Project 3-Cancer cell interaction with oncogenic type 1 collagen in PDAC

$546,750P01FY2021CANIH

University Of Tx Md Anderson Can Ctr, Houston TX

Investigators

Linked publications & trials

Paper 39536083 Paper 39468013 Paper 39232498 Paper 39211217 Paper 38991060 Paper 38985503 Paper 38843329 Paper 38816352 Paper 38802576 Paper 38798370 Paper 38720073 Paper 38714664 Paper 38467382 Paper 38280869 Paper 37942963 Paper 37814010 Paper 37775182 Paper 37696660 Paper 37676964 Paper 37625403 Paper 37625401 Paper 37312426 Paper 37190324 Paper 37174073 Paper 37140994 Paper 37075122 Paper 37069394 Paper 37069167 Paper 37026453 Paper 36935322 Paper 36746143 Paper 36631611 Paper 36585453 Paper 36282600 Paper 36231030 Paper 35868307 Paper 35726190 Paper 35412885 Paper 35348629 Paper 35022962 Paper 34893625 Paper 34889852 Paper 34819622 Paper 34531315 Paper 34529467 Paper 34489603 Paper 34471290 Paper 34429247 Paper 34385458 Paper 34142094 Paper 34117030 Paper 34040169 Paper 33930309 Paper 33905375 Paper 33852841 Paper 33839689 Paper 33742165 Paper 33667385 Paper 33531365 Paper 33504580 Paper 33406434 Paper 33158812 Paper 33152323 Paper 33142117 Paper 33027658 Paper 32967217 Paper 32376951 Paper 32341021 Paper 32341020 Paper 32046984 Paper 31980749 Paper 31942075 Paper 31919052 Paper 31827279 Paper 31663852 Paper 31557131 Paper 31488580 Paper 31406347 Paper 31316073 Paper 31185211 Paper 31134896 Paper 30925917 Paper 30918400 Paper 30905761 Paper 30833752 Paper 30642914 Paper 30635425 Paper 30614183 Paper 30609754 Paper 30470748 Paper 30120146 Paper 30051890 Paper 29941929 Paper 29925948 Paper 29871934 Paper 29769196 Paper 29731362 Paper 29727621 Paper 29702208 Paper 29669940

Abstract

Project 3 - Abstract/Summary The desmoplastic stroma, consisting of fibroblasts, extracellular matrix (ECM) and immune cells, is a defining feature of human pancreatic ductal adenocarcinoma (PDAC), however its precise contribution to cancer progression is still evolving. Type I collagen (Col1), a dominant component of PDAC desmoplasia, is uniquely regulated in PDAC. Our preliminary studies uncovered that cancer cells produce a novel Col1 variant consisting of alpha 1 chain (Col1a1) homotrimers. Genetic deletion of the oncogenic Col1 in cancer cells extends the overall lifespan of PDAC genetically engineered mice (GEMs). Oncogenic Kras (Kras*), a central driver for PDAC, plays a key role in determining the host response, including tumor immunity and metabolic adaptation. We discovered that Kras* drives cancer cells? production of oncogenic Col1 via epigenetic silencing of Col1a2. In contrast with the classical Col1 heterotrimer produced by fibroblasts, oncogenic Col1 uniquely promotes PDAC initiation and progression by influencing tumor metabolism and immunity. Col1 homotrimers bind to a?3b?1 integrin on PDAC cancer cells, a collagen receptor distinctly upregulated in mouse and human PDAC. This induces a sustained activation of FAK, Akt and Erk1/2 when compared with Col1 heterotrimers, promoting cancer cells growth and survival. Oncogenic Col1 also suppresses intratumoral T cells, and oncogenic Col1 deletion synergizes with anti- PD-1 immune checkpoint blockade to suppress tumor growth and increase overall survival of PDAC GEMs. Cancer cell-directed oncogenic Col1 homotrimer signaling also enhances glycolysis and mTOR signaling, supporting the metabolic reprogramming driven by Kras*. In Project 3, in close collaboration with Projects 1 and 2, we will define the role and regulation of Kras*-induced oncogenic Col1 signaling in impacting tumor immunity and metabolism. The proposed aims investigate Col1 homotrimers- a?3b?1 integrin targeting, immunotherapy, and anti-metabolism strategies, as an informed combination treatment modality. Our preliminary data support the feasibility and significance of this novel approach, and exploit a new vulnerability in PDAC signaling, with a translational potential to inform new therapies for PDAC.

View original record on NIH RePORTER →