer

A major focus of Dalerba Lab’s science is in the discovery of biomarkers that can aid in guiding treatment decisions for cancer patients, by enabling physicians to predict which anti-tumor drugs have the highest probability to associate with clinical responses. In previous studies, Piero Dalerba, M.D., associate member of the CDI, and colleagues identified the transcription factor CDX2 as an important predictive biomarker in colon cancer patients. The data showed that in early-stage (Stage 2, Stage 3) colon cancer, lack of CDX2 expression associates with preferential benefit from adjuvant chemotherapy, as per a New England Journal of Medicine paper published in 2016. More recently, the Dalerba Lab has discovered that, in human colon cancer, lack of CDX2 expression is associated with increased sensitivity to paclitaxel, an anti-tumor drug commonly used against many forms of cancer, such as breast and lung cancer, but which is generally considered ineffective against colon cancer. The laboratory is currently working towards the repositioning of paclitaxel as a viable therapeutic option against a minority subset of colon cancers that lack CDX2 expression.

Tong Lab: Picking apart what makes colon cancer ‘tick’

The Tong Lab has an especial focus on colorectal cancer. Kevin Tong, Ph.D., assistant member of the CDI, and colleagues use mouse models and patient-derived organoid systems to understand the molecular mechanisms of colon cancer invasion and metastasis.

The lab has also established a collaborative effort with the John Theurer Cancer Center and the Hackensack Meridian Health Biorepository to assess drug resistances in colon cancer patients to potentially introduce targeted therapy and precision medicine with real-time assessment using organoids. Tong and colleagues recently submitted a manuscript detailing the use of organoid models to address patient-specific resistances, which was just accepted at the Journal of Clinical Oncology.

Lu lab: Development of Immunotherapy for Colorectal Cancer

The laboratory of Binfeng Lu, Ph.D., employs multiple approaches to understand the molecular mechanisms behind cancer resistance to immunotherapy, and uses this knowledge to develop future cancer immunotherapies.

One primary focus of the lab is based on their discovery that epithelial alarmin cytokines are downregulated in advanced cancers, including colorectal cancer. The key principle for creating successful immunotherapies is to restore the immunogenicity of tumor tissues by reintroducing these cytokines into the tumor environment. To achieve this, the lab uses oncolytic viruses, nanoparticles, and protein engineering to specifically target alarmin cytokines to tumor tissues. The differential mechanisms of action of cytokines and cytokine-vehicle combinations are studied not only to gain novel insights into cancer immunobiology, but also to develop differentiated drugs that can help advance the current therapeutic landscape. A second, complementary line of research in the lab focuses on studying the cancer genomics contributing to immune therapy resistance. Several genetic pathways are being intensively investigated to understand how mutations in cancer cells drive resistance, particularly in colorectal cancer. This genomic information will be leveraged as biomarkers to help select patients most likely to benefit from immunotherapy. These biomarkers are critical for providing patients with the best chance of survival by delivering the most effective therapy at the earliest possible stage. These projects are currently funded by NIH R01 grants, the New Jersey Commission on Cancer Research, and the Ruesch Foundation.

Desai Lab: Understanding the proteins of the complement system in colorectal cancer

The laboratory of Jigar Desai, Ph.D., assistant member of the CDI, focuses on the mucosal complement system, involving initial immune responses, and examining how it is regulated by both sterile and non-sterile stimuli, and its critical roles in mucosal and systemic immunity. Specific to the GI system, Desai and colleagues are investigating the novel role of the mucosal complement system in colorectal cancer progression, particularly its microbiota-driven responses and cell-type-specific regulation. Additionally, they are studying how complement-microbiota interactions are modulated in the healthy GI mucosa and how these interactions impact local and systemic immunity.

To address these questions, the laboratory leverages a combination of clinically-relevant preclinical models and cutting-edge techniques, including novel cell-type-specific complement knockout models, 20-parameter multiplexed immunofluorescence, spatial transcriptomics, and ex-vivo modeling with organoids and primary cells. Supported by an exceptional institutional environment, the goal is to uncover new complement-driven mechanisms that play a role in the cancer progression and the maintenance of homeostatic microbiota.

Makohon-Moore Lab: Exploring the evolution of pancreatic and colorectal cancers

Alvin Makohon-Moore, Ph.D., and his colleagues home in on the evolution of cancer, with the goal of understanding how it develops - and how it can be eradicated at all stages. For pancreatic cancer, the lab focuses on understanding why this disease evolves so aggressively, and which mechanisms allow tumor cells to increase fitness. Of particular interest is understanding how these processes occur in harsh microenvironments, such as nutrient or oxygen deprivation, as these are prevalent in pancreatic tumors. Makohon-Moore and his team are also investigating treatments because there are few therapies in pancreatic cancer, and it's unclear how tumor cells evolve resistance. But it’s not just pancreatic cancer; the Makohon-Moore Lab is also doing similar research in colorectal cancer, in concert with CDI partners.

Feinman Lab: The gut microbiome and anti-cancer therapies

The laboratory of Rena Feinman, Ph.D., CDI associate member, focuses on the microbiome of the gut - the ecosystem of microbes that live in the intestines. The understanding of the role of the gut microbiome in cancer - as predictor and modulator of tumorigenesis, immunosurveillance, and treatment response - has revolutionized the field of immuno-oncology. The Feinman Lab seeks innovative and novel strategies to improve outcomes in patients to anticancer therapies. The discovery that compositional differences of the gut microbiome contribute to the heterogeneity of therapeutic responses has prompted the scientists to identify microbiome communities that predict outcomes and immune-related adverse events in patients with multiple myeloma undergoing autologous stem-cell transplantation and immunotherapy. Feinman and colleagues also study the influence of gut and tumor microbiota in immunosurveillance and outcomes in newly diagnosed triple-negative breast cancer patients treated with standard of care neoadjuvant chemotherapy. To complement the prospective observational studies, the laboratory investigates the mechanisms by which gut microbiota modulate immune-mediated control of MM and TNBC in preclinical mouse models. These studies are aimed at identifying unique gut microbiota signatures that are prognostic, and which may lead to the development of microbiota-centered interventions to harness immunotherapeutic responses in treatment-refractory multiple myeloma and triple-negative breast cancer.

Perlin and Shor Labs: Investigating the emergence of antifungal drug resistance in a gut commensal opportunistic fungal pathogen

The research from the laboratories of Dr. Perlin, and colleague Erika Shor, Ph.D., CDI assistant member, focuses on invasive fungal infections. The latest pertaining specifically to the GI system is joint research focused on the evolution and mechanisms of resistance to echinocandins, a frontline antifungal drug class, in a prominent fungal pathogen, Candida glabrata.  The most recent paper on the topic was the most viewed among those published by PLoS Pathogens in the first two weeks of September 2024. The work is supported by an R01 grant from the National Institutes on Allergy and Infectious Diseases to both the Perlin Lab and the Shor Lab. C. glabrata is an opportunistic pathogen of humans that is a harmless resident of the GI tract in many individuals - but which can cause deadly bloodstream or organ infections in those with immune dysfunction. C. glabrata is also notable for rapid acquisition of genetic mutations conferring echinocandin resistance, producing strains refractory to echinocandin therapy. Using preclinical models of the C. glabrata colonization of the GI system, the scientists have identified the tract as an important host niche where echinocandin-resistant mutants emerge in echinocandin-sensitive colonizing fungal populations during drug therapy. The teams have also shown that echinocandin treatment induces a rapid genetic diversification of the gut-colonizing fungal niche and are using advanced genetic and genomic techniques, such as transposon sequencing (in collaboration with the laboratory of Kyle Cunningham, Ph.D., at Johns Hopkins University), to probe the genetic determinants of the acquisition of echinocandin resistance in gut-colonizing C. glabrata. By identifying and validating such determinants, it may become possible to devise intervention strategies that prevent the emergence of echinocandin resistance in C. glabrata.