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Differential activation of the triacylglycerol pathway in lipofibroblasts induces neurogenesis associated with prostate cancer progression

Award Number: R01CA303124
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/12/2025
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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Differential activation of the triacylglycerol pathway in lipofibroblasts induces neurogenesis associated with prostate cancer progression - Excessive neutral lipid or fatty acid levels in the tumor microenvironment (TME) are important mechanisms for carcinoma-associated fibroblast (CAF) activation. We showed that lipid reprogramming in CAFs is sustained by increasing lipogenesis mediator, DGAT1, and identified a CAF subtype that appears to have a key specific role in regulating tumor-neural crosstalk and possibly increased innervation and perineural invasion (PNI). We discovered that neural fibroblasts (NF) derived from peripheral nerves become part of the CAF population, can reprogram lipid storage while promoting neuritic-like processes formation, and stimulate tumor progression. To our knowledge, this newly recognized CAF cell type has not been previously reported and their function studied. African Americans (AA) are at a higher risk of developing and dying from PCa compared to Caucasians (Cau), but the underlying mechanisms are poorly understood. PNI is seen at a higher frequency in AA with solid tumors. We observed higher nerve density in AA patients with PCa. We also found that CAF derived from AA patients had higher levels of brain-derived neurotrophic factor (BDNF), an important regulator of nerve regeneration. Moreover, a possible link between lipids and neural mediators emerged when our preliminary results revealed a positive regulatory loop between BDNF and DGAT1. Therefore, we hypothesize that aggressive PCa in AA is due, in part, to nerve injury-induced activation of CAF through the DGAT1-BDNF axis, promoting a nerve and lipid-rich TME. Furthermore, blockade of the DGAT1-BDNF axis with available inhibitors could provide a new therapeutic tool to suppress lipid reprogramming, block excess neural density, and prevent PNI related to tumor progression. The following specific aims are proposed. The first aim will investigate the mechanisms inducing NF activation and lipid reprogramming in the human prostate TME with high nerve density and/or PNI by identifying factors in NFs harvested from human tumors associated with PNI and increased nerve density in aggressive tumors. The transcriptome landscapes of NFs from PNI+ AA will be evaluated. The second aim will determine whether DGAT1 regulation of BDNF signaling axis is required to promote neurogenesis and the neurogenic switch in the prostate TME. Using knockdown strategies for DGAT1 and/or BDNF in selective stromal cell types (NFs, CAFs from AA and Cau with/without PNI) evaluate in vitro morphology of neuritic processes, ion concentration, and intracellular lipid trafficking and analyze in vivo expression of neural and adrenergic mediators, NF morphometrics and interaction with tumor cells. The third aim will assess the benefits of blocking the DGAT1-BDNF axis effects on PNI in vivo by testing the anti-tumor activity of a BDNF antagonists, DGAT1 inhibitors or both in vivo animal models to assess the ability of inhibitor therapies to block neurogenesis, NF or Schwann cell proliferation, or tumor growth. This study was designed to decipher the origins of higher nerve density and/or PNI and has the potential to identify a new therapeutic strategies to suppress lipid reprogramming and neural-tumor crosstalk associated with PCa progression.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $1,575,170 )
2025	2025	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cancer Biology Research	000	1	9/12/2025	NEW	$1,575,170
														Subtotal = $1,575,170

Grand Total All Awards = $1,575,170

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Differential activation of the triacylglycerol pathway in lipofibroblasts induces neurogenesis associated with prostate cancer progression

Award Number: R01CA303124

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/12/2025

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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