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While it has become apparent that active recruitment of nerve fibers into tumors plays an important role in cancer initiation, progression, recurrence, treatment-resistance, metastasis, and mortality for many malignancies, the diverse molecular mechanisms underlying tumor-nerve crosstalk remain largely unknown and hinders therapeutic targeting of this pervasive pro-tumorigenic process (Shi, Guo et al., Lancet Oncology 2022). One of the differentiating hallmarks of pancreatic ductal adenocarcinoma (PDAC) is an exceptionally high frequency of perineural invasion (PNI), a histopathologic manifestation of tumor-nerve crosstalk whereby cancer cells recruit, migrate towards and envelop or invade peripheral nerves, suggesting that pancreatic cancer is strongly influenced by its interaction with the nervous system. To date, evidence for a handful of neurochemicals/neurotrophins involved in PNI have been uncovered, primarily through ex vivo and animal models, but most of the underlying work was limited by a lack of cell-type information, spatial context, and/or a fragmented focus on one or a small number of candidates such that their potential interplay and relative pathophysiologic importance are unknown. Indeed, our preliminary work using bulk RNA-seq data identified numerous upregulated genes associated with PNI in human PDAC that have not been previously described in association with the tumor-nerve axis (Guo, Hoffman, Clin Canc Res 2021). Moreover, our snRNA-seq data described above uncovered a novel neural-like progenitor malignant gene expression program that is enriched for genes associated with PNI (Hwang, Jagadeesh, Guo, Hoffman, Nat Genetics 2022). We hypothesize that much of the tumor-nerve interactome in PDAC and other malignancies remains unknown and unexplored, some of which may be associated with the neural-like progenitor malignant program we discovered using snRNA-seq. This incomplete understanding of the genetic programs that drive tumor-nerve crosstalk and PNI has hindered the development of drugs targeting the tumor-nerve axis.

Identifying cell-type specific mediators of perineural invasion and nerve recruitment in pancreatic cancer using spatial transcriptomics

We are elucidating cell-type specific mechanisms of perineural invasion and nerve recruitment in pancreatic cancer by comprehensively identifying cell-type specific genes spatially linked to PNI in patient tumors using spatial proteotranscriptomics. To dissect the functional roles of these genes, we are modulating expression of these candidates in cancer cell organoids/fibroblasts through genetic engineering and investigating the effects of these perturbations on cultured neurons and in vivo tumor innervation through co-cultures and orthotopic transplantation.

Dissecting broad mechanisms of collaboration between tumor cells and the peripheral nervous system

We are interested in broadly studying the physical, biochemical and electrical interactions between the neuronal and non-neuronal components of tumors as well as the shared and distinct mechanisms of collaboration with regard to different malignancies and nerve subtypes through diverse co-culture approaches, calcium imaging, optogenetic methods, and advanced microscopy.

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