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SUMMARY:Mechanisms and consequences of pancreatic cancer stromal evolution
  - Mara Sherman\, Oregon Health &amp\; Science University
DTSTART:20210225T130000Z
DTEND:20210225T140000Z
UID:TALK151576@talks.cam.ac.uk
CONTACT:Kate Davenport
DESCRIPTION:The mechanisms underlying evolution of tumor-associated stroma
  remain poorly understood.  In solid tumors featuring a prominent stromal 
 reaction\, an improved understanding of the functions and origins of abund
 ant stromal cell types may facilitate the development of new and effective
  therapies.  Pancreatic ductal adenocarcinoma (PDAC) is the quintessence o
 f a fibro-inflammatory malignancy\, with 50-90% of tumor volume occupied b
 y a dense\, desmoplastic stroma. Cancer-associated fibroblasts (CAFs) are 
 the key cell type which drives the stromal reaction in PDAC\, and recent r
 eports suggest that stromal CAFs represent a heterogeneous population of c
 ells from diverse origins\, potentially including cell types which support
  and others which suppress tumor growth. Pancreatic stellate cells (PSCs) 
 are lipid-storing cells in healthy pancreas which can transdifferentiate t
 o an activated CAF phenotype. PSCs have been suggested as the predominant 
 source of fibroblasts in the PDAC tumor microenvironment. However\, proper
  lineage tracing studies have never been performed\, such that the relativ
 e contribution and specific functions of PSCs in the tumor microenvironmen
 t are unknown. We have developed a novel mouse model to track PSC differen
 tiation and function during pancreatic tumor progression in vivo. This mod
 el revealed that PSC-derived CAFs in fact give rise to a numerically minor
  but functionally significant subset of PDAC CAFs\, and may represent a vi
 able therapeutic target. We adapted our mouse model to enable targeted abl
 ation of PSCs and derivative CAFs within their host tissue for the first t
 ime. Functional studies in this model reveal non-redundant functions for P
 SC-derived CAFs in shaping the PDAC microenvironment\, and highlight the s
 ignificance of mesenchymal lineage heterogeneity for pancreatic tumorigene
 sis. Further\, we find that tumor genotype with respect to p53 status dict
 ates stromal evolutionary routes with respect to cell of origin\, a findin
 g that may extend to additional cancer cell-intrinsic genomic alterations.
  Together\, these findings shed light on mechanisms that shape the tumor m
 icroenvironment during pancreatic cancer progression\, and may hold releva
 nce in additional solid tumor types.
LOCATION:On Zoom please join at https://zoom.us/j/94247154940?pwd=dk1SNmVT
 SnlGZlJCbVNFSUNGMm0wdz09  Meeting ID: 942 4715 4940 Passcode: 143320
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