Defining the Role of Tumor-Neutral Crosstalk in head and Neck Cancer Progression and Treatment Resistance

PROJECT SUMMARY
Solid tumors can shape their microenvironments to maximize their growth and metastatic potential. The formation of new
nerve fibers within and around tumors can alter tumor behavior, and higher densities of nerve fibers in the tumor
microenvironment are associated with poor clinical outcomes in patients with oral, prostate, breast, gastric, pancreatic and
other types of cancer
. Preclinical and pathological studies have described neoneurogenesis, the process by which cancer
cells induce the growth of nerves into tumors, as analogous to neoangiogenesis, in which cancer cells release factors that
elicit the growth of blood vessels into the tumor. However, the exact mechanisms that drive nerves to infiltrate tumors and
support their growth and progression is unknown. Preliminary research shows that cancer cells `communicate' with neurons
The hypothesis of this study is that
axonal sprouting and autonomic reprogramming of existing nerves occur as a result of orchestrated miRNA shuttling from
cancer cells to neurons and via activation of the transcriptional programs that establish neuronal identity and that infiltration
of tumors by autonomic neonerves enables tumor progression. The neonerve's phenotype includes
through shuttling of p53-dependent RNA species that further induce tumor innervation.
transformation into a
sprouting cell able to infiltrate and interact with other cell types, the release of adrenergic neuroactive molecules, and the
development of neurogenic inflammation. Each of these acquired capabilities may promote tumor progression and resistance
to therapy.
The proposed research is innovative because it will capitalize on new concepts in cancer biology and advanced
model systems to yield insights into the mechanisms of tumor progression and identify new targets for cancer therapy.
This
cross-disciplinary proposal will combine expertise from oncology, neurodevelopment, cell biology, neurobiology, cancer
genetics, pathology, and biostatistics to pursue three specific aims: (1) Delineate the signaling events that occur between
cancer cells and neurons during tumorigenesis, using pharmacologic and genetic approaches to understand how cancer cells
cause normally quiescent neurons to reprogram and continually sprout to sustain neoplastic growth. (2) Elucidate the drivers
of tumor-associated neuronal reprogramming. By using human-derived sensory neurons, we will determine how the normal
nerve response to signals from cancer cells supports cancer progression. (3) Characterize sensory nerve reprogramming and its
role in oral cancer progression. Using a genetically engineered syngeneic mouse model, we will elucidate the neural-tumor
interactions that lead to neurogenic inflammation and promote oral cancer progression. Our long-term goal is to elucidate
the reciprocal nerve-cancer signals that drive cancer progression to identify novel targets for therapy. Once the signals that
induce tumor innervation are known, therapeutic approaches to target this critical component of tumor biology can be
developed to improve survival, treatment responses, and patients' quality of life.

Grant Number: 4R37CA242006-06
NIH Institute/Center: NIH
Principal Investigator: Moran Amit