eprintid: 22322
rev_number: 17
eprint_status: archive
userid: 2881
dir: disk0/00/02/23/22
datestamp: 2018-01-22 08:20:09
lastmod: 2018-02-15 11:53:45
status_changed: 2018-01-22 08:20:09
type: doctoralThesis
metadata_visibility: show
creators_name: Sundaram, Aishwarya
title: Linking metabolic syndrome and pancreatic cancer through transcriptional regulation and secreted factors from white adipocytes
subjects: ddc-500
divisions: i-140001
adv_faculty: af-14
abstract: Obesity has reached pandemic proportions, and is associated with several co-morbidities like cardiovascular disorders, hypertension, dyslipidemia, and Type 2 diabetes mellitus. The dysregulated adipose tissue metabolism in obesity leads to an altered adipokine secretion, which can influence energy homeostasis, promote insulin resistance, as well as provide pro-tumorigenic signals to tumor cells. We investigated the link between obesity, and the progression of pancreatic ductal adenocarcinoma (PDAC). Although, obesity has been associated with a poor prognosis in PDAC, the underlying mechanisms are unclear. 

At first, we used adipose tissue specific knockout of TBLR1 (ATKO) mice as a model of obesity, to investigate if the transcriptional inactivation of the transcriptional co-factor Transducin beta like related 1 (TBLR1) promoted PDAC progression. Although, subcutaneous (SC) Panc02 tumors grew significantly larger in the ATKO mice, compared to wt littermates, histological examination of the tumors did not reveal increased proliferation, or adipocyte infiltration in the tumors from ATKO mice. Also, gene expression analysis in tumors from wt and ATKO mice did not reveal any significantly differentially regulated genes. Finally, in vivo effects could not be validated by treating PDAC cells with conditioned media (CM) generated from primary adipocytes of ATKO mice, or from Tblr1 knockdown 3T3-L1 adipocytes.  Therefore, we could not establish a robust link between the absence of Tblr1 in the adipose tissue, to PDAC progression.

Using in vitro assays, we demonstrated that adipocyte-conditioned media (ACM) from differentiated 3T3-L1 adipocytes, but not fibroblasts, promoted PDAC cell viability, proliferation, migration, and invasion in vitro. Therefore, we hypothesized that secreted factors from adipocytes mediate pro-tumorigenic effects on PDAC. Previously it was shown by our group that SC Panc02 tumors grew significantly larger in db/db mice, compared to wt mice. Microarray analysis of the SC inguinal white adipose tissue (iWAT) of db/db, and wt mice identified ob gene encoding leptin as one of the most significantly differentially regulated genes. Although, recombinant leptin did not affect proliferation, or migration of PDAC cell monolayer cultures, it increased the invasion of BxPC3 spheroids through collagen matrix. Most importantly, leptin increased the viability of PDAC cells upon treatment with gemcitabine. Thus, we hypothesized that leptin improves the chemo-resistance of PDAC cells to gemcitabine. However, knockdown of Lepr in PDAC cells did not affect proliferation, and viability upon gemcitabine treatment. Also, Lepr kd Panc02 tumors implanted subcutaneously into wt mice, displayed similar chemo-sensitivity to gemcitabine treatment in vivo, as compared to wt Panc02 tumors. Finally, pharmacological inhibition of human LEPR with anti-LEPR antibody did not affect the chemo-resistance of PDAC cells to gemcitabine. 

In conclusion, although there was a strong effect of ACM from 3T3-L1 cells on PDAC growth in vitro, the effects could not be attributed entirely to leptin. Further investigation is required to identify the secreted factors from dysregulated adipocytes which could play a potential pro-tumorigenic role on PDAC progression, thus providing a link between obesity and PDAC development.
date: 2018
id_scheme: DOI
id_number: 10.11588/heidok.00022322
ppn_swb: 1659219086
own_urn: urn:nbn:de:bsz:16-heidok-223221
date_accepted: 2016-12-09
advisor: HASH(0x55fc30c42288)
language: eng
bibsort: SUNDARAMAILINKINGMET2018
full_text_status: public
place_of_pub: Heidelberg, Germany
citation:   Sundaram, Aishwarya  (2018) Linking metabolic syndrome and pancreatic cancer through transcriptional regulation and secreted factors from white adipocytes.  [Dissertation]     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/22322/1/Final%20PhD%20Thesis-%20Aishwarya%20Sundaram.pdf