The Gulhati lab is focused on basic and translational research in gastrointestinal cancers. Ongoing projects in the lab are focused on:
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy that will soon be the second leading cause of cancer death and remains remarkably resistant to all forms of therapy. There is a pressing need to gain a deeper understanding of the fundamental biology underlying this recalcitrant disease and uncover novel treatment strategies with sustained therapeutic efficacy.
Novel bedside remedies are invariably built upon a comprehensive understanding of cellular and molecular mechanisms underlying disease pathogenesis. Our lab is dissecting the fundamental principles governing pancreatic cancer initiation, metastasis and therapeutic resistance with an emphasis on the functional contribution of the tumor microenvironment. We take an integrated genomics and biological systems-based approach employing a diverse array of experimental models and cutting-edge techniques to conduct mechanistic and translational studies. Our overarching goal is to identify new vulnerabilities and novel treatments that can be translated to the clinic.
Pancreatic tumors demonstrate a marked desmoplastic response as well as an influx of immune cells. Recent work from our lab has focused on understanding the recalcitrance to currently available immunotherapies in pancreatic cancer, using genetically engineered mouse models and human biospecimens. To this end, we have identified a novel combinatorial immunotherapy regimen with remarkable efficacy in shrinking PDAC tumors and curing mice of their disease. Current projects in the lab are exploring: i) signaling pathways downstream of KRAS that mediate cross-talk between pancreatic cancer cells and the stromal microenvironment including immune cells and fibroblasts; ii) the immunosuppressive microenvironment in pancreatic tumors and identification of novel therapeutic targets to increase efficacy of immune checkpoint therapy and chemotherapy; iii) identification and functional validation of novel genes and pathways driving pancreatic cancer initiation, metastasis and therapeutic resistance.
There are trillions of microbes that reside in our gastrointestinal tract. Microbiota composition varies considerably between individuals, and factors including host genotype and diet can impact the gut microbiome. Dysbiosis of the microbiota residing in the human digestive tract has been associated with various gastrointestinal diseases, including colorectal cancer (CRC), the third leading cause of cancer deaths in the US. Characterization of gut microbiomes from humans has revealed a complex, symbiotic relationship between bacteria and host cells, whereby bacteria can modulate the host’s immune response and metabolism. Using gut and oral microbiome samples from CRC patients as well as pre-clinical models, we are delineating the mechanisms underlying the contribution of the gut microbiome towards CRC tumorigenesis, metastasis and therapeutic resistance. Ongoing projects in the lab are exploring the interactions between diet, gut microbes and their metabolites with colorectal cancer cells and immune cells in the tumor microenvironment.